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

作者：Alani RM^*; Young AZ; Shifflett CB

来源：Proceedings of the National Academy of Sciences of the United States of America, 2001, 98(14): 7812-7816.

DOI：10.1073/pnas.141235398

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 Idl in playing a critical role in modulating cellular senescence, no direct genetic evidence has been reported to substantiate such work. Here we show that Idl-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 Idl is able to directly inhibit p16/Ink4a but not p19/ARF promoter activity via its HLH domain, and that Id1inhibits transcriptional activation at E-boxes within the p16/Ink4a promoter. Our data provide, to our knowledge, the first genetic evidence for a role for Idl as an inhibitor of cellular senescence and suggest that Idl 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.

• 出版日期2001-7-3