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

Mol Cancer Res. 2015 Apr;13(4):732-42. doi: 10.1158/1541-7786.MCR-14-0152-T. Epub 2015 Feb 19.

Abstract

The TGFβ 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 TGFβ family is composed of two branches: (i) TGFβs, 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 ΔNp63α act as transcriptional partners for SMAD proteins and thereby influence cellular responses to TGFβ and BMPs. Suppression of p53 or overexpression of ΔNp63α synergistically enhance BMP-induced transcription. Mechanistically, p53 and ΔNp63α 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, TGFβ-induced canonical BMP regulated transcription in a ΔNp63α- and p53-dependent manner. Furthermore, bioinformatic analyses revealed that SMAD2/3 and ΔNp63α coregulate a significant number of transcripts involved in the regulation of epithelial-to-mesenchymal transition. Thus, p53 and ΔNp63α are transcriptional partners for a subset of TGFβ- and BMP-regulated SMAD target genes in the mammary epithelium. Collectively, these results establish an integrated gene network of SMADs, p53, and ΔNp63α that contribute to EMT and metastasis.

Implications: This study identifies aberrant BMP activation as a result of p53 mutation or ΔNp63α expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Humans
  • Signal Transduction
  • Smad Proteins / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Bone Morphogenetic Proteins
  • Smad Proteins
  • TP53 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins