title: Identification of PHRF1 as a tumor suppressor that promotes the TGF-β cytostatic program through selective release of TGIF-driven PML inactivation.
abstract: The homeodomain protein TGIF (TG-interacting factor) restricts TGF-β/Smad cytostatic signaling by interfering with the nucleocytoplasmic transit of the tumor suppressor cPML. Here, we identify PHRF1 as a ubiquitin ligase that enforces TGIF decay by driving its ubiquitination at lysine 130. In so doing, PHRF1 ensures redistribution of cPML into the cytoplasm, where it associates with SARA and coordinates activation of Smad2 by the TGF-β receptor. The PHRF1 gene resides within the tumor suppressor locus 11p15.5, which displays frequent loss in a wide variety of malignancies, including breast cancer. Remarkably, we found that the PHRF1 gene is deleted or silenced in a high proportion of human breast cancer samples and cancer cell lines. Reconstitution of PHRF1 into deficient cells impeded their propensity to form tumors in vivo, most likely because of the reemergence of TGF-β responsiveness. These findings unveil a paradigm behind inactivation of the cPML tumor suppressor network in human malignancies.
authors.affiliation: Laboratory of Cell Signaling and Carcinogenesis, INSERM UMRS938, 184 Rue du Faubourg St-Antoine, 75571 Paris, France.
authors.forename: Asma
authors.initials: A
authors.lastname: Ettahar
authors.forename: Olivier
authors.initials: O
authors.lastname: Ferrigno
authors.forename: Ming-Zhu
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ferrand
authors.forename: Céline
authors.initials: C
authors.lastname: Prunier
authors.forename: Laurence
authors.initials: L
authors.lastname: Levy
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Bourgeade
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Damian G
authors.initials: DG
authors.lastname: Romero
authors.forename: Frédéric
authors.initials: F
authors.lastname: Colland
authors.forename: Azeddine
authors.initials: A
authors.lastname: Atfi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D005260:Female; D016147:Genes, Tumor Suppressor; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D018398:Homeodomain Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D012097:Repressor Proteins; C097504:TGIF1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C070576:PML protein, human