Id1, inhibitor of differentiation/DNA binding, plays an important role in cell proliferation, differentiation, angiogenesis, and tumorigenesis. It has been shown that Id1 is de-regulated in multiple cancers and up-regulation of Id1 correlates with more aggressiveness and higher grades of human cancers. In contrast, the p53 tumor suppressor was found to be mutated or inactivated in most human cancers. Loss of p53 results in early onset of multiple cancers. Although the biological functions of the Id1 oncogene and the p53 tumor suppressor have been intensively investigated, little is known about the upstream regulators of Id1 and the crosstalk between Id1 and p53. Here, we found that Id1 is a downstream effector of the DNA damage-p53-Dec1 pathway. Specifically, we showed that Id1 is down-regulated upon treatment with chemotherapeutic drugs. Interestingly, inhibition of Id1 expression upon DNA damage is partially rescued by p53-knockdown. In addition, we found that Dec1, which was recently identified as a p53 target and mediates p53-dependent cell cycle arrest and senescence, is capable of inhibiting Id1 expression. Conversely, we found that knockdown of Dec1 alleviates DNA damage-induced inhibition of Id1. Moreover, several potential Dec1 responsive elements were identified in the proximal promoter region of the Id1 gene. Finally, we showed that over-expression of Id1 or Id1’, an isoform of Id1, promotes cell proliferation and inhibits p21 expression. Taken together, for the first time, our study suggests that Id1 is a downstream effector of the DNA damage-p53-Dec1 pathway to antagonize the p53 function.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA