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Li HY, Jing YM, Shen X, Tang MY, Shen HH, Li XW, Wang ZS, Su F. Protein tyrosine phosphatase non-receptor II: A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:3913-3931. [PMID: 39350977 PMCID: PMC11438766 DOI: 10.4251/wjgo.v16.i9.3913] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/03/2024] [Accepted: 07/08/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND The incidence of primary liver cancer is increasing year by year. In 2022 alone, more than 900000 people were diagnosed with liver cancer worldwide, with hepatocellular carcinoma (HCC) accounting for 75%-85% of cases. HCC is the most common primary liver cancer. China has the highest incidence and mortality rate of HCC in the world, and it is one of the malignant tumors that seriously threaten the health of Chinese people. The onset of liver cancer is occult, the early cases lack typical clinical symptoms, and most of the patients are already in the middle and late stage when diagnosed. Therefore, it is very important to find new markers for the early detection and diagnosis of liver cancer, improve the therapeutic effect, and improve the prognosis of patients. Protein tyrosine phosphatase non-receptor 2 (PTPN2) has been shown to be associated with colorectal cancer, triple-negative breast cancer, non-small cell lung cancer, and prostate cancer, but its biological role and function in tumors remain to be further studied. AIM To combine the results of relevant data obtained from The Cancer Genome Atlas (TCGA) to provide the first in-depth analysis of the biological role of PTPN2 in HCC. METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database, and the findings were then verified by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and immunoblotting. The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features. Finally, the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining. RESULTS The results of immunohistochemical staining, qRT-PCR, and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways, including cancer-related pathways, the Notch signaling pathway, and the MAPK signaling pathway. Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways, such as the epithelial mesenchymal transition process. A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group. CONCLUSION This study investigated PTPN2 from multiple biological perspectives, revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.
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Affiliation(s)
- Hui-Yuan Li
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Yi-Ming Jing
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xue Shen
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Ming-Yue Tang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Hong-Hong Shen
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xin-Wei Li
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Zi-Shu Wang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Fang Su
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
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Song J, Lan J, Tang J, Luo N. PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review. Int J Mol Sci 2022; 23:ijms231710025. [PMID: 36077422 PMCID: PMC9456094 DOI: 10.3390/ijms231710025] [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: 08/04/2022] [Revised: 08/25/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
PTPN2 (protein tyrosine phosphatase non-receptor 2), also called TCPTP (T cell protein tyrosine phosphatase), is a member of the PTP family signaling proteins. Phosphotyrosine-based signaling of this non-transmembrane protein is essential for regulating cell growth, development, differentiation, survival, and migration. In particular, PTPN2 received researchers’ attention when Manguso et al. identified PTPN2 as a cancer immunotherapy target using in vivo CRISPR library screening. In this review, we attempt to summarize the important functions of PTPN2 in terms of its structural and functional properties, inflammatory reactions, immunomodulatory properties, and tumor immunity. PTPN2 exerts synergistic anti-inflammatory effects in various inflammatory cells and regulates the developmental differentiation of immune cells. The diversity of PTPN2 effects in different types of tumors makes it a potential target for tumor immunotherapy.
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Spalinger MR, McCole DF, Rogler G, Scharl M. Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease. World J Gastroenterol 2016; 22:1034-1044. [PMID: 26811645 PMCID: PMC4716018 DOI: 10.3748/wjg.v22.i3.1034] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 08/31/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) with the onset of inflammatory bowel disease (IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.
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Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Res Treat 2015. [PMID: 26208487 DOI: 10.1007/s10549-015-3516-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976-1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16% (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer.
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Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation. Inflamm Bowel Dis 2015; 21:645-55. [PMID: 25581833 PMCID: PMC4329025 DOI: 10.1097/mib.0000000000000297] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Current hypothesis suggests that genetic, immunological, and bacterial factors contribute essentially to the pathogenesis of inflammatory bowel disease. Variations within the gene loci encoding protein tyrosine phosphatases (PTPs) have been associated with the onset of inflammatory bowel disease. PTPs modulate the activity of their substrates by dephosphorylation of tyrosine residues and are critical for the regulation of fundamental cellular signaling processes. Evidence emerges that expression levels of PTPN2, PTPN11, and PTPN22 are altered in actively inflamed intestinal tissue. PTPN2 seems to be critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses and finally for maintaining intestinal homeostasis. These observations have been confirmed in PTPN2 knockout mice in vivo. Those animals are clearly more susceptible to intestinal and systemic inflammation and feature alterations in innate and adaptive immune responses. PTPN22 controls inflammatory signaling in lymphocytes and mononuclear cells resulting in aberrant cytokine secretion pattern and autophagosome formation. PTPN22 deficiency in vivo results in more severe colitis demonstrating the relevance of PTPN22 for intestinal homeostasis in vivo. Of note, loss of PTPN22 promotes mitogen-activated protein kinase-induced cytokine secretion but limits secretion of nuclear factor κB-associated cytokines and autophagy in mononuclear cells. Loss of PTPN11 is also associated with increased colitis severity in vivo. In summary, dysfunction of those PTPs results in aberrant and uncontrolled immune responses that result in chronic inflammatory conditions. This way, it becomes more and more evident that dysfunction of PTPs displays an important factor in the pathogenesis of chronic intestinal inflammation, in particular inflammatory bowel disease.
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Characterization of PTPN2 and its use as a biomarker. Methods 2014; 65:239-46. [DOI: 10.1016/j.ymeth.2013.08.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 08/07/2013] [Accepted: 08/08/2013] [Indexed: 02/07/2023] Open
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Chistiakov DA, Chistiakova EI. T-cell protein tyrosine phosphatase: A role in inflammation and autoimmunity. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/j.ijdm.2010.05.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Nosikov VV, Seregin YA. Molecular genetics of type 1 diabetes mellitus: Achievements and future trends. Mol Biol 2008. [DOI: 10.1134/s0026893308050142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Hassan MJ, Chishti MS, Jamal SM, Tariq M, Ahmad W. A syndromic form of autosomal recessive congenital microcephaly (Jawad syndrome) maps to chromosome 18p11.22-q11.2. Hum Genet 2007; 123:77-82. [PMID: 18071751 DOI: 10.1007/s00439-007-0452-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2007] [Accepted: 12/02/2007] [Indexed: 10/22/2022]
Abstract
We report a consanguineous Pakistani family with seven affected individuals showing a syndromic form of congenital microcephaly. Clinical features of affected individuals include congenital microcephaly with sharply slopping forehead, moderate to severe mental retardation, anonychia congenita, and digital malformations. By screening human genome with microsatellite markers, this autosomal recessive condition was mapped to a 25.2 cM interval between markers D18S1150 and D18S1100 on chromosome 18p11.22-q12.3. However, the region of continuous homozygosity between markers D18S1150 and D18S997 spanning 15.33 cM, probably define the most likely candidate region for this condition. This region encompasses a physical distance of 12.03 Mb. The highest two-point LOD score of 3.03 was obtained with a marker D18S1104 and multipoint score reached a maximum of 3.43 with several markers. Six candidate genes, CEP76, ESCO1, SEH1L, TUBB6, ZNF519, and PTPN2 were sequenced, and were found to be negative for functional sequence variants.
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Affiliation(s)
- Muhammad Jawad Hassan
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan
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Yi C, McCarty JH, Troutman SA, Eckman MS, Bronson RT, Kissil JL. Loss of the putative tumor suppressor band 4.1B/Dal1 gene is dispensable for normal development and does not predispose to cancer. Mol Cell Biol 2005; 25:10052-9. [PMID: 16260618 PMCID: PMC1280276 DOI: 10.1128/mcb.25.22.10052-10059.2005] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The band 4.1 proteins are cytoskeletal proteins, harboring a conserved FERM domain highly homologous to the N-terminal FERM domain of ezrin, radixin, moesin, and merlin. Recently, a truncated form of the 4.1B protein, termed Dal-1, was identified in a screen as down regulated in adenocarcinoma of the lung and was mapped to chromosome 18p11.3, which is lost in 38% of primary non-small cell lung carcinoma tumors. Analysis of several meningiomas has shown that Dal-1 expression was lost in 76% of the tumors. To further elucidate the function of the 4.1B/Dal-1 gene in development and tumorigenesis we generated mice deficient for this allele. The 4.1B/Dal-1 null mice develop normally and are fertile. Rates of cellular proliferation and apoptosis in brain, mammary, and lung tissues from the 4.1B/Dal-1 null mice were indistinguishable from those seen with wild-type mice. Aging studies indicate that these mice do not have a propensity to develop tumors. Analysis of fibroblasts from these mice demonstrated that the growth characteristics and kinetics of these cells were not different from those of cells from the wild-type mice. These findings indicate that the 4.1B gene is not required for normal development and that 4.1B/Dal-1 does not function as a tumor suppressor gene.
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Affiliation(s)
- Chunling Yi
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
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Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK, Møller NPH. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J 2004; 18:8-30. [PMID: 14718383 DOI: 10.1096/fj.02-1212rev] [Citation(s) in RCA: 223] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The protein tyrosine phosphatases (PTPs) are now recognized as critical regulators of signal transduction under normal and pathophysiological conditions. In this analysis we have explored the sequence of the human genome to define the composition of the PTP family. Using public and proprietary sequence databases, we discovered one novel human PTP gene and defined chromosomal loci and exon structure of the additional 37 genes encoding known PTP transcripts. Direct orthologs were present in the mouse genome for all 38 human PTP genes. In addition, we identified 12 PTP pseudogenes unique to humans that have probably contaminated previous bioinformatics analysis of this gene family. PCR amplification and transcript sequencing indicate that some PTP pseudogenes are expressed, but their function (if any) is unknown. Furthermore, we analyzed the enhanced diversity generated by alternative splicing and provide predicted amino acid sequences for four human PTPs that are currently defined by fragments only. Finally, we correlated each PTP locus with genetic disease markers and identified 4 PTPs that map to known susceptibility loci for type 2 diabetes and 19 PTPs that map to regions frequently deleted in human cancers. We have made our analysis available at http://ptp.cshl.edu or http://science.novonordisk.com/ptp and we hope this resource will facilitate the functional characterization of these key enzymes.
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Affiliation(s)
- Jannik N Andersen
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724-2208, USA
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Smith KP, Lawrence JB. Interactions of U2 gene loci and their nuclear transcripts with Cajal (coiled) bodies: evidence for PreU2 within Cajal bodies. Mol Biol Cell 2000; 11:2987-98. [PMID: 10982395 PMCID: PMC14970 DOI: 10.1091/mbc.11.9.2987] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The Cajal (coiled) body (CB) is a structure enriched in proteins involved in mRNA, rRNA, and snRNA metabolism. CBs have been shown to interact with specific histone and snRNA gene loci. To examine the potential role of CBs in U2 snRNA metabolism, we used a variety of genomic and oligonucleotide probes to visualize in situ newly synthesized U2 snRNA relative to U2 loci and CBs. Results demonstrate that long spacer sequences between U2 coding repeats are transcribed, supporting other recent evidence that U2 transcription proceeds past the 3' box. The presence of bright foci of this U2 locus RNA differed between alleles within the same nucleus; however, this did not correlate with the loci's association with a CB. Experiments with specific oligonucleotide probes revealed signal for preU2 RNA within CBs. PreU2 was also detected in the locus-associated RNA foci, whereas sequences 3' of preU2 were found only in these foci, not in CBs. This suggests that a longer primary transcript is processed before entry into CBs. Although this work shows that direct contact of a U2 locus with a CB is not simply correlated with RNA at that locus, it provides the first evidence of new preU2 transcripts within CBs. We also show that, in contrast to CBs, SMN gems do not associate with U2 gene loci and do not contain preU2. Because other evidence indicates that preU2 is processed in the cytoplasm before assembly into snRNPs, results point to an involvement of CBs in modification or transport of preU2 RNA.
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Affiliation(s)
- K P Smith
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
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Mustelin T, Brockdorff J, Rudbeck L, Gjörloff-Wingren A, Han S, Wang X, Tailor P, Saxena M. The next wave: protein tyrosine phosphatases enter T cell antigen receptor signalling. Cell Signal 1999; 11:637-50. [PMID: 10530872 DOI: 10.1016/s0898-6568(99)00016-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Recent years have seen an exponentially increasing interest in the molecular mechanisms of signal transduction. Much of the focus has been on protein tyrosine kinase-mediated signalling, while the study of protein tyrosine phosphatases has lagged behind. We predict that the phosphatases will become a "hot topic" in the field within the next few years. This review summarizes the current state-of-the-art in our understanding of the structure, regulation and role of protein tyrosine phosphatases in T lymphocyte activation.
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Affiliation(s)
- T Mustelin
- Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
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Xing Y, Johnson CV, Moen PT, McNeil JA, Lawrence J. Nonrandom gene organization: structural arrangements of specific pre-mRNA transcription and splicing with SC-35 domains. J Cell Biol 1995; 131:1635-47. [PMID: 8557734 PMCID: PMC2120660 DOI: 10.1083/jcb.131.6.1635] [Citation(s) in RCA: 183] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
This work demonstrates a highly nonrandom distribution of specific genes relative to nuclear domains enriched in splicing factors and poly(A)+ RNA, and provides evidence for the direct involvement of these in pre-mRNA metabolism. As investigated in hundreds of diploid fibroblasts, human collagen I alpha 1 and beta-actin DNA/RNA showed a very high degree of spatial association with SC-35 domains, whereas three nontranscribed genes, myosin heavy chain, neurotensin, and albumin, showed no such preferential association. Collagen I alpha 1 RNA accumulates within the more central region of the domain, whereas beta-actin RNA localizes at the periphery. A novel approach revealed that collagen RNA tracks are polarized, with the entire gene at one end, on the edge of the domain, and the RNA extending into the domain. Intron 26 is spliced within the RNA track at the domain periphery. Transcriptional inhibition studies show both the structure of the domain and the gene's relationship to it are not dependent upon the continued presence of accumulated collagen RNA, and that domains remaining after inhibition are not just storage sites. Results support a model reconciling light and electron microscopic observations which proposes that transcription of some specific genes occurs at the border of domains, which may also function in the assembly or distribution of RNA metabolic components. In contrast to the apparently random dispersal of total undefined hnRNA synthesis through interdomain space, transcription and splicing for some genes occurs preferentially at specific sites, and a high degree of individual pre-mRNA metabolism is compartmentalized with discrete SC-35 domains.
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Affiliation(s)
- Y Xing
- School, Worcester 01655, USA
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