Chromatin-bound p53 anchors activated Smads and the mSin3A corepressor to confer transforming-growth-factor-beta-mediated transcription repression.
In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP, an oncodevelopmental tumor marker aberrantly reactivated in hepatoma cells. Using p53- and SnoN-depleted hepatoma cell clones, we define a mechanism for repression mediated by this novel transcriptional partnership. We find that p53 anchors activated Smads and the corepressor mSin3A to the AFP distal promoter. Sequential chromatin immunoprecipitation analyses and molecular modeling indicate that p53 and Smad proteins simultaneously occupy overlapping p53 and Smad regulatory elements to establish repression of AFP transcription. In addition to its well-known function in antagonizing transforming growth factor beta (TGF-beta) responses, we find that SnoN actively participates in AFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF-beta signaling restores a dynamic interplay between p53 and TGF-beta effectors that cooperate to effectively target mSin3A to tumor marker AFP and reestablish transcription repression.
Wilkinson
Deepti Srinivas
DS
Department of Biochemistry and Molecular Biology, Unit 1000, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Tsai
Wen-Wei
WW
Schumacher
Maria A
MA
Barton
Michelle Craig
MC
D000818:Animals; D002460:Cell Line / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D051899:Smad2 Protein / Q000737:chemistry / Q000502:physiology*; D051901:Smad4 Protein / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000509:alpha-Fetoproteins / Q000096:biosynthesis* / Q000235:genetics
D002843:Chromatin; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C486157:Skil protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D000509:alpha-Fetoproteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex