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

Amanda L Balboni1, Pratima Cherukuri2, Matthew Ung3

  • 1Program in Experimental and Molecular Medicine, The Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Department of Pharmacology and Toxicology, The Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

Molecular Cancer Research : MCR
|February 21, 2015
PubMed
Abstract

Insights

The study reveals p53 and delta Np63alpha as key partners for SMAD proteins, influencing cellular responses to TGFβ and BMP signaling. This interaction is crucial for regulating genes involved in epithelial-to-mesenchymal transition and metastasis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The TGFβ superfamily regulates critical cellular processes like proliferation and differentiation.
  • The molecular mechanisms behind TGFβ superfamily's pleiotropy and cell-type specificity are not fully understood.
  • SMAD proteins, signaling mediators for TGFβ and BMPs, require coactivators/corepressors for transcriptional output due to weak DNA-binding affinity.

Purpose of the Study:

  • To investigate the role of p53 and ΔNp63α as transcriptional partners for SMAD proteins.
  • To elucidate how p53 and ΔNp63α influence cellular responses to TGFβ and BMP signaling pathways.
  • To understand the integrated gene network involving SMADs, p53, and ΔNp63α in epithelial-to-mesenchymal transition (EMT) and metastasis.

Main Methods:

  • Investigated physical interactions between p53/ΔNp63α and SMAD proteins.
  • Analyzed co-occupancy of p53/ΔNp63α and SMADs at the promoter region of ID2.
  • Utilized bioinformatic analyses to identify coregulated transcripts by SMAD2/3 and ΔNp63α involved in EMT.
  • Assessed the impact of p53 suppression and ΔNp63α overexpression on BMP-induced transcription.

Main Results:

  • p53 and ΔNp63α act as transcriptional partners for SMAD proteins, modulating TGFβ and BMP signaling.
  • Suppression of p53 or overexpression of ΔNp63α synergistically enhances BMP-induced transcription.
  • p53 and ΔNp63α physically interact with SMAD1/5/8 and co-occupy the ID2 promoter.
  • TGFβ-induced transcription is regulated in a ΔNp63α- and p53-dependent manner.
  • SMAD2/3 and ΔNp63α coregulate numerous transcripts involved in EMT.

Conclusions:

  • p53 and ΔNp63α are identified as transcriptional partners for a subset of TGFβ- and BMP-regulated SMAD target genes in mammary epithelium.
  • An integrated gene network of SMADs, p53, and ΔNp63α contributes to EMT and metastasis.
  • Aberrant BMP activation results from p53 mutation or ΔNp63α expression.

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