title: p53 and ΔNp63α Coregulate the Transcriptional and Cellular Response to TGFβ and BMP Signals.
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.
  
  
  CONCLUSIONS
  This study identifies aberrant BMP activation as a result of p53 mutation or ΔNp63α expression.
authors.affiliation: Program 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.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Balboni
authors.affiliation: Department of Pharmacology and Toxicology, The Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Pratima
authors.initials: P
authors.lastname: Cherukuri
authors.affiliation: Department of Genetics, The Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ung
authors.affiliation: Program 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.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: DeCastro
authors.affiliation: Department of Genetics, The Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology and Toxicology, The Audrey and Theodor Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Lebanon, New Hampshire. james.direnzo@dartmouth.edu.
authors.forename: James
authors.initials: J
authors.lastname: DiRenzo
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins