p53 and Delta Np63 alpha differentially bind and regulate target genes involved in cell cycle arrest, DNA repair and apoptosis.
The mechanism by which the p53 family of proteins coordinately regulates select target genes after various types of cell stress is not well understood. To further define factors that dictate regulation of target genes, we examined the binding of p53, DeltaNp63alpha and RNA polymerase II (pol II) to the regulatory regions of select target genes in primary human epidermal keratinocytes (HEKs) using chromatin immunoprecipitation. In rapidly proliferating cells, we observed constitutive binding of DeltaNp63alpha and varying levels of p53 binding, to consensus sites in target genes involved in cell cycle arrest, DNA repair and apoptosis. Following genotoxic stress, p53 occupancy increased whereas DeltaNp63alpha occupancy decreased at the majority of binding sites examined. Microarray analysis of transcripts isolated from HEKs ectopically expressing p53 and DeltaNp63alpha revealed an inverse regulation of select target genes by the two family members. Collectively, our results suggest that DeltaNp63alpha can function as a repressor of select p53 target genes involved in growth arrest, DNA repair and apoptosis, and that the location of the p53 consensus binding site(s) in a target gene may dictate whether pol II is constitutively bound in proliferating cells.
Schavolt
K L
KL
Department of Biochemistry, Center for Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Pietenpol
J A
JA
D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D005810:Multigene Family; D011485:Protein Binding / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000502:physiology
D004268:DNA-Binding Proteins; C495901:TP53 protein, human; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins