Stimulus-specific transcriptional regulation within the p53 network.
The p53 transcriptional network is composed of hundreds of effector genes involved in varied stress-response pathways, including cell cycle arrest and apoptosis. It is not clear how distinct p53 target genes are differentially activated to trigger stress-specific biological responses. We analyzed the p53 transcriptional program upon activation by two DNA-damaging agents, UVC and doxorubicin, versus the non-genotoxic molecule Nutlin-3. In colorectal cancer cells, UVC triggers apoptosis, doxorubicin induces transient cell cycle arrest followed by apoptosis, and Nutlin-3 leads to cell cycle arrest with no significant apoptosis. Quantitative gene expression analysis allowed us to group p53 target genes into three main classes according to their activation profiles in each scenario. The CDK-inhibitor p21 was classified as a Class I gene, being significantly activated under cell cycle arrest conditions (i.e. doxorubicin and Nutlin-3) but not during UVC-induced apoptosis. Chromatin immunoprecipitation analysis of the p21 locus indicates that the level of p53-dependent transcription is determined by the effects of stimulus-specific transcriptional coregulators acting downstream of p53 binding and histone acetylation. In particular, our analysis indicates that the subunits of the CDK-module of the human Mediator complex function as stimulus-specific positive coregulators of p21 transcription.
Donner
Aaron Joseph
AJ
Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, Colorado, USA.
Hoover
Jennifer Michelle
JM
Szostek
Stephanie Aspen
SA
Espinosa
Joaquín Maximiliano
JM
D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D016158:Genes, p53 / Q000502:physiology; D045325:HCT116 Cells; D006657:Histones / Q000502:physiology; D006801:Humans; D011485:Protein Binding / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D002843:Chromatin; D006657:Histones; D016159:Tumor Suppressor Protein p53