p53 and ΔNp63α Coregulate the Transcriptional and Cellular Response to TGFβ and BMP Signals

The TGF beta 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 TGF beta family is composed of two branches: (i) TGF beta s, activins, and nodals, which signal through SMAD2/3, and (ii) bone morphogenetic proteins (BMP), which signal through SMAD1/5/8. SMADs have weak DNA-binding affinity and rely on coactivators and corepressors to specify their transcriptional outputs. This report reveals that p53 and Delta Np63 alpha act as transcriptional partners for SMAD proteins and thereby influence cellular responses to TGF beta and BMPs. Suppression of p53 or overexpression of Delta Np63 alpha synergistically enhance BMP-induced transcription. Mechanistically, p53 and Delta Np63 alpha 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, TGF beta-induced canonical BMP regulated transcription in a Delta Np63 alpha and p53-dependent manner. Furthermore, bioinformatic analyses revealed that SMAD2/3 and Delta Np63 alpha coregulate a significant number of transcripts involved in the regulation of epithelial-to-mesenchymal transition. Thus, p53 and Delta Np63 alpha are transcriptional partners for a subset of TGF beta- and BMP-regulated SMAD target genes in the mammary epithelium. Collectively, these results establish an integrated gene network of SMADs, p53, and Delta Np63 alpha that contribute to EMT and metastasis. Implications: This study identifies aberrant BMP activation as a result of p53 mutation or Delta Np63 alpha expression.