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

The Id family of helix-loop-helix (HLH) transcriptional regulatory proteins does not possess a basic DNA-binding domain and functions as a negative re gulator of basic HLH transcription factors. Id proteins coordinate cell gro wth and differentiation pathways within mammalian cells and have been shown to regulate G(1)-S cell-cycle transitions. Although much recent data has i mplicated Idl in playing a critical role in modulating cellular senescence, no direct genetic evidence has been reported to substantiate such work. He re we show that Idl-null primary mouse embryo fibroblasts undergo premature senescence despite normal growth profiles at early passage. These cells po ssess increased expression of the tumor-suppressor protein p16/Ink4a but no t p19/ARF, and have decreased cyclin-dependent kinase (cdk) 2 and cdk4 kina se activity. We also show that Idl is able to directly inhibit p16/Ink4a bu t not p19/ARF promoter activity via its HLH domain, and that Id1inhibits tr anscriptional activation at E-boxes within the p16/Ink4a promoter. Our data provide, to our knowledge, the first genetic evidence for a role for Idl a s an inhibitor of cellular senescence and suggest that Idl functions to del ay cellular senescence through repression of p16/Ink4a, Because epigenetic and genetic abrogation of p16/Ink4a function has been implicated in the evo lution of several human malignancies, we propose that transcriptional regul ation of p16/Ink4a may also provide a mechanism for the dysregulation of no rmal cellular growth controls during the evolution of human malignancies.