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Yu J, Zhang Z, Chen Y, Wang J, Li G, Tao Y, Zhang Y, Yang Y, Zhang C, Li T, Cheng J, Ji T, Wei Z, Wang W, Fang F, Jiang W, Chu P, Yin H, Wu D, Li X, Wang X, Fan J, Hu S, Zhu Z, Wu S, Lu J, Pan J. Super-Enhancer-Driven IRF2BP2 is Activated by Master Transcription Factors and Sustains T-ALL Cell Growth and Survival. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407113. [PMID: 39454110 PMCID: PMC11714186 DOI: 10.1002/advs.202407113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/10/2024] [Indexed: 10/27/2024]
Abstract
Super enhancers (SEs) are large clusters of transcriptional enhancers driving the expression of genes crucial for defining cell identity. In cancer, tumor-specific SEs activate key oncogenes, leading to tumorigenesis. Identifying SE-driven oncogenes in tumors and understanding their functional mechanisms is of significant importance. In this study, a previously unreported SE region is identified in T-cell acute lymphoblastic leukemia (T-ALL) patient samples and cell lines. This SE activates the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2) and is regulated by T-ALL master transcription factors (TFs) such as ETS transcription factor ERG (ERG), E74 like ETS transcription factor 1 (ELF1), and ETS proto-oncogene 1, transcription factor (ETS1). Hematopoietic system-specific IRF2BP2 conditional knockout mice is generated and showed that IRF2BP2 has minimal impact on normal T cell development. However, in vitro and in vivo experiments demonstrated that IRF2BP2 is crucial for T-ALL cell growth and survival. Loss of IRF2BP2 affects the MYC and E2F pathways in T-ALL cells. Cleavage under targets and tagmentation (CUT&Tag) assays and immunoprecipitation revealed that IRF2BP2 cooperates with the master TFs of T-ALL cells, targeting the enhancer of the T-ALL susceptibility gene recombination activating 1 (RAG1) and modulating its expression. These findings provide new insights into the regulatory network within T-ALL cells, identifying potential new targets for therapeutic intervention.
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Affiliation(s)
- Juanjuan Yu
- Children's Hospital of Soochow UniversitySuzhou215003China
| | - Zimu Zhang
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Yanling Chen
- Children's Hospital of Soochow UniversitySuzhou215003China
| | - Jianwei Wang
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Gen Li
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Yanfang Tao
- Department of Traditional Chinese MedicineChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Yongping Zhang
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Yang Yang
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Chenyue Zhang
- Children's Hospital of Soochow UniversitySuzhou215003China
| | - Tiandan Li
- Children's Hospital of Soochow UniversitySuzhou215003China
| | - Jia Cheng
- Children's Hospital of Soochow UniversitySuzhou215003China
| | - Tongtign Ji
- Children's Hospital of Soochow UniversitySuzhou215003China
| | - Zhongling Wei
- Department of HematologyChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Wenjuan Wang
- Department of PharmacyChildren's Hospital of Soochow UniversitySuzhouJiangsu215025China
| | - Fang Fang
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Wei Jiang
- Department of PediatricsTaizhou Municipal HospitalNo. 581 Shifu RoadTai zhouZhejiang318000China
| | - Peipei Chu
- Department of PediatricsSuzhou Wujiang District Children HospitalNo.176 Garden RoadSuzhouJiangsu215200China
| | - Hongli Yin
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Di Wu
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Xiaolu Li
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Xiaodong Wang
- Department of OrthopaedicsChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Jun‐Jie Fan
- Department of HematologyChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Shaoyan Hu
- Department of HematologyChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Zhen‐Hong Zhu
- Burn and Plastic SurgeryChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Shuiyan Wu
- Pediatric Intensive Care UnitChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Jun Lu
- Department of HematologyChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
| | - Jian Pan
- Institute of Pediatric ResearchChildren's Hospital of Soochow UniversitySuzhouJiangsu215003China
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Colorectal Cancer Diagnosis: The Obstacles We Face in Determining a Non-Invasive Test and Current Advances in Biomarker Detection. Cancers (Basel) 2022; 14:cancers14081889. [PMID: 35454792 PMCID: PMC9029324 DOI: 10.3390/cancers14081889] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancers in the western world. CRC originates from precursor adenomatous polyps, which may over time develop into cancer. Endoscopic evaluation remains the gold-standard investigation for the disease. In the absence of molecular tools for early detection, the removal of neoplastic adenomas via polypectomy remains an important measure to prevent dysplastic adenomas from evolving into invasive carcinoma. Colonoscopy is an intrusive procedure that provides an uncomfortable experience for patients. Kits for testing for the presence of blood hemoglobin in the stool are now widely used, and DNA methylation-based detection kits have been approved in the USA for testing the stool and plasma, but few other molecular biomarkers have found their way into medical practice. This review summarizes current trends in the detection and screening of CRC and provides a definitive review of emerging molecular biomarkers for CRC. Abstract Globally, colorectal cancer (CRC) is the third most common cancer, with 1.4 million new cases and over 700,000 deaths per annum. Despite being one of the most common cancers, few molecular approaches to detect CRC exist. Carcinoembryonic antigen (CEA) is a known serum biomarker that is used in CRC for monitoring disease recurrence or response to treatment. However, it can also be raised in multiple benign conditions, thus having no value in early detection or screening for CRC. Molecular biomarkers play an ever-increasing role in the diagnosis, prognosis, and outcome prediction of disease, however, only a limited number of biomarkers are available and none are suitable for early detection and screening of CRC. A PCR-based Epi proColon® blood plasma test for the detection of methylated SEPT9 has been approved by the USFDA for CRC screening in the USA, alongside a stool test for methylated DNA from CRC cells. However, these are reserved for patients who decline traditional screening methods. There remains an urgent need for the development of non-invasive molecular biomarkers that are highly specific and sensitive to CRC and that can be used routinely for early detection and screening. A molecular approach to the discovery of CRC biomarkers focuses on the analysis of the transcriptome of cancer cells to identify differentially expressed genes and proteins. A systematic search of the literature yielded over 100 differentially expressed CRC molecular markers, of which the vast majority are overexpressed in CRC. In terms of function, they largely belong to biological pathways involved in cell division, regulation of gene expression, or cell proliferation, to name a few. This review evaluates the current methods used for CRC screening, current availability of biomarkers, and new advances within the field of biomarker detection for screening and early diagnosis of CRC.
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Primary Cilia and Their Role in Acquired Heart Disease. Cells 2022; 11:cells11060960. [PMID: 35326411 PMCID: PMC8946116 DOI: 10.3390/cells11060960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/10/2022] Open
Abstract
Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. Adults with congenital heart disease have high rates of acquired heart failure, and usually die from a cardiac cause. Here we explore primary cilia’s role in acquired heart disease. Intraflagellar Transport 88 knockout results in reduced primary cilia, and knockout from cardiac endothelium produces myxomatous degeneration similar to mitral valve prolapse seen in adult humans. Induced primary cilia inactivation by other mechanisms also produces excess myocardial hypertrophy and altered scar architecture after ischemic injury, as well as hypertension due to a lack of vascular endothelial nitric oxide synthase activation and the resultant left ventricular dysfunction. Finally, primary cilia have cell-to-cell transmission capacity which, when blocked, leads to progressive left ventricular hypertrophy and heart failure, though this mechanism has not been fully established. Further research is still needed to understand primary cilia’s role in adult cardiac pathology, especially heart failure.
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Drexler HG, Nagel S, Quentmeier H. Leukemia Cell Lines: In Vitro Models for the Study of Chronic Neutrophilic Leukemia. ACTA ACUST UNITED AC 2021; 28:1790-1794. [PMID: 34068566 PMCID: PMC8161829 DOI: 10.3390/curroncol28030166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 11/16/2022]
Abstract
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm that is genetically characterized by the absence of both the Philadelphia chromosome and BCR-ABL1 fusion gene and the high prevalence of mutations in the colony-stimulating factor 3 receptor (CSF3R). Additional disease-modifying mutations have been recognized in CNL samples, portraying a distinct mutational landscape. Despite the growing knowledge base on genomic aberrations, further progress could be gained from the availability of representative models of CNL. To address this gap, we screened a large panel of available leukemia cell lines, followed by a detailed mutational investigation with focus on the CNL-associated candidate driver genes. The sister cell lines CNLBC-1 and MOLM-20 were derived from a patient with CNL and carry CNL-typical molecular hallmarks, namely mutations in several genes, such as CSF3R, ASXL1, EZH2, NRAS, and SETBP1. The use of these validated and comprehensively characterized models will benefit the understanding of the pathobiology of CNL and help inform therapeutic strategies.
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Affiliation(s)
- Hans G. Drexler
- Faculty of Life Sciences, Technical University of Braunschweig, 38106 Braunschweig, Germany
- Correspondence:
| | - Stefan Nagel
- Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany; (S.N.); (H.Q.)
| | - Hilmar Quentmeier
- Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany; (S.N.); (H.Q.)
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Sun J, Zheng MY, Li YW, Zhang SW. Structure and function of Septin 9 and its role in human malignant tumors. World J Gastrointest Oncol 2020; 12:619-631. [PMID: 32699577 PMCID: PMC7340996 DOI: 10.4251/wjgo.v12.i6.619] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/03/2020] [Accepted: 04/25/2020] [Indexed: 02/05/2023] Open
Abstract
The treatment and prognosis of malignant tumors are closely related to the time when the tumors are diagnosed; the earlier the diagnosis of the tumor, the better the prognosis. However, most tumors are not detected in the early stages of screening and diagnosis. It is of great clinical significance to study the correlation between multiple pathogeneses of tumors and explore simple, safe, specific, and sensitive molecular indicators for early screening, diagnosis, and prognosis. The Septin 9 (SEPT9) gene has been found to be associated with a variety of human diseases, and it plays a role in the development of tumors. SEPT9 is a member of the conserved family of cytoskeletal GTPase, which consists of a P-loop-based GTP-binding domain flanked by a variable N-terminal region and a C-terminal region. SEPT9 is involved in many biological processes such as cytokinesis, polarization, vesicle trafficking, membrane reconstruction, deoxyribonucleic acid repair, cell migration, and apoptosis. Several studies have shown that SEPT9 may serve as a marker for early screening, diagnosis, and prognosis of some malignant tumors, and have the potential to become a new target for anti-cancer therapy. This article reviews the progress in research on the SEPT9 gene in early screening, diagnosis, and prognosis of tumors.
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Affiliation(s)
- Jie Sun
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
| | - Min-Ying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
| | - Yu-Wei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Shi-Wu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300121, China
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Pang SW, Awi NJ, Armon S, Lim WWD, Low JSH, Peh KB, Peh SC, Teow SY. Current Update of Laboratory Molecular Diagnostics Advancement in Management of Colorectal Cancer (CRC). Diagnostics (Basel) 2019; 10:E9. [PMID: 31877940 PMCID: PMC7168209 DOI: 10.3390/diagnostics10010009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/11/2019] [Accepted: 11/23/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the most common cancers globally. The incidence has increased in developing countries in the past few decades, this could be partly attributed to aging populations and unhealthy lifestyles. While the treatment of CRC has seen significant improvement since the advent of target-specific therapies and personalized medicine, CRC is oftentimes detected at late or advanced stages, thereby reducing the efficacy of treatment. Hence, screening for early detection is still the key to combat CRC and to increase overall survival (OS). Considering that the field of medical diagnostics is moving towards molecular diagnostics, CRC can now be effectively screened and diagnosed with high accuracy and sensitivity. Depending on the tumor genotype and genetic profile of the individual, personalized treatments including tyrosine kinase inhibitor therapy and immunotherapy can be administered. Notably, there can be no one single treatment that is effective for all CRC patients due to the variation in tumor genetics, which highlights the importance of molecular diagnostics. This review provides insights on therapeutic modalities, molecular biomarkers, advancement of diagnostic technologies, and current challenges in managing CRC.
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Affiliation(s)
- Siew-Wai Pang
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Noel Jacques Awi
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Subasri Armon
- Pathology Department, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur 50588, Malaysia
| | - Wendy Wan-Dee Lim
- Sunway Medical Centre, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - John Seng-Hooi Low
- Sunway Medical Centre, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Kaik-Boo Peh
- Mahkota Medical Centre, Mahkota Melaka, Jalan Merdeka, Melaka 75000, Malaysia
| | - Suat-Cheng Peh
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
- Sunway Medical Centre, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Sin-Yeang Teow
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
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Desterke C, Gassama-Diagne A. Protein-protein interaction analysis highlights the role of septins in membrane enclosed lumen and mRNA processing. Adv Biol Regul 2019; 73:100635. [PMID: 31420262 DOI: 10.1016/j.jbior.2019.100635] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/01/2019] [Accepted: 07/04/2019] [Indexed: 06/10/2023]
Abstract
Septins are a family of GTP-binding proteins that assemble into non-polar filaments which can be recruited to negatively charged membranes and serve as a scaffold to recruit cytosolic proteins and cytoskeletal elements such as microtubules and actin so that they can perform their important biological functions. Human septins consist of four groups, each with 13 members, and filaments formation usually involve members from each group in specific positions. However, little is known about the molecular mechanisms that drive the binding of septins to membranes and its importance to their biological functions. Here we have built a protein-protein interaction (PPI) network around human septins and highlighted the connections with 170 partners. Functional enrichment by inference of the network of septins and their partners revealed their participation in functions consistent with some of the roles described for septins, including cell cycle, cell division and cell shape, but we also identified septin partners in these functions that had not previously been described. Interestingly, we identified important and multiple connections between septins and mRNA processing and their export from the nucleus. Analysis of the enrichment of gene ontology cellular components highlighted some important interactions between molecules involved in the spliceosome with septin 2 and septin 7 in particular. RNA splicing regulates gene expression, and through it, cell fate, development and physiology. Mutations in components of the in the splicing machinery is linked to several diseases including cancer, thus taken together, the different analyses presented here open new perspectives to elucidate the pathobiological role of septins.
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Affiliation(s)
| | - Ama Gassama-Diagne
- INSERM, Unité 1193, Villejuif, F-94800, France; Université Paris-Sud, UMR-S 1193, Villejuif, F-94800, France.
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Elzamly S, Chavali S, Tonk V, Tonk S, Gaur S, Tarango D, Torabi A. Acute myeloid leukemia with KMT2A-SEPT5 translocation: A case report and review of the literature. SAGE Open Med Case Rep 2018; 6:2050313X17750334. [PMID: 29326822 PMCID: PMC5758965 DOI: 10.1177/2050313x17750334] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 11/22/2017] [Indexed: 01/11/2023] Open
Abstract
Chromosomal rearrangement involving the KMT2A gene is one of the most common genetic alteration in acute myeloid leukemia. A total of 135 different KMT2A rearrangements have been identified, where 94 translocation partner genes are now characterized at the molecular level. Of these 94 translocation partner genes, 35 translocation partner genes occur recurrently, but only 9 specific gene fusions account for more than 90% of cases. Translocation of KMT2A with SEPT5 gene at 22q11.2 is rare, with few reported cases in the literature. In this report, we are presenting a case of KMT2A-SEPT5 fusion in de novo acute myeloid leukemia with t(11;22)(q23;q11.2) with a review of the literature.
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Affiliation(s)
- Shaimaa Elzamly
- Pathology Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Santosh Chavali
- Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, TX, USA
| | - Vijay Tonk
- Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, TX, USA
| | - Sahil Tonk
- Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, TX, USA
| | - Sumit Gaur
- Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX, USA
| | - Darlene Tarango
- Department of Pathology, Texas Tech University Health Science Center, El Paso, TX, USA
| | - Alireza Torabi
- Department of Pathology, Texas Tech University Health Science Center, El Paso, TX, USA
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Son HY, Hwangbo Y, Yoo SK, Im SW, Yang SD, Kwak SJ, Park MS, Kwak SH, Cho SW, Ryu JS, Kim J, Jung YS, Kim TH, Kim SJ, Lee KE, Park DJ, Cho NH, Sung J, Seo JS, Lee EK, Park YJ, Kim JI. Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer. Nat Commun 2017; 8:15966. [PMID: 28703219 PMCID: PMC5511346 DOI: 10.1038/ncomms15966] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 05/16/2017] [Indexed: 01/12/2023] Open
Abstract
Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10-10) and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, we confirmed three previously reported loci (FOXE1, NKX2-1 and DIRC3) and identified seven novel susceptibility loci (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11 and SLC24A6) associated with DTC. Furthermore, we identified specific variants of DTC that have different effects according to cancer type or ethnicity. Our findings provide deeper insight into the genetic contribution to thyroid cancer in different populations.
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Affiliation(s)
- Ho-Young Son
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
| | - Yul Hwangbo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Center for Thyroid Cancer, National Cancer Center, Goyang 10408, Republic of Korea
| | - Seong-Keun Yoo
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea
| | - Sun-Wha Im
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
| | - San Duk Yang
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea
| | - Soo-Jung Kwak
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea
| | - Min Seon Park
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
- Graduate Program in Genetic Counseling, Northwestern University, Chicago, Illinois 60637, USA
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sun Wook Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jun Sun Ryu
- Center for Thyroid Cancer, National Cancer Center, Goyang 10408, Republic of Korea
| | - Jeongseon Kim
- Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
| | - Yuh-Seog Jung
- Center for Thyroid Cancer, National Cancer Center, Goyang 10408, Republic of Korea
| | - Tae Hyun Kim
- Center for Thyroid Cancer, National Cancer Center, Goyang 10408, Republic of Korea
| | - Su-jin Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Kyu Eun Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Do Joon Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Nam Han Cho
- Department of Preventive Medicine Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Joohon Sung
- Department of Epidemiology and Institute of Environment and Health, School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
| | - Jeong-Sun Seo
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea
| | - Eun Kyung Lee
- Center for Thyroid Cancer, National Cancer Center, Goyang 10408, Republic of Korea
| | - Young Joo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea
| | - Jong-Il Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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Abstract
Septins are GTP-binding and membrane-interacting proteins with a highly conserved domain structure involved in various cellular processes, including cytoskeleton organization, cytokinesis, and membrane dynamics. To date, 13 different septin genes have been identified in mammals (SEPT1 to SEPT12 and SEPT14), which can be classified into four distinct subgroups based on the sequence homology of their domain structure (SEPT2, SEPT3, SEPT6, and SEPT7 subgroup). The family members of these subgroups have a strong affinity for other septins and form apolar tri-, hexa-, or octameric complexes consisting of multiple septin polypeptides. The first characterized core complex is the hetero-trimer SEPT2-6-7. Within these complexes single septins can be exchanged in a subgroup-specific manner. Hexamers contain SEPT2 and SEPT6 subgroup members and SEPT7 in two copies each whereas the octamers additionally comprise two SEPT9 subgroup septins. The various isoforms seem to determine the function and regulation of the septin complex. Septins self-assemble into higher-order structures, including filaments and rings in orders, which are typical for different cell types. Misregulation of septins leads to human diseases such as neurodegenerative and bleeding disorders. In non-dividing cells such as neuronal tissue and platelets septins have been associated with exocytosis. However, many mechanistic details and roles attributed to septins are poorly understood. We describe here some important mammalian septin interactions with a special focus on the clinically relevant septin interactions.
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Affiliation(s)
- Katharina Neubauer
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center-University of Freiburg Freiburg, Germany
| | - Barbara Zieger
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center-University of Freiburg Freiburg, Germany
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Abstract
Interest in the biology of mammalian septin proteins has undergone a birth in recent years. Originally identified as critical for yeast budding throughout the 1970s, the septin family is now recognized to extend from yeast to humans and is associated with a variety of events ranging from cytokinesis to vesicle trafficking. An emerging theme for septins is their presence at sites where active membrane or cytoplasmic partitioning is occurring. Here, we briefly review the mammalian septin protein family and focus on a prototypic human and mouse septin, termed SEPT5, that is expressed in the brain, heart, and megakaryocytes. Work from neurobiology laboratories has linked SEPT5 to the exocytic complex of neurons, with implications that SEPT5 regulates neurotransmitter release. Striking similarities exist between neurotransmitter release and the platelet-release reaction, which is a critical step in platelet response to vascular injury. Work from our laboratory has characterized the platelet phenotype from mice containing a targeted deletion of SEPT5. Most strikingly, platelets from SEPT5null animals aggregate and release granular contents in response to subthreshold levels of agonists. Thus, the characterization of a SEPT5-deficient mouse has linked SEPT5 to the Platelet exocytic process and, as such, illustrates it as an important protein for regulating platelet function. Recent data suggest that platelets contain a wide repertoire of different septin proteins and assemble to form macromolecular septin complexes. The mouse platelet provides an experimental framework to define septin function in hemostasis, with implications for neurobiology and beyond.
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Affiliation(s)
- Constantino Martinez
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA
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12
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Behrouz Sharif S, Hashemzadeh S, Mousavi Ardehaie R, Eftekharsadat A, Ghojazadeh M, Mehrtash AH, Estiar MA, Teimoori-Toolabi L, Sakhinia E. Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker. Oncol Lett 2016; 12:5335-5343. [PMID: 28105243 DOI: 10.3892/ol.2016.5327] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Accepted: 08/26/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies, and the third leading cause of cancer mortality worldwide. Timely detection of CRC in patients with earlier stages provides the highest rate of survival. Epigenetic alterations are important in the occurrence and progression of CRC, and represent the primary modifications of cancer cells. Therefore, detection of these alterations in CRC cases are thought to hold great promise as diagnostic biomarkers. It has been shown that the SEPT9 and NTRK3 genes are aberrantly methylated and their detection can be used as biomarkers for early diagnosis of CRC. The present study analyzed promoter methylation status of these genes in CRC patients. Genomic DNA was extracted from 45 CRC and paired adjacent healthy tissues and undergone bisulfite conversion, and the methylation status of NTRK3 and SEPT9 were defined using the MS-HRM assay. Our results showed that there are statistically significant differences in methylation status of NTRK3 and specially SEPT9 between CRC and adjacent normal tissues (P<0.001). High sensitivity and specificity for a specific location in SEPT9 gene promoter as a diagnostic biomarker was observed. SEPT9 promoter hypermethylation may serve as a promising biomarker for the detection of CRC development. However, to validate the biomarker potential of NTRK3 there is a requirement for further investigation.
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Affiliation(s)
- Shahin Behrouz Sharif
- Department of Biochemistry and Clinical Laboratory, Division of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; Department of Molecular Medicine, Pasteur Institute of Iran, Tehran 1316943551, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614731, Iran
| | - Shahriar Hashemzadeh
- Department of General & Vascular Surgery, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Reza Mousavi Ardehaie
- Department of Biochemistry and Clinical Laboratory, Division of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; Department of Molecular Medicine, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Amirtaher Eftekharsadat
- Department of Pathology, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Mortaza Ghojazadeh
- Liver and Gastrointestinal Disease Research Center and Department of General and Thoracic Surgery, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
| | - Amir Hossein Mehrtash
- Department of Molecular Medicine, Pasteur Institute of Iran, Tehran 1316943551, Iran
| | - Mehrdad Asghari Estiar
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran 1471613151, Iran
| | | | - Ebrahim Sakhinia
- Department of Biochemistry and Clinical Laboratory, Division of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran
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Fung KYY, Dai L, Trimble WS. Cell and molecular biology of septins. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2014; 310:289-339. [PMID: 24725429 DOI: 10.1016/b978-0-12-800180-6.00007-4] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Septins are a family of GTP-binding proteins that assemble into cytoskeletal filaments. Unlike other cytoskeletal components, septins form ordered arrays of defined stoichiometry that can polymerize into long filaments and bundle laterally. Septins associate directly with membranes and have been implicated in providing membrane stability and serving as diffusion barriers for membrane proteins. In addition, septins bind other proteins and have been shown to function as multimolecular scaffolds by recruiting components of signaling pathways. Remarkably, septins participate in a spectrum of cellular processes including cytokinesis, ciliogenesis, cell migration, polarity, and cell-pathogen interactions. Given their breadth of functions, it is not surprising that septin abnormalities have also been linked to human diseases. In this review, we discuss the current knowledge of septin structure, assembly and function, and discuss these in the context of human disease.
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Affiliation(s)
- Karen Y Y Fung
- Cell Biology Program, Hospital for Sick Children, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada
| | - Lu Dai
- Cell Biology Program, Hospital for Sick Children, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada
| | - William S Trimble
- Cell Biology Program, Hospital for Sick Children, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
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14
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Tóth K, Wasserkort R, Sipos F, Kalmár A, Wichmann B, Leiszter K, Valcz G, Juhász M, Miheller P, Patai ÁV, Tulassay Z, Molnár B. Detection of methylated septin 9 in tissue and plasma of colorectal patients with neoplasia and the relationship to the amount of circulating cell-free DNA. PLoS One 2014; 9:e115415. [PMID: 25526039 PMCID: PMC4272286 DOI: 10.1371/journal.pone.0115415] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 11/23/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Determination of methylated Septin 9 (mSEPT9) in plasma has been shown to be a sensitive and specific biomarker for colorectal cancer (CRC). However, the relationship between methylated DNA in plasma and colon tissue of the same subjects has not been reported. METHODS Plasma and matching biopsy samples were collected from 24 patients with no evidence of disease (NED), 26 patients with adenoma and 34 patients with CRC. Following bisulfite conversion of DNA a commercial RT-PCR assay was used to determine the total amount of DNA in each sample and the fraction of mSEPT9 DNA. The Septin-9 protein was assessed using immunohistochemistry. RESULTS The percent of methylated reference (PMR) values for SEPT9 above a PMR threshold of 1% were detected in 4.2% (1/24) of NED, 100% (26/26) of adenoma and 97.1% (33/34) of CRC tissues. PMR differences between NED vs. adenoma and NED vs. CRC comparisons were significant (p<0.001). In matching plasma samples using a PMR cut-off level of 0.01%, SEPT9 methylation was 8.3% (2/24) of NED, 30.8% (8/26) of adenoma and 88.2% (30/34) of CRC. Significant PMR differences were observed between NED vs. CRC (p<0.01) and adenoma vs. CRC (p<0.01). Significant differences (p<0.01) were found in the amount of cfDNA (circulating cell-free DNA) between NED and CRC, and a modest correlation was observed between mSEPT9 concentration and cfDNA of cancer (R2 = 0.48). The level of Septin-9 protein in tissues was inversely correlated to mSEPT9 levels with abundant expression in normals, and diminished expression in adenomas and tumors. CONCLUSIONS Methylated SEPT9 was detected in all tissue samples. In plasma samples, elevated mSEPT9 values were detected in CRC, but not in adenomas. Tissue levels of mSEPT9 alone are not sufficient to predict mSEPT9 levels in plasma. Additional parameters including the amount of cfDNA in plasma appear to also play a role.
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Affiliation(s)
- Kinga Tóth
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
- * E-mail:
| | | | - Ferenc Sipos
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Alexandra Kalmár
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
- Molecular Medicine Research Unit, Hungarian Academy of Sciences, Budapest, Hungary
| | - Barnabás Wichmann
- Molecular Medicine Research Unit, Hungarian Academy of Sciences, Budapest, Hungary
| | - Katalin Leiszter
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Gábor Valcz
- Molecular Medicine Research Unit, Hungarian Academy of Sciences, Budapest, Hungary
| | - Márk Juhász
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Pál Miheller
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Árpád V. Patai
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Zsolt Tulassay
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
- Molecular Medicine Research Unit, Hungarian Academy of Sciences, Budapest, Hungary
| | - Béla Molnár
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
- Molecular Medicine Research Unit, Hungarian Academy of Sciences, Budapest, Hungary
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Launay E, Henry C, Meyer C, Chappé C, Taque S, Boulland ML, Ben Abdelali R, Dugay F, Marschalek R, Bastard C, Fest T, Gandemer V, Belaud-Rotureau MA. MLL-SEPT5 fusion transcript in infant acute myeloid leukemia with t(11;22)(q23;q11). Leuk Lymphoma 2013; 55:662-7. [PMID: 23725386 DOI: 10.3109/10428194.2013.809528] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Chromosomal rearrangements involving the MLL gene at band 11q23 are the most common genetic alteration encountered in infant acute myeloid leukemia. Reciprocal translocation represents the most frequent form of MLL rearrangement. Currently, more than 60 partner genes have been identified. We report here a case of de novo acute myeloid leukemia with a t(11;22)(q23;q11) in a 23-month-old child. Fluorescence in situ hybridization study revealed that the 3'MLL segment was translocated onto the derivative chromosome 22 and the breakpoint on chromosome 22 was located in or near the SEPT5 gene at 22q11.21. Long distance inverse-polymerase chain reaction was used to identify precisely the MLL partner gene and confirmed the MLL-SEPT5 fusion transcript. Involvement of the SEPT5 gene in MLL rearrangement occurs very rarely. Clinical, cytogenetic and molecular features of acute myeloid leukemia with a MLL-SEPT5 fusion gene are reviewed.
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Affiliation(s)
- Erika Launay
- Service de Cytogénétique et de Biologie Cellulaire
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16
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Affiliation(s)
- Nolan Beise
- Cell Biology Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
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17
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Lin YH, Wang YY, Chen HI, Kuo YC, Chiou YW, Lin HH, Wu CM, Hsu CC, Chiang HS, Kuo PL. SEPTIN12 genetic variants confer susceptibility to teratozoospermia. PLoS One 2012; 7:e34011. [PMID: 22479503 PMCID: PMC3316533 DOI: 10.1371/journal.pone.0034011] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 02/21/2012] [Indexed: 12/16/2022] Open
Abstract
It is estimated that 10-15% of couples are infertile and male factors account for about half of these cases. With the advent of intracytoplasmic sperm injection (ICSI), many infertile men have been able to father offspring. However, teratozoospermia still remains a big challenge to tackle. Septins belong to a family of cytoskeletal proteins with GTPase activity and are involved in various biological processes e.g. morphogenesis, compartmentalization, apoptosis and cytokinesis. SEPTIN12, identified by c-DNA microarray analysis of infertile men, is exclusively expressed in the post meiotic male germ cells. Septin12(+/+)/Septin12(+/-) chimeric mice have multiple reproductive defects including the presence of immature sperm in the semen, and sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make SEPTIN12 a potential sterile gene in humans. In this study, we sequenced the entire coding region of SEPTIN12 in infertile men (n = 160) and fertile controls (n = 200) and identified ten variants. Among them is the c.474 G>A variant within exon 5 that encodes part of the GTP binding domain. The variant creates a novel splice donor site that causes skipping of a portion of exon 5, resulting in a truncated protein lacking the C-terminal half of SEPTIN12. Most individuals homozygous for the c.474 A allele had teratozoospermia (abnormal sperm <14%) and their sperm showed bent tail and de-condensed nucleus with significant DNA damage. Ex vivo experiment showed truncated SEPT12 inhibits filament formation in a dose-dependent manner. This study provides the first causal link between SEPTIN12 genetic variant and male infertility with distinctive sperm pathology. Our finding also suggests vital roles of SEPT12 in sperm nuclear integrity and tail development.
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Affiliation(s)
- Ying-Hung Lin
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, College of Medicine, Taipei, Taiwan
| | - Ya-Yun Wang
- Department of Obstetrics & Gynecology, National Cheng Kung University, College of Medicine, Tainan, Taiwan
- Institute of Molecular Medicine, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Hau-Inh Chen
- Department of Biochemistry and Molecular Biology, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Yung-Che Kuo
- Graduate Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Yu-Wei Chiou
- Department of Biomedical Engineering, National Cheng Kung University, College of Engineering, Tainan, Taiwan
| | - Hsi-Hui Lin
- Department of Physiology, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Ching-Ming Wu
- Department of Cell Biology & Anatomy, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Chao-Chin Hsu
- Department of Obstetrics and Gynecology, China Medical University, Taichung, Taiwan
| | - Han-Sun Chiang
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, College of Medicine, Taipei, Taiwan
| | - Pao-Lin Kuo
- Department of Obstetrics & Gynecology, National Cheng Kung University, College of Medicine, Tainan, Taiwan
- Department of Biochemistry and Molecular Biology, National Cheng Kung University, College of Medicine, Tainan, Taiwan
- Graduate Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan
- * E-mail:
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18
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Gozal YM, Seyfried NT, Gearing M, Glass JD, Heilman CJ, Wuu J, Duong DM, Cheng D, Xia Q, Rees HD, Fritz JJ, Cooper DS, Peng J, Levey AI, Lah JJ. Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration. Mol Neurodegener 2011; 6:82. [PMID: 22126117 PMCID: PMC3259087 DOI: 10.1186/1750-1326-6-82] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Accepted: 11/29/2011] [Indexed: 12/12/2022] Open
Abstract
Background Detergent-insoluble protein accumulation and aggregation in the brain is one of the pathological hallmarks of neurodegenerative diseases. Here, we describe the identification of septin 11 (SEPT11), an enriched component of detergent-resistant fractions in frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (FTLD-U), using large-scale unbiased proteomics approaches. Results We developed and applied orthogonal quantitative proteomic strategies for the unbiased identification of disease-associated proteins in FTLD-U. Using these approaches, we proteomically profiled detergent-insoluble protein extracts prepared from frontal cortex of FTLD-U cases, unaffected controls, or neurologic controls (i.e. Alzheimer's disease; AD). Among the proteins altered specifically in FTLD-U, we identified TAR DNA binding protein-43 (TDP-43), a known component of ubiquitinated inclusions. Moreover, we identified additional proteins enriched in detergent-resistant fractions in FTLD-U, and characterized one of them, SEPT11, in detail. Using independent highly sensitive targeted proteomics approaches, we confirmed the enrichment of SEPT11 in FTLD-U extracts. We further showed that SEPT11 is proteolytically cleaved into N-terminal fragments and, in addition to its prominent glial localization in normal brain, accumulates in thread-like pathology in affected cortex of FTLD-U patients. Conclusions The proteomic discovery of insoluble SEPT11 accumulation in FTLD-U, along with novel pathological associations, highlights a role for this cytoskeleton-associated protein in the pathogenesis of this complex disorder.
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Affiliation(s)
- Yair M Gozal
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Duhoux FP, Ameye G, Lambert C, Herman M, Iossifidis S, Constantinescu SN, Libouton JM, Demoulin JB, Poirel HA. Novel head-to-head gene fusion of MLL with ZC3H13 in a JAK2 V617F-positive patient with essential thrombocythemia without blast cells. Leuk Res 2011; 36:e27-30. [PMID: 21962339 DOI: 10.1016/j.leukres.2011.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 08/18/2011] [Accepted: 09/05/2011] [Indexed: 11/16/2022]
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Tóth K, Galamb O, Spisák S, Wichmann B, Sipos F, Valcz G, Leiszter K, Molnár B, Tulassay Z. The influence of methylated septin 9 gene on RNA and protein level in colorectal cancer. Pathol Oncol Res 2011; 17:503-9. [PMID: 21267688 DOI: 10.1007/s12253-010-9338-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2009] [Accepted: 11/22/2010] [Indexed: 02/05/2023]
Abstract
Colorectal cancer is one of the leading death causes in the world. Specificity and sensitivity of the present screening methods are unsuitable and their compliance is too low. Nowadays the most effective method is the colonoscopy, because it gives not only macroscopic diagnosis but therapeutic possibility as well, however the compliance of the patients is very low. Hence development of new diagnostic methods is needed. Altered expression of septin 9 was found in several tumor types including colorectal cancer. The aim of this study was to detect the methylation related mRNA and protein expression changes of septin 9 in colorectal adenoma-dysplasia-carcinoma sequence and to analyze its reversibility by demethylation treatment. Septin 9 protein expression showed significant difference between normal and colorectal cancer (CRC) samples (p < 0,001). According to biopsy microarray results, septin 9 mRNA expression decreased in the progression of colon neoplastic disease (p < 0,001). In laser microdissected epithelial cells, septin 9 significantly underexpressed in CRC compared to healthy controls (p < 0,001). The expression of septin9_v1 region was higher in the healthy samples, while septin9_v2, v4, v4*, v5 overexpression were detected in cancer epithelial cells compared to normal. The septin 9 mRNA and protein levels of HT29 cells increased after demethylation treatment. The increasing methylation of septin 9 gene during colorectal adenoma-dysplasia-carcinoma sequence progression is reflected in the decreasing mRNA and protein expression, especially in the epithelium. These changes can be reversed by demethylation agents converting this screening marker gene into therapeutic target.
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Affiliation(s)
- Kinga Tóth
- Semmelweis University, 2nd Department of Internal Medicine, Budapest, Hungary.
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21
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Cerveira N, Bizarro S, Teixeira MR. MLL-SEPTIN gene fusions in hematological malignancies. Biol Chem 2011; 392:713-24. [PMID: 21714766 DOI: 10.1515/bc.2011.072] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The mixed lineage leukemia (MLL) locus is involved in more than 60 different rearrangements with a remarkably diverse group of fusion partners in approximately 10% of human leukemias. MLL rearrangements include chromosomal translocations, gene internal duplications, chromosome 11q deletions or inversions and MLL gene insertions into other chromosomes, or vice versa. MLL fusion partners can be classified into four distinct categories: nuclear proteins, cytoplasmatic proteins, histone acetyltransferases and septins. Five different septin genes (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been identified as MLL fusion partners, giving rise to chimeric fusion proteins in which the N terminus of MLL is fused, in frame, to almost the entire open reading frame of the septin partner gene. The rearranged alleles result from heterogeneous breaks in distinct introns of both MLL and its septin fusion partner, originating distinct gene fusion variants. MLL-SEPTIN rearrangements have been repeatedly identified in de novo and therapy related myeloid neoplasia in both children and adults, and some clinicopathogenetic associations are being uncovered. The fundamental roles of septins in cytokinesis, membrane remodeling and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton and MLL deregulation could be involved in the pathogenesis of hematological malignancies.
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Affiliation(s)
- Nuno Cerveira
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
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22
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A translocation in acute lymphoblastic leukemia that cytogenetically mimics the recurrent MLL-AFF1 translocation and fuses SEPT11 to MLL. ACTA ACUST UNITED AC 2010; 201:48-51. [PMID: 20633769 DOI: 10.1016/j.cancergencyto.2010.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 04/13/2010] [Accepted: 05/04/2010] [Indexed: 11/20/2022]
Abstract
A 55-year-old man sought care for aggressive acute lymphoblastic leukemia (ALL), which developed 8 years after he had received chemotherapeutic treatment for nephrotic syndrome. The sole cytogenetic abnormality observed in bone marrow-derived metaphases was a t(4;11)(q21;q23), which is a frequently occurring translocation in ALL. However, subsequent reverse transcriptase-polymerase chain reaction for the expected mixed lineage leukemia [trithorax homolog, Drosophila] (MLL)-AFF1 fusion transcript was negative. Further fluorescence in situ hybridization (FISH) analysis narrowed the 4q21 breakpoint down to a 250-kb region proximal of AFF1. This comprised four genes, of which septin11 (SEPT11) was further analyzed. Reverse transcriptase-polymerase chain reaction revealed expression of a chimeric MLL-SEPT11 transcript, thus identifying what is to our knowledge a hitherto undescribed translocation in ALL. Sequence analysis of cDNA showed in-frame fusion of MLL exon 11 to SEPT11 exon 2. This MLL-SEPT11 fusion is cytogenetically indistinguishable from the recurrent t(4;11)(q21;q23). Thus, it is crucial to characterize cytogenetic aberrations in leukemia by molecular methods, even in cases where a known recurrent translocation is presumed. This report expands the spectrum of ALL-related translocations and hypothesizes on the mechanism leading to the MLL-SEPT11 fusion. Five septins have been identified thus far as MLL fusion partners in leukemia. Their putative oncogenic role may be related to forced MLL dimerization by the septin coiled coil and GTP-binding domains, which could convert MLL to an oncogene.
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Expression pattern of the septin gene family in acute myeloid leukemias with and without MLL-SEPT fusion genes. Leuk Res 2010; 34:615-21. [DOI: 10.1016/j.leukres.2009.08.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Revised: 08/11/2009] [Accepted: 08/14/2009] [Indexed: 02/05/2023]
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Xu S, Jia ZF, Kang C, Huang Q, Wang G, Liu X, Zhou X, Xu P, Pu P. Upregulation of SEPT7 gene inhibits invasion of human glioma cells. Cancer Invest 2010; 28:248-58. [PMID: 19916744 DOI: 10.3109/07357900903179609] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVES To explore the role of SEPT7 in glioma cell invasion. METHODS SEPT7 was transfected into human glioma cell lines U251 and TJ899, the invasive abilities were evaluated by transwell assay, scratch assay, and 3-D/2-D Matrigel growth. The expression of MMP2/9, MT1-MMP, integrin alpha(v)beta(3), and TIMP1/2 was detected by immunohistochemistry, immunofluorescence, and Western blot analyses. Distribution of alpha-tubulin was examined by laser scanning confocal analysis. RESULT After SEPT7 trasfection, cell invasion was inhibited, expression of MMP2/9, MT1-MMP, and integrin alpha(v)beta(3) was decreased, while TIMP1/2 was increased, and alpha-tubulin was redistributed. CONCLUSION These results suggest that SEPT7 plays an important role in the glioma cell invasion.
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Affiliation(s)
- Song Xu
- Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
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Liu M, Shen S, Chen F, Yu W, Yu L. Linking the septin expression with carcinogenesis. Mol Biol Rep 2010; 37:3601-8. [PMID: 20195767 DOI: 10.1007/s11033-010-0009-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2010] [Accepted: 02/15/2010] [Indexed: 12/30/2022]
Abstract
The septin is a conserved GTP binding protein family which is involved in multiple cellular processes. Many evidences have indicated that some septins were abnormally expressed in certain kinds of tumors and the altered expressions were related to the process of carcinogenesis. To better understand the relationship between septins and cancer, we compared the expression of 14 human septin family members in 35 kinds of tumor types with their normal counterparts using the publicly available ONCOMINE microarray database. We found altered expression of most septin members in many kinds of tumors. Significantly, SEPT2, SEPT8, SEPT9, SEPT11 were consistently up-regulated, and SEPT4, SEPT10 were down-regulated in most cancer types investigated. Furthermore, the abnormal expressions were also in accordance with the tumor malignancies or prognosis of corresponding cancer patients. These findings have contributed to the view that septins may belong to a kind of cancer critical genes. More septins might act as potential oncogenes or tumor suppressor genes in cancer development.
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Affiliation(s)
- Ming Liu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, 200433, People's Republic of China
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26
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Santos J, Cerveira N, Correia C, Lisboa S, Pinheiro M, Torres L, Bizarro S, Vieira J, Viterbo L, Mariz JM, Teixeira MR. Coexistence of alternative MLL-SEPT9 fusion transcripts in an acute myeloid leukemia with t(11;17)(q23;q25). ACTA ACUST UNITED AC 2010; 197:60-4. [PMID: 20113838 DOI: 10.1016/j.cancergencyto.2009.10.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2009] [Revised: 10/17/2009] [Accepted: 10/17/2009] [Indexed: 12/31/2022]
Abstract
We present the characterization at the RNA level of an acute myeloid leukemia with a t(11;17)(q23;q25) and a MLL rearrangement demonstrated by FISH. Molecular analysis led to the identification of two coexistent in-frame MLL-SEPT9 fusion transcripts (variants 1 and 2), presumably resulting from alternative splicing. Real-time quantitative RT-PCR analysis showed that the relative expression of the MLL-SEPT9 fusion variant 2 was 1.88 fold higher than the relative expression of MLL-SEPT9 fusion variant 1. This is the first description of a MLL-SEPT9 fusion resulting in coexistence of two alternative splicing variants, each of which previously found isolated in myeloid leukemias.
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Affiliation(s)
- Joana Santos
- Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, Porto, Portugal
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Peterson EA, Petty EM. Conquering the complex world of human septins: implications for health and disease. Clin Genet 2010; 77:511-24. [PMID: 20236126 DOI: 10.1111/j.1399-0004.2010.01392.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in must eukaryotes. Septins can bind and hydrolyze GTP, which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1-SEPT14, which encode dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N-terminus and/or C-terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alterations of these proteins, by mutation or expression changes, have been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from alterations of expression in solid tumors or translocations in leukemias [mixed lineage leukemia (MLL)]. Expression changes in septins have also been associated with neurological conditions such as Alzheimer's and Parkinson's disease, as well as retinopathies, hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder hereditary neuralgic amyotrophy (HNA). Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications.
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Affiliation(s)
- E A Peterson
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
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Tóth K, Galamb O, Spisák S, Wichmann B, Sipos F, Leiszter K, Molnár J, Molnár B, Tulassay Z. [Free circulating DNA based colorectal cancer screening from peripheral blood: the possibility of the methylated septin 9 gene marker]. Orv Hetil 2009; 150:969-77. [PMID: 19443305 DOI: 10.1556/oh.2009.28625] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
DNA methylation acts in early tumorigenesis. Its detection is possible either from tissue, stool or peripheral blood. Septin 9 is a sensitive methylation marker, which has been studied in several cancers such as breast and ovarian tumors and in neurological or hematological diseases. Septin proteins have an important role from cytoskeleton organisation to development of embryonal pattern. Nowadays intensive researches are going on about the relation between the septin 9 gene hypermethylation and colorectal cancer development.
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Affiliation(s)
- Kinga Tóth
- Semmelweis Egyetem, Altalános Orvostudományi Kar, II. Belgyógyászati Klinika, Budapest.
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Cerveira N, Santos J, Bizarro S, Costa V, Ribeiro FR, Lisboa S, Correia C, Torres L, Vieira J, Snijder S, Mariz JM, Norton L, Mellink CH, Buijs A, Teixeira MR. Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia. BMC Cancer 2009; 9:147. [PMID: 19445675 PMCID: PMC2689242 DOI: 10.1186/1471-2407-9-147] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2008] [Accepted: 05/15/2009] [Indexed: 01/18/2023] Open
Abstract
Background A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in MLL-related leukemia. Recently, we have established the MLL-SEPT2 gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified MLL and SEPT2 gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of MLL-SEPT2-associated myeloid neoplasms so far described in the literature. Methods Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: CBFB-MYH11 (n = 13), PML-RARA (n = 12); RUNX1-RUNX1T1 (n = 12), normal karyotype (n = 11), and MLL gene fusions other than MLL-SEPT2 (n = 10). We also studied all three MLL-SEPT2 myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient. Results When compared with normal controls, we found a 12.8-fold reduction of wild-type SEPT2 and MLL-SEPT2 combined expression in cases with the MLL-SEPT2 gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type MLL and MLL-SEPT2 combined expression (p = 0.028). The down-regulation of SEPT2 in MLL-SEPT2 myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other MLL gene fusions). In addition, MLL expression was also down-regulated in the group of MLL fusions other than MLL-SEPT2, when compared with the normal control group (p = 0.023) Conclusion We found a significant down-regulation of both SEPT2 and MLL in MLL-SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2.
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Affiliation(s)
- Nuno Cerveira
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
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Kurosu T, Tsuji K, Ohki M, Miki T, Yamamoto M, Kakihana K, Koyama T, Taniguchi S, Miura O. A variant-type MLL/SEPT9 fusion transcript in adult de novo acute monocytic leukemia (M5b) with t(11;17)(q23;q25). Int J Hematol 2008; 88:192-196. [PMID: 18642054 DOI: 10.1007/s12185-008-0133-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2007] [Revised: 05/22/2008] [Accepted: 05/23/2008] [Indexed: 12/19/2022]
Abstract
As a result of recurrent chromosomal translocations in acute leukemias, the mixed-lineage-leukemia (MLL) gene fuses with a variety of partner genes, which include several members of the septin gene family. SEPT9 is a very rare but recurrent fusion partner of MLL, and has recently been implicated in the oncogenesis of various malignancies. Herein, we report a case of de novo acute monocytic leukemia (M5b) with t(11;17)(q23;q25). MLL involvement was revealed by fluorescent in situ hybridization (FISH) analysis, and an MLL/SEP9 fusion transcript was detected by RT-PCR. Sequencing analysis further showed that, in contrast to originally reported cases, MLL exon 8 was fused not with SEPT9 exon 3 but with exon 2, which codes for the unique N-terminal region of the SEPT9_v1 isoform, the region implicated in the regulation of gene expression and cell proliferation. We did not detect any mutation of FLT3, which was expressed at a relatively low level in the leukemic cells. Relapsing after a very short complete remission, the leukemia progressed rapidly and became fatal in spite of intensive therapies including hematopoietic stem cell transplantation. It is thus suggested that, in common with the original MLL/SEPT9 cases, monocytic differentiation and a poor prognosis may also be associated with acute myeloid leukemia with the variant MLL/SEPT9 fusion transcript.
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Affiliation(s)
- Tetsuya Kurosu
- Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan.
| | - Kana Tsuji
- Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan.,Laboratory Molecular Genetics of Hematology, Graduate School of Health Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan
| | - Manabu Ohki
- Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan
| | - Tohru Miki
- Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan
| | - Masahide Yamamoto
- Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan
| | - Kazuhiko Kakihana
- Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan
| | - Takatoshi Koyama
- Laboratory Molecular Genetics of Hematology, Graduate School of Health Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan
| | - Shuichi Taniguchi
- Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon, Minatoku, Tokyo, 105-8470, Japan
| | - Osamu Miura
- Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan
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Characterization of a SEPT9 interacting protein, SEPT14, a novel testis-specific septin. Mamm Genome 2007; 18:796-807. [PMID: 17922164 DOI: 10.1007/s00335-007-9065-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2007] [Accepted: 08/21/2007] [Indexed: 01/08/2023]
Abstract
Septins are a highly conserved family of GTP-binding cytoskeletal proteins implicated in multiple cellular functions, including membrane transport, apoptosis, cell polarity, cell cycle regulation, cytokinesis, and oncogenesis. Here we describe the characterization of a novel interacting partner of the septin family, initially cloned from a human testis expression library following yeast two-hybrid isolation to identify SEPT9 binding partners. Upon further genomic characterization and bioinformatics analyses it was determined that this novel septin-interacting partner was also a new member of the mammalian septin family, named SEPT14. SEPT14 maps to 7p11.2 in humans and includes a conserved GTPase domain and a predicted carboxy-terminus coiled-coil domain characteristic of other septins. Three potential translational start methionines were identified by 5' RACE-PCR encoding proteins of 432-, 427-, and 425-residue peptides, respectively. SEPT14 shares closest homology to SEPT10, a human dendritic septin, and limited homology to SEPT9 isoforms. SEPT14 colocalized with SEPT9 when coexpressed in cell lines, and epitope-tagged forms of these proteins coimmunoprecipitated. Moreover, SEPT14 was coimmunoprecipitated from rat testes using SEPT9 antibodies, and yeast two-hybrid analysis suggested SEPT14 interactions with nine additional septins. Multitissue Northern blotting showed testis-specific expression of a single 5.0-kb SEPT14 transcript. RT-PCR analysis revealed that SEPT14 was not detectable in normal or cancerous ovarian, breast, prostate, bladder, or kidney cell lines and was only faintly detected in fetal liver, tonsil, and thymus samples. Interestingly, SEPT14 was expressed in testis but not testicular cancer cell lines by RT-PCR, suggesting that further investigation of SEPT14 as a testis-specific tumor suppressor is necessary.
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Strehl S, König M, Meyer C, Schneider B, Harbott J, Jäger U, von Bergh ARM, Loncarevic IF, Jarosova M, Schmidt HH, Moore SDP, Marschalek R, Haas OA. Molecular dissection of t(11;17) in acute myeloid leukemia reveals a variety of gene fusions with heterogeneous fusion transcripts and multiple splice variants. Genes Chromosomes Cancer 2006; 45:1041-9. [PMID: 16897742 DOI: 10.1002/gcc.20372] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The majority of translocations that involve the long arms of chromosomes 11 and 17 in acute myeloid leukemia appear identical on the cytogenetic level. Nevertheless, they are diverse on the molecular level. At present, two genes are known in 11q23 and four in 17q12-25 that generate five distinct fusion genes: MLL-MLLT6/AF17, MLL-LASP1, MLL-ACACA or MLL-SEPT9/MSF, and ZBTB16/PLZF-RARA. We analyzed 14 cases with a t(11;17) by fluorescence in situ hybridization and molecular genetic techniques and determined the molecular characteristics of their fusion genes. We identified six different gene fusions that comprised seven cases with a MLL-MLLT6/AF17, three with a MLL-SEPT9/MSF, and one each with MLL-LASP1, MLL-ACACA, and ZBTB16/PLZF-RARA fusions. In the remaining case, a MLL-SEPT6/Xq24 fusion suggested a complex rearrangement. The MLL-MLLT6/AF17 transcripts were extremely heterogeneous and the detection of seven different in-frame transcript and splice variants enabled us to predict the protein domains relevant for leukemogenesis. The putative MLL-MLLT6 consensus chimeric protein consists of the AT-hook DNA-binding, the methyltransferase, and the CXXC zinc-finger domains of MLL and the highly conserved octapeptide and the leucine-zipper dimerization motifs of MLLT6. The MLL-SEPT9 transcripts showed a similar high degree of variability. These analyses prove that the diverse types of t(11;17)-associated fusion genes can be reliably identified and delineated with a proper combination of cytogenetic and molecular genetic techniques. The heterogeneity of transcripts encountered in cases with MLL-MLLT6/AF17 and MLL-SEPT9/MSF fusions clearly demonstrates that thorough attention has to be paid to the appropriate selection of primers to cover all these hitherto unrecognized fusion variants.
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MESH Headings
- Adolescent
- Adult
- Aged
- Alternative Splicing
- Child
- Child, Preschool
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 17
- DNA-Binding Proteins/genetics
- Female
- Histone-Lysine N-Methyltransferase
- Homeodomain Proteins/genetics
- Humans
- In Situ Hybridization
- Infant
- Leukemia, Monocytic, Acute/genetics
- Leukemia, Myelomonocytic, Acute/genetics
- Male
- Middle Aged
- Myeloid-Lymphoid Leukemia Protein/genetics
- Neoplasm Proteins/genetics
- Oncogene Proteins, Fusion/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Translocation, Genetic
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Affiliation(s)
- Sabine Strehl
- CCRI, Children's Cancer Research Institute, Kinderspitalgasse 6, Vienna, Austria.
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Bläser S, Röseler S, Rempp H, Bartsch I, Bauer H, Lieber M, Lessmann E, Weingarten L, Busse A, Huber M, Zieger B. Human endothelial cell septins: SEPT11 is an interaction partner of SEPT5. J Pathol 2006; 210:103-10. [PMID: 16767699 DOI: 10.1002/path.2013] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The septin SEPT11 is a novel member of the highly conserved septin family. Septins are cytoskeletal GTPases, which form heteropolymeric complexes. They are involved in cytokinesis and other cellular processes, such as vesicle trafficking and exocytosis. SEPT11 has strong homology to SEPT8. Previously, we identified the interaction of SEPT5 and SEPT8. Using the yeast two-hybrid system, we now demonstrate that SEPT11 partners with SEPT5. The molecular interaction of SEPT11 with SEPT5 was verified by coprecipitation of SEPT5 and SEPT11 from lysates of the human T-cell leukaemia cell line JURKAT and by fluorescence resonance energy transfer. The interaction between SEPT5 and SEPT11 requires the GTP-binding domain and the C-terminal extension. Western analysis in various mouse and human tissues revealed that expression of SEPT11 is restricted to the same tissues as those expressing SEPT5, suggesting that SEPT11 and SEPT5 are components of a cell-specific septin complex. SEPT5, which is expressed in human umbilical vein endothelial cells (HUVECs), has been reported to play an important role in exocytosis. We now report that HUVECs also express SEPT11. Given the interactivity between SEPT5 and SEPT11 as shown above and their coexpression in HUVECs, it may be that a complex formed by these two proteins is involved in the exocytosis mechanism in HUVECs.
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Affiliation(s)
- S Bläser
- Department of Paediatrics and Adolescent Medicine, University Hospital Freiburg, Mathildenstrasse 1, D-79106 Germany
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Cerveira N, Correia C, Bizarro S, Pinto C, Lisboa S, Mariz JM, Marques M, Teixeira MR. SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23). Oncogene 2006; 25:6147-52. [PMID: 16682951 DOI: 10.1038/sj.onc.1209626] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
We have identified a new mixed lineage leukemia (MLL) gene fusion partner in a patient with treatment-related acute myeloid leukemia (AML) presenting a t(2;11)(q37;q23) as the only cytogenetic abnormality. Fluorescence in situ hybridization demonstrated a rearrangement of the MLL gene and molecular genetic analyses identified a septin family gene, SEPT2, located on chromosome 2q37, as the fusion partner of MLL. RNA and DNA analyses showed the existence of an in-frame fusion of MLL exon 7 with SEPT2 exon 3, with the genomic breakpoints located in intron 7 and 2 of MLL and SEPT2, respectively. Search for DNA sequence motifs revealed the existence of two sequences with 94.4% homology with the topoisomerase II consensus cleavage site in MLL intron 7 and SEPT2 intron 2. SEPT2 is the fifth septin family gene fused with MLL, making this gene family the most frequently involved in MLL-related AML (about 10% of all known fusion partners). The protein encoded by SEPT2 is highly homologous to septins 1, 4 and 5 and is involved in the coordination of several key steps of mitosis. Further studies are warranted to understand why the septin protein family is particularly involved in the pathogenesis of MLL-associated leukemia.
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MESH Headings
- Amino Acid Sequence
- Base Sequence
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 2
- DNA, Neoplasm
- Exons
- Female
- Histone-Lysine N-Methyltransferase
- Humans
- In Situ Hybridization, Fluorescence
- Karyotyping
- Leukemia, Myeloid/chemically induced
- Leukemia, Myeloid/genetics
- Middle Aged
- Molecular Sequence Data
- Myeloid-Lymphoid Leukemia Protein/genetics
- Phosphoric Monoester Hydrolases/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Homology, Nucleic Acid
- Translocation, Genetic
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Affiliation(s)
- N Cerveira
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
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Ono R, Ihara M, Nakajima H, Ozaki K, Kataoka-Fujiwara Y, Taki T, Nagata KI, Inagaki M, Yoshida N, Kitamura T, Hayashi Y, Kinoshita M, Nosaka T. Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4. Mol Cell Biol 2006; 25:10965-78. [PMID: 16314519 PMCID: PMC1316963 DOI: 10.1128/mcb.25.24.10965-10978.2005] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Septins are evolutionarily conserved GTP-binding proteins that can heteropolymerize into filaments. Recent studies have revealed that septins are involved in not only diverse normal cellular processes but also the pathogenesis of various diseases, including cancer. SEPT6 is ubiquitously expressed in tissues and one of the fusion partner genes of MLL in the 11q23 translocations implicated in acute leukemia. However, the roles of this septin in vivo remain elusive. We have developed Sept6-deficient mice that exhibited neither gross abnormalities, changes in cytokinesis, nor spontaneous malignancy. Sept6 deficiency did not cause any quantitative changes in any of the septins evaluated in this study, nor did it cause any additional changes in the Sept4-deficient mice. Even the depletion of Sept11, a close homolog of Sept6, did not affect the Sept6-null cells in vitro, thus implying a high degree of redundancy in the septin system. Furthermore, a loss of Sept6 did not alter the phenotype of myeloproliferative disease induced by MLL-SEPT6, thus suggesting that Sept6 does not function as a tumor suppressor. To our knowledge, this is the first report demonstrating that a disruption of the translocation partner gene of MLL in 11q23 translocation does not contribute to leukemogenesis by the MLL fusion gene.
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Affiliation(s)
- Ryoichi Ono
- Division of Hematopoietic Factors, The Institute of Medical Science, The University of Tokyo, Minato-ku, Japan
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Abstract
Septins are an evolutionarily conserved family of genes that encode a P loop-based GTP-binding domain flanked by a polybasic domain and (usually) a coiled-coil region. They have roles in cytokinesis, vesicle trafficking, polarity determination, and can form membrane diffusion barriers, as well as in microtubule and actin dynamics. Septins can form hetero-oligomeric complexes and possibly function as dynamic protein scaffolds. Recently, it has been shown that there are at least 13 human septin genes that exhibit extensive alternate splicing. There are complex patterns of human septin gene expression and recently it has been found that alterations in septin expression are seen in human diseases including neoplasia. This review summarises the essential properties of septins and outlines the accumulating evidence for their involvement in human neoplasia. Septins may belong to the class of cancer critical genes where alteration in expression profile (including alterations in the spectrum of transcripts expressed) may underpin their role in neoplasia as opposed to specific mutational events.
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Affiliation(s)
- S E H Russell
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, University Floor, Tower Block, Belfast City Hospital, Belfast BT9 7AB, UK
| | - P A Hall
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, University Floor, Tower Block, Belfast City Hospital, Belfast BT9 7AB, UK
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, University Floor, Tower Block, Belfast City Hospital, Belfast BT9 7AB, UK. E-mail:
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Hall PA, Jung K, Hillan KJ, Russell SEH. Expression profiling the human septin gene family. J Pathol 2005; 206:269-78. [PMID: 15915442 DOI: 10.1002/path.1789] [Citation(s) in RCA: 134] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The septins are an evolutionarily conserved family of GTP-binding proteins involved in diverse processes including vesicle trafficking, apoptosis, remodelling of the cytoskeleton, infection, neurodegeneration, and neoplasia. The present paper reports a comprehensive study of septin gene expression by DNA microarray methods in 10 360 samples of normal, diseased, and tumour tissues. A novel septin, SEPT13, has been identified and is shown to be related to SEPT7. It is shown that SEPT13 and the other known human septins are expressed in all tissue types but some show high expression in lymphoid (SEPT1, 6, 9, and 12) or brain tissues (SEPT2, 3, 4, 5, 7, 8, and 11). For a given septin, some isoforms are highly expressed in the brain and others are not. For example, SEPT8_v2 and v1, 1* and 3 are highly expressed in the brain and cluster with SEPT2, 3, 4, 5, 7, and 11. However, a probe set specific for SEPT8_v1 with low brain expression clusters away from this set. Similarly, SEPT4 has lymphoid and non-lymphoid forms; SEPT2 has lymphoid and central nervous system (CNS) forms; and SEPT6 and SEPT9 are elevated in lymphoid tissues but both have forms that cluster away from the lymphoid forms. Perturbation of septin expression was widespread in disease and tumours of the various tissues examined, particularly for conditions of the CNS, where alterations in all 13 septin genes were identified. This analysis provides a comprehensive catalogue of the septin family in health and disease. It is a key step in understanding the role of septins in physiological and pathological states and provides insight into the complexity of septin biology.
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Affiliation(s)
- Peter A Hall
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, University Floor, Tower Block, Belfast City Hospital, Belfast BT9 7AB, UK.
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38
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Abstract
The mixed-lineage leukemia (MLL) gene is a trithorax group (trxG) gene that was originally identified at chromosomal translocations in patients developing acute leukemia. Although Polycomb group (PcG) genes, which counteract trxG genes, were found to play essential roles in hematopoiesis, little has been understood about the roles of trxG genes in hematopoiesis except for MLL. MLL has been found fused with 1 of more than 30 different partner genes to yield a diverse collection of MLL fusion oncoproteins that lead to the aberrant expression of HOX genes. Recent studies have revealed that MLL assembles, as do some trxG proteins, into a chromatin-modifying transcriptional regulatory supercomplex to regulate epigenetic pathways, including the methylation of histone H3 lysine 4, which is conferred by the Su (var)3-9, enhancer of zeste, and tritho-rax (SET) domain. Other studies also indicated that MLL plays a nonredundant and essential role in definitive hematopoiesis and induces the proliferation and differentiation of hematopoietic progenitors by maintaining appropriate up-regulation of HOX genes. Further progress in the field will provide novel insights into trxG- and PcG-mediated hematopoiesis and help us understand the epigenetic process by which developing stem cells coordinate proliferation and differentiation.
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Affiliation(s)
- Ryoichi Ono
- Division of Hematopoietic Factors, The Institute of Medical Science, The University of Tokyo, Japan
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Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T, Kitamura T, Hayashi Y, Nosaka T. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J Clin Invest 2005; 115:919-29. [PMID: 15761502 PMCID: PMC1062890 DOI: 10.1172/jci22725] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2004] [Accepted: 01/18/2005] [Indexed: 11/17/2022] Open
Abstract
The mechanisms by which mixed-lineage leukemia (MLL) fusion products resulting from in utero translocations in 11q23 contribute to leukemogenesis and infant acute leukemia remain elusive. It is still controversial whether the MLL fusion protein is sufficient to induce acute leukemia without additional genetic alterations, although carcinogenesis in general is known to result from more than 1 genetic disorder accumulating during a lifetime. Here we demonstrate that the fusion partner-mediated homo-oligomerization of MLL-SEPT6 is essential to immortalize hematopoietic progenitors in vitro. MLL-SEPT6 induced myeloproliferative disease with long latency in mice, but not acute leukemia, implying that secondary genotoxic events are required to develop leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3 (FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. In these systems, MLL-ENL, another type of the fusion product that seems to act as a monomer, also induced the transformation in vitro and leukemogenesis in vivo in concert with activated FLT3. These findings show direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.
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Affiliation(s)
- Ryoichi Ono
- Division of Hematopoietic Factors, The Institute of Medical Science, Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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40
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Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T, Kitamura T, Hayashi Y, Nosaka T. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J Clin Invest 2005. [DOI: 10.1172/jci200522725] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Abstract
Septins are an evolutionarily conserved group of GTP-binding and filament-forming proteins that belong to the large superclass of P-loop GTPases. While originally discovered in yeast as cell division cycle mutants with cytokinesis defects, they are now known to have diverse cellular roles which include polarity determination, cytoskeletal reorganization, membrane dynamics, vesicle trafficking, and exocytosis. Septin proteins form homo- and hetero-oligomeric polymers which can assemble into higher-order filaments. They are also known to interact with components of the cytoskeleton, ie actin and tubulin. The precise role of GTP binding is not clear but a current model suggests that it is associated with conformational changes which alter binding to other proteins. There are at least 12 human septin genes, and although information on expression patterns is limited, most undergo complex alternative splicing with some degree of tissue specificity. Nevertheless, an increasing body of data implicates the septin family in the pathogenesis of diverse disease states including neoplasia, neurodegenerative conditions, and infections. Here the known biochemical properties of mammalian septins are reviewed in the light of the data from yeast and other model organisms. The data implicating septins in human disease are considered and a model linking these data is proposed. It is posited that septins can act as regulatable scaffolds where the stoichiometry of septin associations, modifications, GTP status, and the interactions with other proteins allow the regulation of key cellular processes including polarity determination. Derangements of such septin scaffolds thus explain the role of septins in disease states.
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Affiliation(s)
- Peter A Hall
- Centre for Cancer Research & Cell Biology, Queens University Belfast, U Floor, Belfast City Hospital, Belfast BT9 7AB, UK
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