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有读书笔记有附件Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus

阿平 添加于 2009-5-7 19:50 | 3464 次阅读 | 0 个评论

  •  作 者

    Chen H, Gu X, Su I-hsin, Bottino R, Contreras JL, Tarakhovsky A, Kim SK

  •  摘 要

    Proliferation of pancreatic islet beta cells is an important mechanism for self-renewal and for adaptive islet expansion. Increased expression of the Ink4a/Arf locus, which encodes the cyclin-dependent kinase inhibitor p16(INK4a) and tumor suppressor p19(Arf), limits beta-cell regeneration in aging mice, but the basis of beta-cell Ink4a/Arf regulation is poorly understood. Here we show that Enhancer of zeste homolog 2 (Ezh2), a histone methyltransferase and component of a Polycomb group (PcG) protein complex, represses Ink4a/Arf in islet beta cells. Ezh2 levels decline in aging islet beta cells, and this attrition coincides with reduced histone H3 trimethylation at Ink4a/Arf, and increased levels of p16(INK4a) and p19(Arf). Conditional deletion of beta-cell Ezh2 in juvenile mice also reduced H3 trimethylation at the Ink4a/Arf locus, leading to precocious increases of p16(INK4a) and p19(Arf). These mutant mice had reduced beta-cell proliferation and mass, hypoinsulinemia, and mild diabetes, phenotypes rescued by germline deletion of Ink4a/Arf. beta-Cell destruction with streptozotocin in controls led to increased Ezh2 expression that accompanied adaptive beta-cell proliferation and re-establishment of beta-cell mass; in contrast, mutant mice treated similarly failed to regenerate beta cells, resulting in lethal diabetes. Our discovery of Ezh2-dependent beta-cell proliferation revealed unique epigenetic mechanisms underlying normal beta-cell expansion and beta-cell regenerative failure in diabetes pathogenesis.

  •  详细资料

    • 关键词: Aging/metabolism; Animals; Antibiotics, Antineoplastic/pharmacology; Cell Proliferation/drug effects; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism; Diabetes Mellitus/*metabolism; Female; Gene Deletion; *Gene Expression Regulation/drug effects; Histone-Lysine N-Methyltransferase/*metabolism; Histones/metabolism; Humans; Insulin-Secreting Cells/cytology/drug effects/*metabolism; Male; Mice; Mice, Inbred C57BL; Streptozocin/pharmacology
    • 文献种类: Journal Article
    • 期刊名称: Genes & Development
    • 期刊缩写: Genes Dev
    • 期卷页: 2009年  第23卷 第8期 975-985页
    • 地址: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    • ISBN: 1549-5477
    • 备注:PMID:19390090

  • 学科领域 生物医药 » 生物学

  •  所属群组

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  •  标 签

    ezh2  ink4a  糖尿病 

  • 相关链接 DOI URL 

  •  附 件

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  •  阿平 的文献笔记  订阅

    还是ezh2，不过这次是关于糖尿病了。随着年龄的增长，beta细胞中EZH2表达水平越来越低，那么p16(INK4a) 和p19(Arf)表达越来越高，这就糖尿病的风险就不断增加。从这个层面讲，多表达些EZH2有利于防止糖尿病的发生，但是当EZH2表达太多的时候又提高发生肿瘤的风险？所以最终还是要有个适当的表达量才会是合适，

    这个观念也很合理，太多和太少都不行，保持中庸才能存活。但是不过如果能通过调控EZH2来治疗糖尿病或者肿瘤，那将意义重大。

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