Identification of PHRF1 as a tumor suppressor that promotes the TGF-β cytostatic program through selective release of TGIF-driven PML inactivation

Asma Ettahar; Olivier Ferrigno; Ming-Zhu Zhang; Mutsuko Ohnishi; Nathalie Ferrand; Céline Prunier; Laurence Levy; Marie-Françoise Bourgeade; Ivan Bieche; Damian G Romero; Frédéric Colland; Azeddine Atfi

doi:10.1016/j.celrep.2013.07.009

Identification of PHRF1 as a tumor suppressor that promotes the TGF-β cytostatic program through selective release of TGIF-driven PML inactivation

Cell Rep. 2013 Aug 15;4(3):530-41. doi: 10.1016/j.celrep.2013.07.009. Epub 2013 Aug 1.

Authors

Asma Ettahar¹, Olivier Ferrigno, Ming-Zhu Zhang, Mutsuko Ohnishi, Nathalie Ferrand, Céline Prunier, Laurence Levy, Marie-Françoise Bourgeade, Ivan Bieche, Damian G Romero, Frédéric Colland, Azeddine Atfi

Affiliation

¹ Laboratory of Cell Signaling and Carcinogenesis, INSERM UMRS938, 184 Rue du Faubourg St-Antoine, 75571 Paris, France.

PMID: 23911286
DOI: 10.1016/j.celrep.2013.07.009

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Dogs
Female
Genes, Tumor Suppressor
Hep G2 Cells
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Interferon Regulatory Factor-7 / genetics*
Interferon Regulatory Factor-7 / metabolism
Madin Darby Canine Kidney Cells
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Phosphorylation
Promyelocytic Leukemia Protein
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Repressor Proteins / genetics
Repressor Proteins / metabolism
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic
Transfection
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism*
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism
Ubiquitination

Substances

Homeodomain Proteins
IRF7 protein, human
Interferon Regulatory Factor-7
Nuclear Proteins
Promyelocytic Leukemia Protein
RNA, Messenger
Repressor Proteins
TGIF1 protein, human
Transcription Factors
Transforming Growth Factor beta
Tumor Suppressor Proteins
PML protein, human

Grants and funding

FP20RR016476/FP/OFP OPHS HHS/United States