3397

ID1

inhibitor of DNA binding 1, dominant negative helix-loop-helix protein;ID1;inhibitor of DNA binding 1, dominant negative helix-loop-helix protein

DNA-binding protein inhibitor ID-1|class B basic helix-loop-helix protein 24|dJ857M17.1.2 (inhibitor of DNA binding 1, dominant negative helix-loop-helix protein)|inhibitor of differentiation 1

20q11

protein-coding

It has been established that Id proteins can block the basic helix-loop-helix (HLH) transcription factors, thereby impacting the onset of senescence in keratinocytes, as well as influencing tumorigenesis involving squamous cell carcinomas. However, the ability of Id-1 to influence the immunologic response of epithelial cells to cytokines implicated in cutaneous oncology such as gamma interferon (IFN-gamma) has not been determined. Using a whole population of human keratinocytes infected with a retrovirus to induce over-expression of Id-1, the influence on early differentiation of rapidly proliferating keratinocytes was assessed, as was the response to IFN-gamma. While induction of involucrin, a marker of early differentiation, was not altered in Id-1 overexpressing keratinocytes, the IFN-gamma mediated increase in intercellular adhesion molecule-1 (ICAM-1) and HLA-DR was reduced. No change in constitutive or inducible levels of MHC class I antigen, CD95 (Fas antigen) or LFA-3 (CD58) was observed in this system. Immunostaining and Western blot analysis revealed over-expression of Id-1 in basal cell carcinomas (BCCs). These tumors not only strongly and diffusely expressed Id-1, but were also characterized by reduced ICAM-1 and HLA-DR expression. Thus, dysregulated Id-1 may not only contribute to delaying the senescence program in keratinocytes, it may also contribute to the escape of the relatively undifferentiated tumor cells in BCC from immune surveillance.

Id1, a member of Id family of helix-loop-helix transcriptional regulatory proteins, is implicated in cellular senescence by repressing p16(INK4a) expression, but the mechanisms and cellular effects in human diploid fibroblasts remain unknown. Here we analyzed the patterns of p16(INK4a) and Id1 expression during the lifespan of 2BS cells and presented the inverse correlation between these two proteins. Immunoprecipitation assays demonstrated the presence of endogenous interaction of Id1 and E47 proteins that was strong in young 2BS cells and weakened during replicative senescence and, thereby, influenced the transcription activation of p16(INK4a) by E47. Furthermore, we found that E47 protein could bind to the E-box-containing region in p16(INK4a) promoter in senescent cells by chromatin immunoprecipitation analyses, suggesting that E47 is indeed ultimately involved in the regulation of p16(INK4a) transcription in vivo. Silencing Id1 expression in young cells by RNA interference induced an increased p16(INK4a) level and premature cellular senescence, whereas silencing E47 expression inhibited the expression of p16(INK4a) and delayed the onset of senescent phenotype. The present study demonstrated not only the capacity of Id1 to regulate p16(INK4a) gene expression by E47, but also the phenotypic consequence of the regulation on cellular senescence, moreover, raised the possibility of Id1-specific gene silencing for human cancer therapy.