title: Mutant p53 promotes tumor cell malignancy by both positive and negative regulation of the transforming growth factor β (TGF-β) pathway.
abstract: Specific p53 mutations abrogate tumor-suppressive functions by gaining new abilities to promote tumorigenesis. Inactivation of p53 is known to distort TGF-β signaling, which paradoxically displays both tumor-suppressive and pro-oncogenic functions. The molecular mechanisms of how mutant p53 simultaneously antagonizes the tumor-suppressive and synergizes the tumor-promoting function of the TGF-β pathway remain elusive. Here we demonstrate that mutant p53 differentially regulates subsets of TGF-β target genes by enhanced binding to the MH2 domain in Smad3 upon the integration of ERK signaling, therefore disrupting Smad3/Smad4 complex formation. Silencing Smad2, inhibition of ERK, or introducing a phosphorylation-defective mutation at Ser-392 in p53 abrogates the R175H mutant p53-dependent regulation of these TGF-β target genes. Our study shows a mechanism to reconcile the seemingly contradictory observations that mutant p53 can both attenuate and cooperate with the TGF-β pathway to promote cancer cell malignancy in the same cell type.
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ji
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.affiliation: the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ali
authors.initials: A
authors.lastname: Amjad
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Qingwu
authors.initials: Q
authors.lastname: Liu
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: the Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China jianruxiao@163.com.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China, the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, and xiaotaol@bcm.edu.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Migration; SMAD Transcription Factor; TGF-β; Tumor Cell Biology; p53