核PTEN肿瘤抑制因子通过维持异染色质结构发挥作用。
Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure.
作者信息
Gong Lili, Govan Jeane M, Evans Elizabeth B, Dai Hui, Wang Edward, Lee Szu-Wei, Lin Hui-Kuan, Lazar Alexander J, Mills Gordon B, Lin Shiaw-Yih
机构信息
a Department of Systems Biology ; The University of Texas MD Anderson Cancer Center ; Houston , TX USA.
出版信息
Cell Cycle. 2015;14(14):2323-32. doi: 10.1080/15384101.2015.1044174.
Abstract
The tumor suppressor, PTEN, is one of the most commonly mutated genes in cancer. Recently, PTEN has been shown to localize in the nucleus and is required to maintain genomic stability. Here, we show that nuclear PTEN, independent of its phosphatase activity, is essential for maintaining heterochromatin structure. Depletion of PTEN leads to loss of heterochromatic foci, decreased chromatin compaction, overexpression of heterochromatic genes, and reduced protein stability of heterochromatin protein 1 α. We found that the C-terminus of PTEN is required to maintain heterochromatin structure. Additionally, cancer-associated PTEN mutants lost their tumor-suppressor function when their heterochromatin structure was compromised. We propose that this novel role of PTEN accounts for its function in guarding genomic stability and suppressing tumor development.
摘要
肿瘤抑制因子PTEN是癌症中最常发生突变的基因之一。最近研究表明，PTEN定位于细胞核，对维持基因组稳定性至关重要。在此，我们发现细胞核中的PTEN，不依赖其磷酸酶活性，对于维持异染色质结构至关重要。PTEN的缺失导致异染色质位点丧失、染色质压缩减少、异染色质基因过表达以及异染色质蛋白1α的蛋白质稳定性降低。我们发现PTEN的C末端对于维持异染色质结构是必需的。此外，当异染色质结构受损时，与癌症相关的PTEN突变体失去了它们的肿瘤抑制功能。我们提出，PTEN的这一新功能解释了其在保护基因组稳定性和抑制肿瘤发展中的作用。
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本文引用的文献
1
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Cell Rep. 2014 Sep 25;8(6):2003-2014. doi: 10.1016/j.celrep.2014.08.008. Epub 2014 Sep 4.
2
PTEN C-terminal deletion causes genomic instability and tumor development.PTEN基因C端缺失会导致基因组不稳定和肿瘤发生。
Cell Rep. 2014 Mar 13;6(5):844-54. doi: 10.1016/j.celrep.2014.01.030. Epub 2014 Feb 20.
3
Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress.核 PTEN 控制 DNA 修复和对遗传毒性应激的敏感性。
Science. 2013 Jul 26;341(6144):395-9. doi: 10.1126/science.1236188.
4
High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome.PTEN 错构瘤肿瘤综合征患者的癌症累积风险较高。
J Med Genet. 2013 Apr;50(4):255-63. doi: 10.1136/jmedgenet-2012-101339. Epub 2013 Jan 18.
5
p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs.p53 与 DNA 甲基化和自杀性干扰素反应合作，维持重复序列和非编码 RNA 的表观遗传沉默。
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):E89-98. doi: 10.1073/pnas.1216922110. Epub 2012 Dec 10.
6
Chromatin organization is a major influence on regional mutation rates in human cancer cells.染色质构象在人类癌细胞的区域性突变率中起着重要影响。
Nature. 2012 Aug 23;488(7412):504-7. doi: 10.1038/nature11273.
7
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8
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9
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Science. 2011 Feb 4;331(6017):593-6. doi: 10.1126/science.1200801. Epub 2011 Jan 13.
10
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EMBO Mol Med. 2009 Sep;1(6-7):315-22. doi: 10.1002/emmm.200900041.
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