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CDK8 is a stimulus-specific positive coregulator of p53 target genes
CDK8 is a stimulus-specific positive coregulator of p53 target genes
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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.
Donner AJ, Szostek S, Hoover JM, Espinosa JM
Molecular cell
2007-07-06 00:00
27
1
121-33
Acetylation,Cell Line, Tumor,Chromatin,Cyclin-Dependent Kinase Inhibitor p21,Cyclin-Dependent Kinases,Doxorubicin,Enzyme Activation,Fluorouracil,Gene Expression Profiling,Gene Expression Regulation,Histones,Humans,Promoter Regions (Genetics),Protein Binding,Protein Transport,Proto-Oncogene Proteins c-mdm2,RNA Polymerase II,Radiation, Ionizing,Transcription, Genetic,Tumor Suppressor Protein p53,Chromatin,Cyclin-Dependent Kinase Inhibitor p21,Histones,Tumor Suppressor Protein p53,Doxorubicin,Fluorouracil,CDK8 protein, human,Cyclin-Dependent Kinases,RNA Polymerase II,MDM2 protein, human,Proto-Oncogene Proteins c-mdm2
Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309, USA.
Mol. Cell
NCI CA117907, NCI CM05054
1097-2765
10.1016/j.molcel.2007.05.026
S1097-2765(07)00327-9
0
False
17612495
