Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a.

Alani RM; Young AZ; Shifflett CB

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Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a.

机译：Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a.

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The Id family of helix-loop-helix (HLH) transcriptional regulatory proteins does not possess a basic DNA-binding domain and functions as a negative regulator of basic HLH transcription factors. Id proteins coordinate cell growth and differentiation pathways within mammalian cells and have been shown to regulate G(1)-S cell-cycle transitions. Although much recent data has implicated Id1 in playing a critical role in modulating cellular senescence, no direct genetic evidence has been reported to substantiate such work. Here we show that Id1-null primary mouse embryo fibroblasts undergo premature senescence despite normal growth profiles at early passage. These cells possess increased expression of the tumor-suppressor protein p16/Ink4a but not p19/ARF, and have decreased cyclin-dependent kinase (cdk) 2 and cdk4 kinase activity. We also show that Id1 is able to directly inhibit p16/Ink4a but not p19/ARF promoter activity via its HLH domain, and that Id1 inhibits transcriptional activation at E-boxes within the p16/Ink4a promoter. Our data provide, to our knowledge, the first genetic evidence for a role for Id1 as an inhibitor of cellular senescence and suggest that Id1 functions to delay cellular senescence through repression of p16/Ink4a. Because epigenetic and genetic abrogation of p16/Ink4a function has been implicated in the evolution of several human malignancies, we propose that transcriptional regulation of p16/Ink4a may also provide a mechanism for the dysregulation of normal cellular growth controls during the evolution of human malignancies.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2001年第14期|7812-7816|共5页
作者
Alani RM; Young AZ; Shifflett CB;
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作者单位

Oncology Center, Johns Hopkins University School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Room 336, Baltimore, MD 21231-1000, USA. ralani;

hylo.life.uiuc.edu;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Cell Aging; DNA-Binding Proteins; Protein p16; Transcription Factors; Id protein; 细胞衰老; DNA结合蛋白质类; 蛋白质p16; 转录因子;

Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a.

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