CDK8 is a stimulus-specific positive coregulator of p53 target genes.

The p53 transcriptional network orchestrates alternative stress responses such as cell-cycle arrest and apoptosis. Here we investigate the mechanism of differential expression of p21, a key mediator of p53-dependent cell-cycle arrest. We demonstrate that the transcriptional activity of the p21 promoter varies greatly in response to distinct p53-activating stimuli. Chromatin immunoprecipitation analysis of the p21 locus indicates that histone acetyltransferases, general transcription factors, and Mediator subunits are assembled into alternative transcriptional complexes of different activity. Interestingly, core Mediator subunits MED1 and MED17 are recruited to the p21 locus regardless of the p53-activating stimuli utilized. In contrast, three subunits of the CDK module of Mediator (CDK8, MED12, and cyclin C) are exclusively recruited during conditions of strong p21 transcriptional activation. Furthermore, increased binding of CDK8 to p53 target genes correlates positively with transcriptional strength. RNAi experiments demonstrate that CDK8 functions as a coactivator within the p53 transcriptional program.