p53 and DNp63a Coregulate the Transcriptional and Cellular Response to TGFb and BMP Signals

The TGFb superfamily regulates a broad range of cellular processes, including proliferation, cell-fate specification, differentiation, and migration. Molecular mechanisms underlying this high degree of pleiotropy and cell-type specificity are not well understood. The TGFb family is composed of two branches: (i) TGFbs, activins, and nodals, which signal through SMAD2/3, and (ii) bone morphogenetic proteins (BMP), which signal through SMAD1/5/8. SMADs have weakDNA-binding affinity and rely on coactivators and corepressors to specify their transcriptional outputs. This report reveals that p53 and DNp63a act as transcriptional partners for SMAD proteins and thereby influence cellular responses to TGFb and BMPs. Suppression of p53 or overexpression of DNp63a synergistically enhance BMP-induced transcription. Mechanistically, p53 and DNp63a physically interact with SMAD1/5/8 proteins and co-occupy the promoter region of inhibitor of differentiation (ID2), a prosurvival BMP target gene. Demonstrating further convergence of these pathways, TGFbinduced canonical BMP regulated transcription in a DNp63aand p53-dependent manner. Furthermore, bioinformatic analyses revealed that SMAD2/3 and DNp63a coregulate a significant number of transcripts involved in the regulation of epithelial-tomesenchymal transition. Thus, p53 and DNp63a are transcriptional partners for a subset of TGFband BMP-regulated SMAD target genes in the mammary epithelium. Collectively, these results establish an integrated gene network of SMADs, p53, and DNp63a that contribute to EMT and metastasis. Implications: This study identifies aberrant BMP activation as a result of p53mutation orDNp63a expression.MolCancer Res; 13(4);