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Pirnie R, P Gillespie K, Mesaros C, Blair IA. Reappraisal of oxidized HMGB1 as a mediator and biomarker. Future Sci OA 2022; 8:FSO828. [PMID: 36874369 PMCID: PMC9979160 DOI: 10.2144/fsoa-2022-0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 01/12/2023] [Indexed: 02/12/2023] Open
Abstract
HMGB1 is a dual-function protein that acts as a chromatin-binding protein and as a danger-associated molecular pattern (DAMP) when released from activated immune cells or injured tissue. In much of the HMGB1 literature, immunomodulatory effects of extracellular HMGB1 are proposed to depend on its oxidation state. However, many of the foundational studies for this model have been retracted or flagged with expressions of concern. The literature on HMGB1 oxidation reveals a diversity of redox proteoforms of HMGB1 that are inconsistent with current models of redox modulation regulating HMGB1 secretion. A recent study of acetaminophen toxicity has identified previously unrecognized HMGB1 oxidized proteoforms. HMGB1 undergoes oxidative modifications that could serve as pathology-specific biomarkers and drug targets.
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Affiliation(s)
- Ross Pirnie
- Center of Excellence in Environmental Toxicology & Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kevin P Gillespie
- Center of Excellence in Environmental Toxicology & Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Clementina Mesaros
- Center of Excellence in Environmental Toxicology & Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ian A Blair
- Center of Excellence in Environmental Toxicology & Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
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2
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Yang L, Li Y, Feng X, Zhang S, Xie Y. WITHDRAWN: HMGB1 and COX2 are regulated during organ damage following obesity-induced hypertension in a metabolic syndrome mouse model. Mol Cell Probes 2020:101592. [PMID: 32389788 DOI: 10.1016/j.mcp.2020.101592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/20/2020] [Accepted: 04/29/2020] [Indexed: 10/24/2022]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- Lingchao Yang
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yigang Li
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China
| | - Xiangfei Feng
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China
| | - Song Zhang
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yuquan Xie
- Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China
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Scovell WM. High mobility group protein 1: A collaborator in nucleosome dynamics and estrogen-responsive gene expression. World J Biol Chem 2016; 7:206-222. [PMID: 27247709 PMCID: PMC4877529 DOI: 10.4331/wjbc.v7.i2.206] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 02/19/2016] [Accepted: 03/14/2016] [Indexed: 02/05/2023] Open
Abstract
High mobility group protein 1 (HMGB1) is a multifunctional protein that interacts with DNA and chromatin to influence the regulation of transcription, DNA replication and repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, adenosine triphosphate-independent manner. As a result, the canonical nucleosome is converted to two stable, physically distinct nucleosome conformers. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes (N’ and N’’) remain stable and exhibit a number of characteristics that are distinctly different from the canonical nucleosome. These findings complement previous studies that showed (1) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (2) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that a major facet of the mechanism of HMGB1 action involves a restructuring of aspects of the nucleosome that appear to relax structural constraints within the nucleosome. The findings are extended to reveal the differences between ER and the other steroid hormone receptors. A working proposal outlines mechanisms that highlight the multiple facets that HMGB1 may utilize in restructuring the nucleosome.
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High Mobility Group B Proteins, Their Partners, and Other Redox Sensors in Ovarian and Prostate Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:5845061. [PMID: 26682011 PMCID: PMC4670870 DOI: 10.1155/2016/5845061] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 07/27/2015] [Indexed: 01/02/2023]
Abstract
Cancer cells try to avoid the overproduction of reactive oxygen species by metabolic rearrangements. These cells also develop specific strategies to increase ROS resistance and to express the enzymatic activities necessary for ROS detoxification. Oxidative stress produces DNA damage and also induces responses, which could help the cell to restore the initial equilibrium. But if this is not possible, oxidative stress finally activates signals that will lead to cell death. High mobility group B (HMGB) proteins have been previously related to the onset and progressions of cancers of different origins. The protein HMGB1 behaves as a redox sensor and its structural changes, which are conditioned by the oxidative environment, are associated with different functions of the protein. This review describes recent advances in the role of human HMGB proteins and other proteins interacting with them, in cancerous processes related to oxidative stress, with special reference to ovarian and prostate cancer. Their participation in the molecular mechanisms of resistance to cisplatin, a drug commonly used in chemotherapy, is also revised.
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Ge WS, Fan JG, Chen YW, Xu LM. Expression and purification of functional HMGB1 A box by fusion with SUMO. Mol Med Rep 2015; 12:6527-32. [PMID: 26352592 PMCID: PMC4626187 DOI: 10.3892/mmr.2015.4308] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 08/17/2015] [Indexed: 01/14/2023] Open
Abstract
High-mobility-group-box chromosomal protein 1 (HMGB1) is a ubiquitous and abundant nuclear protein in eukaryotic cells. Nuclear HMGB1 serves an important role in maintaining nuclear stability under stress. However, extracellular HMGB1 exerts actions, which are distinctly different compared with these intracellular functions. HMGB1, when released extracellularly, is a potent innate signal, which initiates host defense mechanisms or tissue regeneration. HMGB1 has two DNA-binding domains: HMG A box and B box. The HMGB1 A box exhibits an antagonistic, anti-inflammatory effect, and is a potential therapeutic target, however, the large-scale expression and purification of the HMGB1 A box with high efficiency remains to be reported. In the present study, a SUMO-fusion expression system was used to express and purify high levels of functional HMGB1 A box to meet the requirements of therapeutic protein production.
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Affiliation(s)
- Wen-Song Ge
- Department of Gastroenterology, Shanghai Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Jian-Gao Fan
- Department of Gastroenterology, Shanghai Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Ying-Wei Chen
- Department of Gastroenterology, Shanghai Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Lei-Ming Xu
- Department of Gastroenterology, Shanghai Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
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M. Scovell W, R. Joshi S. The changing paradigm: estrogen receptor α recognition on DNA and within the dynamic nature of nucleosomes. AIMS MOLECULAR SCIENCE 2015. [DOI: 10.3934/molsci.2015.2.48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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R. Lambert J, K. Nordeen S. A role for the non-conserved N-terminal domain of the TATA-binding protein in the crosstalk between cell signaling pathways and steroid receptors. AIMS MOLECULAR SCIENCE 2015. [DOI: 10.3934/molsci.2015.2.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Abstract
High-mobility group box 1 (HMGB1) was originally defined as a ubiquitous nuclear protein, but it was later determined that the protein has different roles both inside and outside of cells. Nuclear HMGB1 regulates chromatin structure and gene transcription, whereas cytosolic HMGB1 is involved in inflammasome activation and autophagy. Extracellular HMGB1 has drawn attention because it can bind to related cell signalling transduction receptors, such as the receptor for advanced glycation end products, Toll-like receptor (TLR)2, TLR4 and TLR9. It also participates in the development and progression of a variety of diseases. HMGB1 is actively secreted by stimulation of the innate immune system, and it is passively released by ischaemia or cell injury. This review focuses on the important role of HMGB1 in the pathogenesis of acute and chronic sterile inflammatory conditions. Strategies that target HMGB1 have been shown to significantly decrease inflammation in several disease models of sterile inflammation, and this may represent a promising clinical approach for treatment of certain conditions associated with sterile inflammation.
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Affiliation(s)
- A Tsung
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Li LC, Gao J, Li J. Emerging role of HMGB1 in fibrotic diseases. J Cell Mol Med 2014; 18:2331-9. [PMID: 25284457 PMCID: PMC4302638 DOI: 10.1111/jcmm.12419] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 08/04/2014] [Indexed: 12/17/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be passively released from necrotic cells or actively secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 is a multifunctional cytokine that contributes to the process of infection, injury, inflammation, apoptosis, and immune responses by binding to specific cell-surface receptors. Recently, emerging studies indicate that HMGB1 is closely involved in fibrotic disorders including cystic fibrosis, liver fibrosis and pulmonary fibrosis, while HMGB1 signal inhibitions protect against the experimental models of fibrotic diseases. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses. This review focuses on the crucial role of HMGB1 in the pathogenesis of fibrotic diseases and inhibition of which may represent a promising clinical approach for treating tissue fibrosis.
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Affiliation(s)
- Liu-Cheng Li
- Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China; Third-Grade Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine (TCM-2009-202), Pharmaceutical Preparation Section, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Liu Y, Yang L, Tao K, Vizcaychipi MP, Lloyd DM, Sun X, Irwin MG, Ma D, Yu W. Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release. BMC Gastroenterol 2014; 14:12. [PMID: 24410860 PMCID: PMC3928909 DOI: 10.1186/1471-230x-14-12] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 12/30/2013] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND The nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI). Hydrogen treatment was recently associated with down-regulation of the expression of HMGB1 and pro-inflammatory cytokines during sepsis and myocardial IRI, but it is not known whether hydrogen has an effect on HMGB1 in liver IRI. METHODS A rat model of 60 minutes 70% partial liver ischemia reperfusion injury was used. Hydrogen enriched saline (2.5, 5 or 10 ml/kg) was injected intraperitoneally 10 minutes before hepatic reperfusion. Liver injury was assessed by serum alanine aminotransferase (ALT) enzyme levels and histological changes. We also measured malondialdehyde (MDA), hydroxynonenal (HNE) and 8-hydroxy-guanosine (8-OH-G) levels as markers of the peroxidation injury induced by reactive oxygen species (ROS). In addition, pro-inflammatory cytokines including TNF-α and IL-6, and high mobility group box B1 protein (HMGB1) were measured as markers of post ischemia-reperfusion inflammation. RESULTS Hydrogen enriched saline treatment significantly attenuated the severity of liver injury induced by ischemia-reperfusion. The treatment group showed reduced serum ALT activity and markers of lipid peroxidation and post ischemia reperfusion histological changes were reduced. Hydrogen enriched saline treatment inhibited HMGB1 expression and release, reflecting a reduced local and systemic inflammatory response to hepatic ischemia reperfusion. CONCLUSION These results suggest that, in our model, hydrogen enriched saline treatment is protective against liver ischemia-reperfusion injury. This effect may be mediated by both the anti-oxidative and anti-inflammatory effects of the solution.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Weifeng Yu
- Department of Anesthesia & Intensive Care, Eastern Hepatobiliary Surgical hospital, the Second Military Medical University, Shanghai 200433, China.
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HMGB1 acts in synergy with lipopolysaccharide in activating rheumatoid synovial fibroblasts via p38 MAPK and NF-κB signaling pathways. Mediators Inflamm 2013; 2013:596716. [PMID: 24302816 PMCID: PMC3834620 DOI: 10.1155/2013/596716] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Revised: 09/05/2013] [Accepted: 09/21/2013] [Indexed: 12/15/2022] Open
Abstract
Synovial fibroblasts (SF) play a central role in the inflammatory and
destructive process in rheumatoid arthritis (RA). High-mobility
group box chromosomal protein 1 (HMGB1) or lipopolysaccharide
(LPS) alone failed to induce significant changes in proliferation
of cultured SF from RA patients, but premixed HMGB1 with LPS
(HMGB1-LPS) significantly facilitated SF proliferation. HMGB1
alone failed to induce IL-6, MMP-3, and MMP-13 production in
cultured SF but greatly enhanced LPS-induced expression of IL-6,
MMP-3, and MMP-13 at both mRNA and protein levels. HMGB1-LPS
synergistically upregulated TLR4 and receptor for advanced
glycation endproducts (RAGE) expression on the surface of SF. Both
blockers of TLR4 and RAGE significantly inhibited the synergistic
effects of HMGB1-LPS on the production of IL-6 and MMPs, but
blocking antibodies to TLR2 failed. HMGB1-LPS synergistically
increased intracellular levels of phosphorylated p38 and
phosphorylated IκB. Furthermore, both NF-κB inhibitor Bay11-7085
and p38 inhibitor SB203580 significantly suppressed the enhanced
production of IL-6 and MMPs induced by HMGB1-LPS. In conclusion,
HMGB1 acts in synergy with LPS to upregulate TLR4 and RAGE
expression on the surface of SF in RA and then to augment IL-6,
MMP-3, and MMP-13 production, which depends on p38 MAPK and NF-κB
activation.
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Huang ZB, Dai XH, Xiao MF, Zhou RR, Zhao SS, Zhang BX, Yi PP, Chen RC, Li WT, Yaser AM, Huang Y, Fan XG. HMGB1 release by human liver L02 and HepG2 cells induced by lipopolysaccharide. Mol Med Rep 2013; 8:103-12. [PMID: 23685705 DOI: 10.3892/mmr.2013.1482] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Accepted: 04/26/2013] [Indexed: 11/06/2022] Open
Abstract
Liver cells release the high mobility group box-1 (HMGB1) protein when exposed to lipopolysaccharides (LPSs). However, the timing and levels of protein released remain unclear. The present study aimed to characterize the secretion of the late pro-inflammatory cytokine HMGB1 by liver L02 and HepG2 cells. The human mononuclear macrophage cell line U937 was used as a control. Various concentrations of LPS were added to human U937, L02 and HepG2 cells for different durations, and the cells were analyzed at different time-points following this addition. Reverse transcription polymerase chain reaction (RT-PCR) was used to measure cellular HMGB1 mRNA levels, western blotting was performed to detect HMGB1 in cellular supernatants and the translocation of HMGB1 from the nucleus to the cytosol was examined using immunofluorescence staining. L02 and HepG2 cells exhibited higher HMGB1 mRNA levels compared with the control U937 cells 20 and 24 h following continuous exposure to LPS. U937 cells exhibited higher HMGB1 mRNA levels compared with the corresponding L02 and HepG2 cells 16 h following LPS exposure. The phase of HMGB1 protein detected in the cellular supernatants of L02 and HepG2 cells (16 h) was later than that of U937 cells (8 h). For the three cell lines, HMGB1 levels demonstrated a time dependency; however, the protein level was the highest in U937 cells. In the three cell lines, translocation of HMGB1 from the nucleus to the cytosol occurred; however, the phases of HMGB1 translocation in L02 and HepG2 cells occurred later than in U937 cells. LPS-induced secretion of the late pro‑inflammatory cytokine HMGB1 by liver cells is characterized by a late phase of release and smaller quantity, and the process of HMGB1 secretion appears to be associated with HMGB1 translocation.
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Affiliation(s)
- Ze-Bing Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Hunan, PR China
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Chen Y, Sun W, Gao R, Su Y, Umehara H, Dong L, Gong F. The role of high mobility group box chromosomal protein 1 in rheumatoid arthritis. Rheumatology (Oxford) 2013; 52:1739-47. [PMID: 23584368 DOI: 10.1093/rheumatology/ket134] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
High mobility group box chromosomal protein 1 (HMGB1) is a ubiquitous highly conserved single polypeptide in all mammal eukaryotic cells. HMGB1 exists mainly within the nucleus and acts as a DNA chaperone. When passively released from necrotic cells or actively secreted into the extracellular milieu in response to appropriate signal stimulation, HMGB1 binds to related cell signal transduction receptors, such as RAGE, TLR2, TLR4 and TLR9, and becomes a proinflammatory cytokine that participates in the development and progression of many diseases, such as arthritis, acute lung injury, graft rejection immune response, ischaemia reperfusion injury and autoimmune liver damage. Only a small amount of HMGB1 release occurs during apoptosis, which undergoes oxidative modification on Cys106 and delivers tolerogenic signals to suppress immune activity. This review focuses on the important role of HMGB1 in the pathogenesis of RA, mainly manifested as the aberrant expression of HMGB1 in the serum, SF and synovial tissues; overexpression of signal transduction receptors; abnormal regulation of osteoclastogenesis and bone remodelling leading to the destruction of cartilage and bones. Intervention with HMGB1 may ameliorate the pathogenic conditions and attenuate disease progression of RA. Therefore administration of an HMGB1 inhibitor may represent a promising clinical approach for the treatment of RA.
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Affiliation(s)
- Yu Chen
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095th Jiefang Avenue, Wuhan, Hubei 430030, China.
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Joshi SR, Sarpong YC, Peterson RC, Scovell WM. Nucleosome dynamics: HMGB1 relaxes canonical nucleosome structure to facilitate estrogen receptor binding. Nucleic Acids Res 2012; 40:10161-71. [PMID: 22941653 PMCID: PMC3488250 DOI: 10.1093/nar/gks815] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
High mobility group protein 1 (HMGB1) interacts with DNA and chromatin to influence the regulation of transcription, DNA repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome (N) in a nonenzymatic, ATP-independent manner. Although estrogen receptor (ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes (N′ and N″) remain stable and exhibit characteristics distinctly different from the canonical nucleosome. These findings complement previous studies that showed (i) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and (ii) knock down of HMGB1 expression by siRNA precipitously reduced transcriptional activation. The findings indicate that one aspect of the mechanism of HMGB1 action involves a restructuring of the nucleosome that appears to relax structural constraints within the nucleosome.
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Affiliation(s)
- Sachindra R Joshi
- Department of Chemistry and Biological Sciences, Bowling Green State University, Bowling Green, OH 43403, USA
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15
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Oshima G, Shinoda M, Tanabe M, Ebinuma H, Nishiyama R, Takano K, Yamada S, Miyasho T, Masugi Y, Matsuda S, Suda K, Fukunaga K, Matsubara K, Hibi T, Yagi H, Hayashida T, Yamagishi Y, Obara H, Itano O, Takeuchi H, Kawachi S, Saito H, Hibi T, Maruyama I, Kitagawa Y. Increased plasma levels of high mobility group box 1 in patients with acute liver failure. ACTA ACUST UNITED AC 2012; 48:154-62. [PMID: 22585050 DOI: 10.1159/000338363] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Accepted: 03/07/2012] [Indexed: 11/19/2022]
Abstract
BACKGROUND High-mobility group box 1 (HMGB1) is a monocyte-derived late-acting inflammatory mediator, which is released in conditions such as shock, tissue injury and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in patients with acute liver failure (ALF). PATIENTS AND METHODS We determined the plasma levels of HMGB1 and aspartate aminotransferase (AST) in 7 healthy volunteers (HVs), 40 patients with liver cirrhosis (LC), 37 patients with chronic hepatitis (CH), 18 patients with severe acute hepatitis (AH), and 14 patients with fulminant hepatitis (FH). The 14 patients with FH were divided into two subgroups depending upon the history of plasma exchange (PE) before their plasma sample collection. The hepatic levels of HMGB1 were measured in tissue samples from 3 patients with FH who underwent living-donor liver transplantation and from 3 healthy living donors. Hepatic tissue samples were also subjected to immunohistochemical examination for HMGB1. RESULTS The plasma levels of HMGB1 (ng/ml) were higher in patients with liver diseases, especially in FH patients with no history of PE, than in HVs (0.3 ± 0.3 in HVs, 4.0 ± 2.0 in LC, 5.2 ± 2.6 in CH, 8.6 ± 4.8 in severe AH, 7.8 ± 2.7 in FH with a history of PE, and 12.5 ± 2.6 in FH with no history of PE, p < 0.05 in each comparison). There was a strong and statistically significant relationship between the mean plasma HMGB1 level and the logarithm of the mean AST level (R = 0.900, p < 0.05). The hepatic tissue levels of HMGB1 (ng/mg tissue protein) were lower in patients with FH than in healthy donors (539 ± 116 in FH vs. 874 ± 81 in healthy donors, p < 0.05). Immunohistochemical staining for HMGB1 was strong and clear in the nuclei of hepatocytes in liver sections from healthy donors, but little staining in either nuclei or cytoplasm was evident in specimens from patients with FH. CONCLUSION We confirmed that plasma HMGB1 levels were increased in patients with ALF. Based on a comparison between HMGB1 contents in normal and ALF livers, it is very likely that HMGB1 is released from injured liver tissue.
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Affiliation(s)
- G Oshima
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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Joshi SR, Ghattamaneni RB, Scovell WM. Expanding the paradigm for estrogen receptor binding and transcriptional activation. Mol Endocrinol 2011; 25:980-94. [PMID: 21527498 DOI: 10.1210/me.2010-0302] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Estrogen receptor (ER) binds to a spectrum of functional estrogen response elements (ERE) within the human genome, including ERE half-sites (HERE), inverted and direct repeats. This has been confounding, because ER has been reported to bind weakly, if at all, to these sites in vitro. We show that ER binds strongly to these nonconventional EREs, and the binding is enhanced by the presence of high-mobility group protein B1 (HMGB1). Collectively, these and previous findings reinforce the notion of the plasticity of strong ER/ERE interactions, consistent with their broader range of observed binding specificity. In addition, transient transfection studies using luciferase reporter gene assays show that these EREs drive luciferase activity, and HMGB1 enhances transcriptional activity. Furthermore, HMGB1 gene expression knockdown results in a precipitous drop in luciferase activity, suggesting a prominent role for HMGB1 in activation of estrogen/ER-responsive genes. Therefore, these data advocate that the minimal target site for ER is a cHERE (consensus HERE) that occurs in many different contexts and that HMGB1 enhances both the binding affinity and transcriptional activity. This challenges the current paradigm for ER binding affinity and functional activity and suggests that the paradigm requires significant reevaluation and modification. These findings also suggest a possible mechanism for a cross talk between genes regulated by ER and class II nuclear receptors.
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Affiliation(s)
- S R Joshi
- Department of Chemistry, Bowling Green State University, Bowling Green, Ohio 43403, USA
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Wu CX, Sun H, Liu Q, Guo H, Gong JP. LPS induces HMGB1 relocation and release by activating the NF-κB-CBP signal transduction pathway in the murine macrophage-like cell line RAW264.7. J Surg Res 2011; 175:88-100. [PMID: 21571302 DOI: 10.1016/j.jss.2011.02.026] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 02/06/2011] [Accepted: 02/09/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND High mobility group protein B1 (HMGB1) is an important late inflammatory mediator in sepsis. Understanding the mechanisms that regulate HMGB1 release from cells and their downstream signal transduction pathways may lead to the ability to develop anti-HMGB1 therapies to treat inflammation. MATERIALS AND METHODS We stimulated murine macrophage-like RAW 264.7 cells with lipopolysaccharide (LPS) and LPS+ ethylpyruvate (EP) and examined the resulting HMGB1 expression and release. We also studied the expression of related signal transduction factors (NF-κB, p38 MAPK, and CBP). RESULTS AND CONCLUSION Gene expression of HMGB1 mRNA in RAW264.7 cell showed no significant change at 0-18 h after stimulation with LPS, but increased significantly at 24, 36, and 48 h. HMGB1 mRNA expression in the LPS+EP group was significantly lower than in LPS alone. HMGB1 was distributed mainly in the nucleus; the cytoplasmic level was low before LPS stimulation. After stimulation with LPS, cytoplasmic HMGB1 increased gradually and plateaued at a high level at 12-48 h. Nuclear HMGB1 decreased gradually at 12-24 h, then increased, maintaining a comparatively high level at 36-48 h. EP prevented this pattern significantly. LPS induced p38 MAPK activation and NF-κB signal pathways first, followed by CBP activation. Activated CBP acetylated HMGB1 was stored in a crino-lysosome and secreted activated NF-κB resulted in increased transcription and synthesis of HMGB1, but the expression of up-regulated HMGB1 mRNA was delayed. Extracellular HMGB1 originated from early synthetic reserves present in the nucleus. New HMGB1 protein was synthesized in the nucleus and transferred into the cytoplasm, causing an increase in HMGB1 in the nucleus and cytoplasm. EP inhibits HMGB1 mRNA up-regulation and release from LPS- stimulated macrophages. The molecular function of EP is to attenuate the activation p38 MAPK, NF-κB, and CBP signaling pathways.
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Affiliation(s)
- Chuan-Xin Wu
- Department of Hepatobiliary Surgery, Chongqing Medical University, Second Affiliated Hospital, Chongqing, China
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18
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MIYASHO T, NAKAMURA K, NOMURA S, KAWASAKO K, NAKADE T, YAMADA S, YOKOTA H. High Mobility Group Box 1 (HMGB1) Protein is Present in the Cerebrospinal Fluid of Dogs with Encephalitis. J Vet Med Sci 2011; 73:917-22. [DOI: 10.1292/jvms.10-0444] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Taku MIYASHO
- Department of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University
| | - Kozo NAKAMURA
- Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University
| | - Sachiko NOMURA
- Department of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University
| | - Kazufumi KAWASAKO
- Department of Veterinary Pathology, School of Veterinary Medicine, Rakuno Gakuen University
| | - Tetsuya NAKADE
- Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University
| | | | - Hiroshi YOKOTA
- Department of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University
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19
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Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis 2010; 15:1098-113. [PMID: 20198437 DOI: 10.1007/s10495-010-0478-8] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease.
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20
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Guo HF, Liu SX, Zhang YJ, Liu QJ, Hao J, Gao LX. High mobility group box 1 induces synoviocyte proliferation in rheumatoid arthritis by activating the signal transducer and activator transcription signal pathway. Clin Exp Med 2010; 11:65-74. [DOI: 10.1007/s10238-010-0116-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Accepted: 10/12/2010] [Indexed: 11/27/2022]
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21
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HMGB1 in systemic lupus Erythematosus: Its role in cutaneous lesions development. Autoimmun Rev 2010; 9:661-5. [PMID: 20546955 DOI: 10.1016/j.autrev.2010.05.015] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Accepted: 05/10/2010] [Indexed: 12/29/2022]
Abstract
The chromatin non-histone DNA binding protein high mobility group box one (HMGB1) has recently been extensively studied in autoimmune diseases. In addition to its nuclear functions, HMGB1 has been identified as alarmin that can 'alarm' both innate and adaptive immunity. HMGB1 can amplify inflammation and enhance immune responses by interacting with the receptor for Advanced Glycation End Products (RAGE) and Toll-like receptors 2,4 and 9 (TLRs) . Release of HMGB1 occurs during cell activation as well as cell death. Cells die by apoptosis and eventually necrosis which both are thought to lead to release of HMGB1 into the microenvironment. In the past years disturbed apoptosis or clearance of apoptotic cells has been put forward as a major pathophysiological feature in autoimmune diseases such as Systemic Lupus Erythematosus (SLE), which is a prototypic autoimmune disease that affects many organs. Accumulation of apoptotic cells has been found in SLE. Also, elevated levels of HMGB1 have been detected in the serum of SLE patients and increased expression of HMGB1 was demonstrated in skin lesions of lupus patients. In this review the general characteristics and activities of HMGB1 are highlighted and its role in SLE will be discussed with special attention to its involvement in the pathogenesis of skin lesions.
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22
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Circulating levels of a soluble form of receptor for advanced glycation end products and high-mobility group box chromosomal protein 1 in patients with acute pancreatitis. Pancreas 2009; 38:e215-20. [PMID: 19786934 DOI: 10.1097/mpa.0b013e3181bb59a7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES To study in patients with acute pancreatitis (AP) the plasma soluble form of the receptor for advanced glycation end products (sRAGE) and high-mobility group box chromosomal protein 1 (HMGB1) levels, followed-up for 12 days after hospitalization, in relation to the occurrence of organ failure and mortality. METHODS Thirty-eight patients with severe AP and organ failure (grade 2). A control group (127 patients) consisted of 38 patients with severe AP without organ failure (grade 1) and 89 patients with mild AP (grade 0). Plasma samples for determination of HMGB1 and sRAGE levels were collected on admission and on days 1 and 2, days 3 and 4, and days 7 and 12 after admission. RESULTS The median of the highest sRAGE levels was higher in grade 2 patients (472 pg/mL; interquartile range [IQR], 259-912) than in grade 0 plus grade 1 patients (349 pg/mL; IQR, 209-544; P = 0.024). Among the patients with detectable HMGB1, the median of the highest HMGB1 levels was 117 ng/mL (IQR, 56-212; n = 24) in grade 2 patients and 87 ng/mL (IQR, 54-161; n = 62) in grade 0 plus grade 1 patients (P = 0.310). CONCLUSIONS We demonstrate that sRAGE level, but not HMGB1 level, is significantly higher in AP patients who develop organ failure than in AP patients without organ failure who recover.
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23
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Schultz-Norton JR, Ziegler YS, Likhite VS, Yates JR, Nardulli AM. Isolation of novel coregulatory protein networks associated with DNA-bound estrogen receptor alpha. BMC Mol Biol 2008; 9:97. [PMID: 18973695 PMCID: PMC2585101 DOI: 10.1186/1471-2199-9-97] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2008] [Accepted: 10/30/2008] [Indexed: 12/19/2022] Open
Abstract
Background DNA-bound transcription factors recruit an array of coregulatory proteins that influence gene expression. We previously demonstrated that DNA functions as an allosteric modulator of estrogen receptor α (ERα) conformation, alters the recruitment of regulatory proteins, and influences estrogen-responsive gene expression and reasoned that it would be useful to develop a method of isolating proteins associated with the DNA-bound ERα using full-length receptor and endogenously-expressed nuclear proteins. Results We have developed a novel approach to isolate large complexes of proteins associated with the DNA-bound ERα. Purified ERα and HeLa nuclear extracts were combined with oligos containing ERα binding sites and fractionated on agarose gels. The protein-DNA complexes were isolated and mass spectrometry analysis was used to identify proteins associated with the DNA-bound receptor. Rather than simply identifying individual proteins that interact with ERα, we identified interconnected networks of proteins with a variety of enzymatic and catalytic activities that interact not only with ERα, but also with each other. Characterization of a number of these proteins has demonstrated that, in addition to their previously identified functions, they also influence ERα activity and expression of estrogen-responsive genes. Conclusion The agarose gel fractionation method we have developed would be useful in identifying proteins that interact with DNA-bound transcription factors and should be easily adapted for use with a variety of cultured cell lines, DNA sequences, and transcription factors.
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Affiliation(s)
- Jennifer R Schultz-Norton
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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24
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Temple SEL, Cheong KY, Price P, Waterer GW. The microsatellite, macrophage migration inhibitory factor -794, may influence gene expression in human mononuclear cells stimulated withE. coliorS. pneumoniae. Int J Immunogenet 2008; 35:309-16. [DOI: 10.1111/j.1744-313x.2008.00781.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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25
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Liu H, Yao YM, Ding LH, Zhang H, Yuan B, Song Q, Ye QN, Huang CF, Sheng ZY. High mobility group box-1 protein acts as a coactivator of nuclear factor of activated T cells-2 in promoting interleukin-2 transcription. Int J Biochem Cell Biol 2008; 41:641-8. [PMID: 18707018 DOI: 10.1016/j.biocel.2008.07.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2008] [Revised: 07/06/2008] [Accepted: 07/22/2008] [Indexed: 11/15/2022]
Abstract
High mobility group box-1 protein, an abundant and conserved constituent of vertebrate nuclei, has recently been reported to be an endogenous immune signal [Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Reports 2004;5:825-30]. High mobility group box-1 protein can trigger the release of interleukin-2 and interleukin-12 from lymphocytes. However, at present the underlying mechanism remains unknown. It has been clarified that nuclear factor of activated T cells-2 transduces most immunological signals in T cells and modulates the production of interleukin-2. So it is natural that we asked whether high mobility group box-1 protein could promote production of interleukin-2 in a nuclear factor of activated T cells-2-dependent way. Our experiments firstly showed that high mobility group box-1 protein could bind to nuclear factor of activated T cells-2 in vivo and in vitro. High mobility group box-1 protein cotransfection markedly upregulated the transcription activity of nuclear factor of activated T cells-2 in promoting interleukin-2 reporter gene transcription, which was demonstrated to be dose-dependent. Cotransfection of high mobility group box-1 protein and nuclear factor of activated T cells-2 induced an 18.4-time increase of interleukin-2 activity in 293T cells and a 117.7-time increase in Hela cells. Moreover, inhibition of either high mobility group box-1 protein or nuclear factor of activated T cells -2 expression by sRNAi led to significant decrease of transcription activity of interleukin-2 reporter gene, suggesting that high mobility group box-1 protein and nuclear factor of activated T cells-2 both take important roles in facilitating interleukin-2 transcription, and high mobility group box-1 protein could act as a coactivator for nuclear factor of activated T cells-2 in enhancing transcription of interleukin-2. This discovery has not been reported elsewhere, and helps to understand the newly highlighted immunological role of high mobility group box-1 protein.
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Affiliation(s)
- Hui Liu
- Surgical Intensive Care Unit, Chinese PLA General Hospital, Beijing 100853, PR China
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26
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El Marzouk S, Gahattamaneni R, Joshi SR, Scovell WM. The plasticity of estrogen receptor-DNA complexes: binding affinity and specificity of estrogen receptors to estrogen response element half-sites separated by variant spacers. J Steroid Biochem Mol Biol 2008; 110:186-95. [PMID: 18479910 DOI: 10.1016/j.jsbmb.2008.03.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2007] [Accepted: 03/28/2008] [Indexed: 11/25/2022]
Abstract
The consensus estrogen response element (cERE) contains a palindromic sequence of two 6-base pair (bp) half-sites separated by a spacer size of 3bp. This study investigates the extent to which estrogen receptors, ERalpha and ERbeta can bind target sequences not considered as conventional EREs. We determined the effect of spacer size (n=0-4) on the binding affinity and conformation of ERalpha and ERbeta in these complexes and the effect of HMGB1 on the complexation. We find (1) both receptors bind similarly and with progressively reduced affinity to cEREn, as n differs from 3; (2) however, both receptors bind as strongly to the cERE with no spacer (cERE0) as to cERE3; (3) HMGB1 enhances ER binding affinity in all complexes, resulting in strong and comparable binding affinities in all complexes examined; (4) the full-length ER binding differs strikingly from similar binding studies for the ER DNA binding domain (ERDBD), with the full-length ER dimer exhibiting strong binding affinity, enormous plasticity and retaining binding cooperativity as the spacer size varies; (5) both protease digestion profiles and monoclonal antibody binding assays indicate the conformation of the receptor in the ER/ERE complex is sensitive to the spacer size; (6) the ER/cERE0 complex appears to be singularly different than the other ER/cEREn complexes in binding and conformation. This multifaceted approach reinforces the notion of the plasticity in ER binding and leads to the hypothesis that in most cases, the minimum requirement for estrogen receptor binding is the ERE half-site, in which one or more cofactors, such as HMGB1, can cooperate to decrease ER binding specificity, while increasing its binding affinity.
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Affiliation(s)
- S El Marzouk
- Department of Chemistry and The Center for Biomolecular Dynamics, Bowling Green State University, Bowling Green, OH 43403, United States
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27
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Influence of nucleophosmin/B23 on DNA binding and transcriptional activity of the androgen receptor in prostate cancer cell. Oncogene 2007; 27:2858-67. [PMID: 18037965 DOI: 10.1038/sj.onc.1210942] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The promotion and progression of prostate cancer (PCa) are associated with androgen receptor (AR) signalling. AR functions are modulated by a variety of co-factors amongst which we identified the nucleophosmin (NPM/B23), a member of the histone chaperone family. Here, we show that NPM is overexpressed in PCa compared to normal adjacent tissues. AR and NPM interact in vitro and in vivo, and NPM is critical for androgen-dependent transcriptional activation in LNCaP cells as an anti-NPM siRNA downregulates transcription of a transfected androgen response element (ARE)-containing reporter promoter as well as expression of the endogenous androgen responsive prostate-specific antigen (PSA) gene. By investigating the effect of NPM on AR, we have also observed that NPM enhances AR binding to an ARE in vitro in electrophoretic gel mobility-shift assay experiments. Chromatin immunoprecipitation studies further demonstrated that both AR and NPM associate with AREs of the PSA gene in vivo. Altogether, our data suggest that the molecular histone chaperone NPM could regulate AR functions by promoting assembly of AR-containing regulatory complexes and that high levels of NPM might alter AR functions in PCa.
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Yamada S, Maruyama I, Takemoto T, Akahoshi T. Recent advances in inflammatory markers.-HMGB1 and TREM-1-. Inflamm Regen 2007. [DOI: 10.2492/inflammregen.27.88] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Sawa H, Ueda T, Takeyama Y, Yasuda T, Shinzeki M, Nakajima T, Kuroda Y. Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis. World J Gastroenterol 2006; 12:7666-70. [PMID: 17171797 PMCID: PMC4088050 DOI: 10.3748/wjg.v12.i47.7666] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the effects of anti-high mobility group box 1 (HMGB1) neutralizing antibody in experimental severe acute pancreatitis (SAP).
METHODS: SAP was induced by creating closed duodenal loop in C3H/HeN mice. SAP was induced immediately after intraperitoneal injection of anti-HMGB1 neutralizing antibody (200 μg). Severity of pancreatitis, organ injury (liver, kidney and lung), and bacterial translocation to pancreas was examined 12 h after induction of SAP.
RESULTS: Anti-HMGB1 neutralizing antibody significantly improved the elevation of the serum amylase level and the histological alterations of pancreas and lung in SAP. Anti-HMGB1 antibody also significantly ameliorated the elevations of serum alanine aminotransferase and creatinine in SAP. However, anti-HMGB1 antibody worsened the bacterial translocation to pancreas.
CONCLUSION: Blockade of HMGB1 attenuated the development of SAP and associated organ dysfunction, suggesting that HMGB1 may act as a key mediator for inflammatory response and organ injury in SAP.
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Affiliation(s)
- Hidehiro Sawa
- Department of Gastroenterological Surgery, Kobe University Graduate School of Medical Sciences, Kobe 650-0017, Japan.
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30
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Yasuda T, Ueda T, Takeyama Y, Shinzeki M, Sawa H, Nakajima T, Ajiki T, Fujino Y, Suzuki Y, Kuroda Y. Significant increase of serum high-mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis. Pancreas 2006; 33:359-63. [PMID: 17079940 DOI: 10.1097/01.mpa.0000236741.15477.8b] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Multiple organ failure because of systemic inflammatory response in the early phase and sepsis in the late phase is the main contributor to high mortality in severe acute pancreatitis (SAP). High-mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator and increases in various pathological conditions such as sepsis. The aim of this study was to investigate contributions of HMGB1 in SAP. METHODS We measured serum HMGB1 concentrations by an enzyme-linked immunosorbent assay in 45 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and clinical factors was analyzed. RESULTS The mean value of serum HMGB1 levels was significantly higher in patients with SAP (5.4 +/- 1.3 ng/mL) than that in healthy volunteers (1.7 +/- 0.3 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Japanese severity score and Glasgow score. Serum HMGB1 levels were significantly positively correlated with lactate dehydrogenase, C-reactive protein, and total bilirubin. The HMGB1 levels were higher in patients with organ dysfunction and infection during the clinical course. The HMGB1 levels in nonsurvivors were higher than those in survivors. Serum HMGB1 levels gradually declined after the admission. CONCLUSIONS Serum HMGB1 levels were significantly increased in patients with SAP and were correlated with disease severity. These results suggest that HMGB1 may act as a key mediator for inflammation and organ failure in SAP.
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Affiliation(s)
- Takeo Yasuda
- Department of Gastroenterological Surgery, Kobe University Graduate School of Medical Sciences, Japan.
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31
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Roemer SC, Donham DC, Sherman L, Pon VH, Edwards DP, Churchill MEA. Structure of the progesterone receptor-deoxyribonucleic acid complex: novel interactions required for binding to half-site response elements. Mol Endocrinol 2006; 20:3042-52. [PMID: 16931575 PMCID: PMC2532839 DOI: 10.1210/me.2005-0511] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The DNA binding domain (DBD) of nuclear hormone receptors contains a highly conserved globular domain and a less conserved carboxyl-terminal extension (CTE). Despite previous observations that the CTEs of some classes of nuclear receptors are structured and interact with DNA outside of the hexanucleotide hormone response element (HRE), there has been no evidence for such a CTE among the steroid receptors. We have determined the structure of the progesterone receptor (PR)-DBD-CTE DNA complex at a resolution of 2.5 A, which revealed binding of the CTE to the minor groove flanking the HREs. Alanine substitutions of the interacting CTE residues reduced affinity for inverted repeat HREs separated by three nucleotides, and essentially abrogated binding to a single HRE. A highly compressed minor groove of the trinucleotide spacer and a novel dimerization interface were also observed. A PR binding site selection experiment revealed sequence preferences in the trinucleotide spacer and flanking DNA. These results, taken together, support the notion that sequences outside of the HREs influence the DNA binding affinity and specificity of steroid receptors.
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Affiliation(s)
- Sarah C Roemer
- Program in Molecular Biology, Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA
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32
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Yamada S, Maruyama I. HMGB1, a novel inflammatory cytokine. Clin Chim Acta 2006; 375:36-42. [PMID: 16979611 DOI: 10.1016/j.cca.2006.07.019] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2006] [Revised: 07/11/2006] [Accepted: 07/13/2006] [Indexed: 11/16/2022]
Abstract
High mobility group box 1 (HMGB1) exhibits unique biochemical functions as a biologically intrinsic requisite factor and as a toxin. As such, it is imperative to understand the mechanism by which these seemingly and diametrically opposed functions are exerted. To effectively discriminate these actions is important to accurately and precisely determine the concentration of HMGB1 in biological samples. Research in this fascinating field, however, has been lacking due to the absence of a simple analytical system for HMGB1 that can be adapted for large sample numbers. In this report, we review the physiological and pathological significance of HMGB1 and describe the development of an assay method for this pleiotropic protein.
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Affiliation(s)
- Shingo Yamada
- Central Institute, Shino-Test Corporation, Sagamihara, Kanagawa, Japan.
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33
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Solomon IH, Hager JM, Safi R, McDonnell DP, Redinbo MR, Ortlund EA. Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity. J Mol Biol 2005; 354:1091-102. [PMID: 16289203 DOI: 10.1016/j.jmb.2005.10.009] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2005] [Revised: 09/23/2005] [Accepted: 10/06/2005] [Indexed: 12/22/2022]
Abstract
The DNA-binding and ligand-binding functions of nuclear receptors are localized to independent domains separated by a flexible hinge. The DNA-binding domain (DBD) of the human liver receptor homologue-1 (hLRH-1), which controls genes central to development and metabolic homeostasis, interacts with monomeric DNA response elements and contains an Ftz-F1 motif that is unique to the NR5A nuclear receptor subfamily. Here, we present the 2.2A resolution crystal structure of the hLRH-1 DBD in complex with duplex DNA, and elucidate the sequence-specific DNA contacts essential for the ability of LRH-1 to bind to DNA as a monomer. We show that the unique Ftz-F1 domain folds into a novel helix that packs against the DBD but does not contact DNA. Mutations expected to disrupt the positioning of the Ftz-F1 helix do not eliminate DNA binding but reduce the transcriptional activity of full-length LRH-1 significantly. Moreover, we find that altering the Ftz-F1 helix positioning eliminates the enhancement of LRH-1-mediated transcription by the coactivator GRIP1, an action that is associated primarily with the distantly located ligand-binding domain (LBD). Taken together, these results indicate that subtle structural changes in a nuclear receptor DBD can exert long-range functional effects on the LBD of a receptor, and significantly impact transcriptional regulation.
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MESH Headings
- Alanine/metabolism
- Amino Acid Motifs
- Amino Acid Sequence
- Amino Acid Substitution
- Arginine/chemistry
- Base Sequence
- Binding Sites
- Carrier Proteins/metabolism
- Crystallography, X-Ray
- DNA/chemistry
- DNA/metabolism
- DNA-Binding Proteins/chemistry
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/isolation & purification
- DNA-Binding Proteins/metabolism
- Fluorescence Polarization
- Fushi Tarazu Transcription Factors/chemistry
- Fushi Tarazu Transcription Factors/genetics
- Fushi Tarazu Transcription Factors/metabolism
- Genes, Reporter
- Glutamic Acid/metabolism
- Glycine/chemistry
- Glycine/metabolism
- HeLa Cells
- Humans
- Hydrogen Bonding
- Ligands
- Luciferases/metabolism
- Models, Chemical
- Models, Molecular
- Molecular Sequence Data
- Nerve Tissue Proteins/metabolism
- Oxygen/chemistry
- Promoter Regions, Genetic
- Protein Binding
- Protein Conformation
- Protein Structure, Tertiary
- Receptors, Cytoplasmic and Nuclear/chemistry
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/isolation & purification
- Receptors, Cytoplasmic and Nuclear/metabolism
- Response Elements
- Transcription Factors/chemistry
- Transcription Factors/genetics
- Transcription Factors/isolation & purification
- Transcription Factors/metabolism
- Transcription, Genetic
- Water/chemistry
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Affiliation(s)
- Isaac H Solomon
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Zhao X, Patton JR, Davis SL, Florence B, Ames SJ, Spanjaard RA. Regulation of nuclear receptor activity by a pseudouridine synthase through posttranscriptional modification of steroid receptor RNA activator. Mol Cell 2004; 15:549-58. [PMID: 15327771 DOI: 10.1016/j.molcel.2004.06.044] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2004] [Revised: 06/08/2004] [Accepted: 06/17/2004] [Indexed: 11/18/2022]
Abstract
Nuclear receptors (NRs) induce transcription through association with coactivator complexes. We identified a pseudouridine synthase (PUS), mPus1p, as a coactivator for retinoic acid receptor (mRAR)gamma and other NR-dependent transactivation. mPus1p is a member of the truA subfamily of PUSs, a class of enzymes that isomerize uridine to pseudouridine in noncoding RNAs, such as tRNA, to ensure proper folding and function. mPus1p binds the first zinc finger of mRARgamma and also associates with other NRs. Interestingly, mPus1p pseudouridylates coactivator Steroid Receptor RNA Activator (SRA), and when coexpressed, mPus1p and SRA cooperatively enhance mRARgamma-mediated transcription. mPus1p, mRARgamma, and SRA exist in a retinoid-independent, promoter bound complex in the nucleus although mPus1p is also expressed in the nucleolus, where it likely modifies tRNA. Finally, we show that mPus1p-coactivator function required SRA, mPus1p-associated mRARgamma binding, and PUS activities. mPus1p-dependent pseudouridylation of SRA represents an additional type of posttranscriptional modification of a NR-coactivator complex that is important for NR signaling.
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MESH Headings
- Animals
- Cell Line, Tumor
- Humans
- Hydro-Lyases/genetics
- Hydro-Lyases/metabolism
- Macromolecular Substances
- Mice
- Promoter Regions, Genetic
- Protein Binding
- Protein Structure, Tertiary
- Pseudouridine/metabolism
- RNA Processing, Post-Transcriptional
- RNA, Long Noncoding
- RNA, Untranslated/metabolism
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, Retinoic Acid/genetics
- Receptors, Retinoic Acid/metabolism
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/metabolism
- Signal Transduction/physiology
- Transcription, Genetic
- Transcriptional Activation
- Two-Hybrid System Techniques
- Retinoic Acid Receptor gamma
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Affiliation(s)
- Xiansi Zhao
- Department of Otolaryngology, Boston University School of Medicine, Boston, MA 02118, USA
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35
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Abstract
High mobility group-1 (HMGB-1) enhances the DNA interactions and possesses a transcriptional activation potential for several families of sequence-specific transcriptional activators. In order to examine the effect of HMGB-1 on the cell cycle progression in MCF-7 cells, the HMGB-1 expression vector was transfected into synchronized MCF-7 cells, and the effect of HMGB-1 overexpression on the cell cycle was examined. The HMGB-1 protein level in the transfected cells increased 4.87-fold compared to the non-transfected cells. There were few changes in the cell cycle phase distribution after HMGB-1 overexpression in the MCF-7 cells. Following the estrogen treatment, the cell cycle progressed in both the HMGB-1 overexpressed MCF-7 and the mock-treated cells. However, a larger proportion of HMGB-1 overexpressing MCF-7 cells progressed to the either S or G2 phase than the mock-treated cells. The mRNA levels of the cell cycle regulators changed after being treated with estrogen in both the HMGB-1 overexpressing MCF-7 and the mock-treated cells, but the changes in the expression level of the cell cycle regulator genes were more prominent in the HMGB-1 overexpressing MCF-7 cells than in the mock-treated cells. In conclusion, HMGB-1 overexpression itself does not alter the MCF-7 cell cycle progression, but the addition of estrogen to the HMGB-1 overexpressing MCF-7 cells appears to accelerate the cell cycle progression.
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Affiliation(s)
- Sarah Yoon
- Center for Clinical Medicine & Samsung Biomedical Research Institute, Seoul, Korea
| | - Jin Young Lee
- Center for Clinical Medicine & Samsung Biomedical Research Institute, Seoul, Korea
| | - Byung-Koo Yoon
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - DukSoo Bae
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - DooSeok Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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36
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Kajitani T, Mizutani T, Yamada K, Yazawa T, Sekiguchi T, Yoshino M, Kawata H, Miyamoto K. Cloning and characterization of granulosa cell high-mobility group (HMG)-box protein-1, a novel HMG-box transcriptional regulator strongly expressed in rat ovarian granulosa cells. Endocrinology 2004; 145:2307-18. [PMID: 14764631 DOI: 10.1210/en.2003-1343] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Specific events in the ovary are dependent on gene expression in the tissue. By screening a rat ovarian granulosa cell cDNA library, a cDNA clone encoding a novel transcription factor-like protein containing a high-mobility group-box, referred to as granulosa cell high-mobility group-box protein-1 (GCX-1), was identified. The expression of GCX-1 is restricted to the hypothalamus, pituitary, testis, uterus, and ovary but was not detected in the adrenal gland. An in situ hybridization study revealed that the expression of GCX-1 was restricted to granulosa cell layers in early-stage follicles, and the expression was very low in large antral follicles and the corpus luteum, but localized expression in the testis or pituitary was not clear. Endogenous GCX-1 protein in the granulosa cells was identified by a Western blot analysis, and an analysis using the green fluorescence protein-GCX-1 fusion protein revealed that the GCX-1 protein was localized in the cell nucleus. GAL4 fusion protein-based assays demonstrated that GCX-1 is a potent transcriptional activator, and its putative transactivation domain was mapped to the region between amino acid residues 25 and 63 from the N terminus. These data strongly suggest that GCX-1 is likely a novel transcriptional activator that is exclusively expressed in reproductive tissues involving the hypothalamo-pituitary-gonadal axis, and functions as a specific regulator of follicular development, and may also participate in other specific events related to reproduction, particularly in the female.
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Affiliation(s)
- Takashi Kajitani
- Department of Biochemistry, Fukui Medical University, Matsuoka, Fukui, 910-1193, Japan
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37
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Curtin D, Ferris HA, Häkli M, Gibson M, Jänne OA, Palvimo JJ, Shupnik MA. Small nuclear RING finger protein stimulates the rat luteinizing hormone-beta promoter by interacting with Sp1 and steroidogenic factor-1 and protects from androgen suppression. Mol Endocrinol 2004; 18:1263-76. [PMID: 14988433 DOI: 10.1210/me.2003-0221] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
GnRH controls expression of the LH subunit genes, alpha and LHbeta, with the LHbeta subunit regulated most dramatically. Two enhancer regions, distal and proximal, on the rat LHbeta gene promoter cooperate for full basal expression and GnRH stimulation. It has been hypothesized that the transcription factors binding to these regions, Sp1, Egr-1, and steroidogenic factor 1 (SF-1), may interact directly or indirectly via a coactivator. One such coactivator may be small nuclear RING finger protein (SNURF), which is expressed in pituitary tissue and the LbetaT2 gonadotrope cell line. In transfection experiments in LbetaT2 cells, SNURF stimulated basal expression of LHbeta and increased overall GnRH stimulation. SNURF specifically stimulated LHbeta, with no effect on the alpha-subunit promoter. SNURF interacts with Sp1 and SF-1, but not Egr-1, in pull-down experiments. Point mutations or deletions of SNURF functional domains demonstrated that Sp1 and SF-1 interactions with SNURF are required for SNURF stimulatory effects on the LHbeta promoter. Endogenous SNURF is associated with the LHbeta promoter on native chromatin, suggesting that it plays a physiological role in LHbeta gene expression. SNURF also binds the androgen receptor, and SNURF overexpression overcomes androgen suppression of GnRH-stimulated LHbeta but not alphasubunit promoter activity. SNURF mutations that disrupt Sp1 or SF-1 binding eliminate rescue by SNURF. We conclude that SNURF may mediate interactions between the distal and proximal GnRH response regions of the LHbeta promoter to stimulate transcription and can also protect the promoter from androgen suppression.
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Affiliation(s)
- Denis Curtin
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
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38
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Ruh MF, Chrivia JC, Cox LK, Ruh TS. The interaction of the estrogen receptor with mononucleosomes. Mol Cell Endocrinol 2004; 214:71-9. [PMID: 15062546 DOI: 10.1016/j.mce.2003.11.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2003] [Accepted: 11/12/2003] [Indexed: 11/28/2022]
Abstract
To directly activate specific gene expression, the estrogen receptor (ER) must bind to estrogen receptor response elements (EREs) in the context of nucleosomes. In order to investigate the interaction of the ER with mononucleosomes, we developed a mononucleosome gel shift assay. A 164 bp high specific activity [(32)P]probe DNA (32 bp consensus ERE with flanking regions separated by 23 nucleotides from an artificial nucleosome positioning sequence) was prepared. Nuclear extracts from MCF-7 cells or recombinant human ERalpha were incubated with the labeled ERE +/- excess ERE. A retarded band was seen which was completely obliterated with excess ERE, confirming the specificity of binding. This probe was then used to make reconstituted mononucleosomes by sequential dilution of a high salt histone preparation. The nucleosomes were purified by sucrose density gradients and footprinting analysis was performed to demonstrate that the mononucleosomes were rotationally phased as seen by a periodic digestion pattern (10 bp) of the nucleosomes versus ERE. Nucleosomes were incubated with nuclear extracts containing ER or recombinant ERalpha. Dose dependence in the shift of the mononucleosomes with increasing concentrations of ER was observed. Specificity was demonstrated in experiments with excess ERE and anti-ER antibody. Footprinting analysis was also performed. We also determined that addition of high mobility group protein-2 (HMGB-2, a protein closely related to HMGB-1) with the ER increased the interaction of ER with mononucleosomes. These studies will allow us to address the interactions of ER with core histones containing a multiplicity of variants and modifications in nucleosomal structure.
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Affiliation(s)
- Mary F Ruh
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 S Grand Boulevard, St Louis, MO 63104, USA.
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39
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Melvin VS, Harrell C, Adelman JS, Kraus WL, Churchill M, Edwards DP. The role of the C-terminal extension (CTE) of the estrogen receptor alpha and beta DNA binding domain in DNA binding and interaction with HMGB. J Biol Chem 2004; 279:14763-71. [PMID: 14739282 DOI: 10.1074/jbc.m313335200] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
HMGB-1/-2 are coregulatory proteins that facilitate the DNA binding and transcriptional activity of steroid receptor members of the nuclear receptor family of transcription factors. We investigated the influence and mechanism of action of HMGB-1/-2 (formerly known as HMG-1/-2) on estrogen receptor alpha (ERalpha) and ERbeta. Both ER subtypes were responsive to HMGB-1/-2 with respect to enhancement of receptor DNA binding affinity and transcriptional activity in cells. Responsiveness to HMGB-1/-2 was dependent on the C-terminal extension (CTE) region of the ER DNA binding domain (DBD) and correlated with a direct protein interaction between HMGB-1/-2 and the CTE. Thus the previously reported higher DNA binding affinity and transcription activity of ERalpha as compared with ERbeta is not due to a lack of ERbeta interaction with HMGB-1/-2. Using chimeric receptor DBDs, the higher intrinsic DNA binding affinity of ERalpha than ERbeta was shown to be due to a unique property of the ERalpha CTE, independent of HMGB-1/-2. The CTE of both ER subtypes was also shown to be required for interaction with ERE half-sites. These studies reveal the importance of the CTE and HMGB-1/-2 for ERalpha and ERbeta interaction with their cognate target DNAs.
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Affiliation(s)
- Vida Senkus Melvin
- Molecular Biology Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
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40
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Walker CL, Hunter D, Everitt JI. Uterine leiomyoma in the Eker rat: A unique model for important diseases of women. Genes Chromosomes Cancer 2003; 38:349-56. [PMID: 14566855 DOI: 10.1002/gcc.10281] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Eker rats carry a defect in the Tsc-2 tumor suppressor gene and female Eker rats develop uterine leiomyoma with a high frequency. The presentation, response to hormones and molecular alterations in these mesenchymal smooth muscle tumors, closely resembles their cognate human disease. Female rats and tumor-derived cell lines from Eker rat leiomyomas (ELT lines) have been developed as an in vivo/in vitro model system for preclinical studies to identify novel therapeutic agents for this disease and for studying disease pathogenesis. In addition to serving as a model for uterine leiomyoma, Eker rats have proven valuable for studying lymphangioleiomyomatosis, a related proliferative smooth muscle disease of women.
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Affiliation(s)
- Cheryl Lyn Walker
- University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
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41
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Amir AL, Barua M, McKnight NC, Cheng S, Yuan X, Balk SP. A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4. J Biol Chem 2003; 278:30828-34. [PMID: 12799378 DOI: 10.1074/jbc.m301208200] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
T cell factor (Tcf) proteins bind beta-catenin and are downstream effectors of Wnt/beta-catenin signals. A recently demonstrated interaction between beta-catenin and the androgen receptor (AR) ligand binding domain has suggested that AR may be a Tcf-independent Wnt/beta-catenin effector. This study demonstrates that there is a direct interaction between the AR DNA binding domain (DBD) and Tcf4. Tcf4 bound specifically to a glutathione S-transferase-ARDBD fusion protein and could be coimmunoprecipitated with beta-catenin and transfected AR or endogenous AR in prostate cancer cells. Transfected Tcf4 repressed the transcriptional activity of full-length AR and a VP16-ARDBD fusion protein, and this repression was only partially reversed by transfected beta-catenin. AR activation by cyproterone acetate, a partial agonist that did not support beta-catenin binding to the AR, was also repressed by Tcf4, further indicating that repression was not due to beta-catenin sequestration. Tcf4 could recruit beta-catenin to the AR DBD in vitro and to the cyproterone acetate-liganded AR in vivo. Chromatin immunoprecipitation experiments in LNCaP prostate cancer cells showed that endogenous AR was bound to a Tcf4-responsive element in the c-myc promoter. These findings indicate that AR and Tcf4 can interact directly and that this interaction may occur on the promoters or enhancers of particular genes. The direct AR-Tcf4 interaction, in conjunction AR- and Tcf4-beta-catenin binding, provides a mechanism for cooperative and selective gene regulation by AR and the Wnt/beta-catenin-Tcf pathway that may contribute to normal and neoplastic prostate growth.
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Affiliation(s)
- Avital L Amir
- Cancer Biology Program, Hematology-Oncology Division, the Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
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Dasgupta A, Scovell WM. TFIIA abrogates the effects of inhibition by HMGB1 but not E1A during the early stages of assembly of the transcriptional preinitiation complex. BIOCHIMICA ET BIOPHYSICA ACTA 2003; 1627:101-10. [PMID: 12818428 DOI: 10.1016/s0167-4781(03)00080-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Successful assembly of the transcriptional preinitiation complex (PIC) is prerequisite to transcriptional initiation. At each stage of PIC assembly, regulation may occur as repressors and activators compete with and influence the incorporation of general transcription factors (GTFs). Both TFIIA and HMGB1 bind individually to the TATA-binding protein (TBP) to increase the rate of binding and to stabilize TBP binding to the TATA element. The competitive binding between these two cofactors for TBP/TATA was examined to show that TFIIA binds preferentially to TBP and inhibits HMGB1 binding. TFIIA can also readily dissociate HMGB1 from the preestablished HMGB1/TBP/TATA complex. This suggests that TFIIA and HMGB1 may bind to the same or overlapping sites on TBP and/or compete for similar DNA sites that are 5' to the TATA element. In addition, EMSA studies show that adenovirus E1A(13S) oncoprotein is unable to disrupt either the preestablished TFIIA/TBP/TATA or TFIIA/TFIIB/TBP/TATA complexes, but does inhibit complex formation when all transcription factors were simultaneously added. The inhibitory effect of E1A(13S) on the assembly of the PIC is overcome when excess TBP is added back in the reaction, while addition of either excess TFIIA or TFIIB were ineffective. This shows that the main target for E1A(13S) is free TBP and emphasizes the primary competition between E1A and the TATA-element for unbound TBP. This may be the principal point, if not the only point, at which E1A can target TBP to exert its inhibitory effect. This work, coupled with previous findings in our laboratory, indicates that TFIIA is much more effective than TFIIB in reversing the inhibitory effect of HMGB1 binding in the early stages of PIC assembly, which is consistent with the in vitro transcription results.
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Affiliation(s)
- A Dasgupta
- Department of Biological Sciences, Bowling Green State University, Bowling Green, OH 43403-0213, USA
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43
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Klass J, Murphy FV, Fouts S, Serenil M, Changela A, Siple J, Churchill MEA. The role of intercalating residues in chromosomal high-mobility-group protein DNA binding, bending and specificity. Nucleic Acids Res 2003; 31:2852-64. [PMID: 12771212 PMCID: PMC156723 DOI: 10.1093/nar/gkg389] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Ubiquitous high-mobility-group (HMGB) chromosomal proteins bind DNA in a non-sequence- specific fashion to promote chromatin function and gene regulation. Minor groove DNA binding of the HMG domain induces substantial DNA bending toward the major groove, and several interfacial residues contribute by DNA intercalation. The role of the intercalating residues in DNA binding, bending and specificity was systematically examined for a series of mutant Drosophila HMGB (HMG-D) proteins. The primary intercalating residue of HMG-D, Met13, is required both for high-affinity DNA binding and normal DNA bending. Leu9 and Tyr12 directly interact with Met13 and are required for HMG domain stability in addition to linear DNA binding and bending, which is an important function for these residues. In contrast, DNA binding and bending is retained in truncations of intercalating residues Val32 and Thr33 to alanine, but DNA bending is decreased for the glycine substitutions. Furthermore, substitution of the intercalating residues with those predicted to be involved in the specificity of the HMG domain transcription factors results in increased DNA affinity and decreased DNA bending without increased specificity. These studies reveal the importance of residues that buttress intercalating residues and suggest that features of the HMG domain other than a few base-specific hydrogen bonds distinguish the sequence-specific and non-sequence-specific HMG domain functions.
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Affiliation(s)
- Janet Klass
- Department of Pharmacology, The University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
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44
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Pullerits R, Jonsson IM, Verdrengh M, Bokarewa M, Andersson U, Erlandsson-Harris H, Tarkowski A. High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis. ARTHRITIS AND RHEUMATISM 2003; 48:1693-700. [PMID: 12794838 DOI: 10.1002/art.11028] [Citation(s) in RCA: 140] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis. METHODS Mice were injected intraarticularly with 1 microg or 5 microg of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor kappaB (NF-kappaB) activation was detected by electrophoretic mobility shift assay. RESULTS Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-kappaB, a major pathway leading to IL-1 production. CONCLUSION Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-kappaB activation.
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Affiliation(s)
- Rille Pullerits
- Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Gothenburg, Sweden.
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45
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Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X, Harris HE, Czura CJ, Wang H, Ulloa L, Wang H, Warren HS, Moldawer LL, Fink MP, Andersson U, Tracey KJ, Yang H. Structural Basis for the Proinflammatory Cytokine Activity of High Mobility Group Box 1. Mol Med 2003. [DOI: 10.1007/bf03402105] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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46
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Hentschke M, Süsens U, Borgmeyer U. Domains of ERRgamma that mediate homodimerization and interaction with factors stimulating DNA binding. EUROPEAN JOURNAL OF BIOCHEMISTRY 2002; 269:4086-97. [PMID: 12180985 DOI: 10.1046/j.1432-1033.2002.03102.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The estrogen receptor-related receptor gamma (ERRgamma/ERR3/NR3B3) is an orphan member of the nuclear receptor superfamily closely related to the estrogen receptors. To explore the DNA binding characteristics, the protein-DNA interaction was studied in electrophoretic mobility shift assays (EMSAs). In vitro translated ERRgamma binds as a homodimer to direct repeats (DR) without spacing of the nuclear receptor half-site 5'-AGGTCA-3' (DR-0), to extended half-sites, and to the inverted estrogen response element. Using ERRgamma deletion constructs, binding was found to be dependent on the presence of sequences in the ligand binding domain (LBD). A far-Western analysis revealed that ERRgamma forms dimers even in the absence of DNA. Two elements, located in the hinge region and in the LBD, respectively, are necessary for DNA-independent dimerization. DNA binding of bacterial expressed ERRgamma requires additional factors present in the serum and in cellular extracts. Fusion proteins of the germ cell nuclear factor (GCNF/NR6A1) with ERRgamma showed that the characteristic feature to be stimulated by additional factors can be transferred to a heterologous protein. The stimulating activity was further characterized and its target sequence narrowed down to a small element in the hinge region.
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Affiliation(s)
- Moritz Hentschke
- Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Universität Hamburg, Germany
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47
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Melvin VS, Roemer SC, Churchill MEA, Edwards DP. The C-terminal extension (CTE) of the nuclear hormone receptor DNA binding domain determines interactions and functional response to the HMGB-1/-2 co-regulatory proteins. J Biol Chem 2002; 277:25115-24. [PMID: 12006575 DOI: 10.1074/jbc.m110400200] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Previously, we and others reported that the high mobility group proteins, HMGB-1/-2, enhance DNA binding in vitro and transactivation in situ by the steroid hormone subgroup of nuclear receptors but did not influence these functions of class II receptors. We show here that the DNA binding domain (DBD) is sufficient to account for the selective influence of HMGB-1/-2 on the steroid class of receptors. Furthermore, the use of chimeric DBDs reveals that this selectivity is dependent on the C-terminal extension (CTE), amino acid sequences adjacent to the zinc finger core DBD. HMGB-1/-2 interact directly with the DBDs of steroid but not class II receptors, and this interaction requires the CTE. This in vitro interaction correlates with a requirement of the CTE for maximal HMGB-1/-2 enhancement of DNA binding in vitro and transcriptional activation in cells. Finally, class II receptor DBDs have a much higher intrinsic affinity for DNA than steroid receptor DBDs, and this affinity difference is also dependent on the CTE. These results reveal the importance of the steroid receptor CTE for DNA binding affinity and functional response to HMGB-1/-2.
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Affiliation(s)
- Vida Senkus Melvin
- Program in Molecular Biology and the Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA
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48
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Fang WH, Yao YM, Shi ZG, Yu Y, Wu Y, Lu LR, Sheng ZY. The significance of changes in high mobility group-1 protein mRNA expression in rats after thermal injury. Shock 2002; 17:329-33. [PMID: 11954836 DOI: 10.1097/00024382-200204000-00016] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There has been a widespread impression that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mediate the toxicity of high doses of lipopolysaccharide (LPS, endotoxin) and are key factors in septic shock. However, the clinical efficacy of treatment with antagonists of TNF-alpha and IL-1beta is still controversial, suggesting that mediators other than TNF-alpha and IL-1beta might contribute causally to endotoxin-induced death. Recent studies implicated high mobility group-1 (HMG-1) protein as a late mediator of endotoxin lethality in mice. However, the role of HMG-1 in mediating multiple organ damage-associating trauma has not been studied. This study was designed to investigate changes in HMG-1 gene expression in vital organs, and its potential role in mediating multiple organ damage following major burns. Wistar rats were subjected to a 35 percent full-thickness thermal injury, and randomly divided into three groups as follows: normal controls (n = 7), thermal injury (n = 24), and recombinant bactericidal/permeability-increasing protein (rBPI21) treatment (n = 12). Tissue samples from liver and lungs were collected to measure tissue endotoxin levels and HMG-1 mRNA expression. In addition, blood samples were obtained for measurement of organ function parameters. Our data demonstrated a significant increase in HMG-1 gene expression in tissues at 24 h postburn, which remained markedly elevated up to 72 h after thermal injury (P< 0.05-0.01). Treatment with rBPI21 could significantly decrease tissue HMG-1 mRNA expression in the liver and lung (P < 0.01). In addition, there were high positive correlations between hepatic HMG-1 mRNA and serum aminoleucine transferase (ALT) and aspartate aminotransferase (AST) levels, and also between pulmonary HMG-1 mRNA and myeloperoxidase activities (P < 0.05-0.01). Taken together, these findings indicate that thermal injury per se can markedly enhance HMG-1 gene expression in various organs. Up-regulation of HMG-1 expression may be involved in the pathogenesis of endogenous endotoxin-mediated multiple organ damage secondary to major burns.
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Affiliation(s)
- Wen-Hui Fang
- The Department of Microbiology and Immunology, Trauma Research Center, Postgraduate Medical College, Beijing, People's Republic of China
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49
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Abstract
Overcoming local DNA rigidity is required to perform three-dimensional DNA-protein configuration at promoter regions. The abundant architectural nonhistone chromosomal HMG box proteins are nonsequence-specific; however, they have been established to specifically recognize distorted DNA. Using transient transfection to overexpress two different members of the HMGB-1/2 family of DNA architectural factors, we demonstrate that these proteins provide a general enhancement in reporter gene expression irrespective of the promoter being considered. Evidences are also provided indicating that stimulation may not be achieved by recruitment of the proteins by regulatory factors or as a consequence of major chromatin unfolding as previously suggested. Interestingly, the influence of the HMG box proteins under study was overridden when the promoters were either induced or stimulated by Trichostatin A (TSA) but recovered upon extended induction period. These results also support the concept that the architectural role of these proteins can contribute to the preinitiation complex assembly required for basal transcription, but to a much lesser extent to the poised promoter scaffolding characteristic of activated transcription.
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Affiliation(s)
- Stéphane Veilleux
- Département de Biochimie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
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50
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Saville B, Poukka H, Wormke M, Janne OA, Palvimo JJ, Stoner M, Samudio I, Safe S. Cooperative coactivation of estrogen receptor alpha in ZR-75 human breast cancer cells by SNURF and TATA-binding protein. J Biol Chem 2002; 277:2485-97. [PMID: 11696545 DOI: 10.1074/jbc.m109021200] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
SNURF is a small RING finger protein that binds the zinc finger region of steroid hormone receptors and enhances Sp1- and androgen receptor-mediated transcription in COS and CV-1 cells. In this study, we show that SNURF coactivates both wild-type estrogen receptor alpha (ERalpha) (4-fold)- and HE19 (ERalpha deletion of activation function 1 (AF1)) (210-fold)-mediated activation of an estrogen-responsive element promoter in ZR-75 cells. In mammalian two-hybrid assays in ZR-75 cells SNURF interactions were estrogen (E2)-dependent and were not observed with the antiestrogen ICI 182,780. ERalpha interacted with multiple regions of SNURF; SNURF interactions with ERalpha were dependent on AF2, and D538N, E542Q, and D545N mutations in helix 12 abrogated both SNURF-ERalpha binding and coactivation. Moreover, peptide fusion proteins that inhibit interactions between helix 12 of ERalpha with LXXLL box-containing proteins also blocked ERalpha coactivation by SNURF. However, cotransfection of SNURF with prototypical steroid receptor coactivators 1, 2, and 3 that contain LXXLL box motifs did not enhance E2 responsiveness, whereas TATA-binding protein (TBP) and SNURF cooperatively coactivated ERalpha-mediated transactivation. The results are consistent with a unique model for cooperative coactivation of ERalpha that requires ligand binding, repositioning of helix 12, recruitment of TBP, and interaction with SNURF, which binds both ERalpha and TBP.
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Affiliation(s)
- Bradley Saville
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA
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