Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling

Su Ryeon Seo; Nathalie Ferrand; Nourdine Faresse; Céline Prunier; Lucile Abécassis; Marcia Pessah; Marie-Francoise Bourgeade; Azeddine Atfi

doi:10.1016/j.molcel.2006.06.018

Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling

Mol Cell. 2006 Aug;23(4):547-59. doi: 10.1016/j.molcel.2006.06.018.

Authors

Su Ryeon Seo¹, Nathalie Ferrand, Nourdine Faresse, Céline Prunier, Lucile Abécassis, Marcia Pessah, Marie-Francoise Bourgeade, Azeddine Atfi

Affiliation

¹ INSERM U673, Hôpital St-Antoine, 184 Rue du Faubourg St-Antoine, 75571 Paris.

PMID: 16916642
DOI: 10.1016/j.molcel.2006.06.018

Abstract

The homeodomain protein TGIF has been implicated in the negative regulation of TGF-beta signaling. In this study, we report an unexpected role of TGIF in the inhibition of Smad2 phosphorylation, which occurs by a mechanism independent of its association with Smad2. This inhibitory function of TGIF is executed in concert with c-Jun, which facilitates the interaction of TGIF with cPML, resulting in the nuclear sequestration of cPML and the disruption of the cPML-SARA complex. Notably, knockdown of TGIF by siRNA caused increased association of cPML with SARA and cytoplasmic accumulation of cPML. Furthermore, c-Jun(-/-) fibroblasts exhibit enhanced association of cPML with SARA. c-Jun(-/-) fibroblasts also lose their sensitivity to TGIF-mediated disruption of the cPML-SARA complex and of nuclear sequestration of cPML. We suggest that the interaction of TGIF with cPML through c-Jun may negatively regulate TGF-beta signaling through controlling the localization of cPML and, consequently, the assembly of the cPML-SARA complex.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
COS Cells
Cell Nucleus / metabolism*
Cells, Cultured
Chlorocebus aethiops
Dogs
Down-Regulation / drug effects
Epithelial Cells / cytology
Epithelial Cells / drug effects
Homeodomain Proteins / metabolism*
Humans
Mice
Neoplasm Proteins / metabolism*
Nuclear Proteins / metabolism*
Phosphorylation / drug effects
Promyelocytic Leukemia Protein
Protein Binding
Proto-Oncogene Proteins c-jun / deficiency
Proto-Oncogene Proteins c-jun / metabolism
Repressor Proteins / metabolism*
Signal Transduction / drug effects*
Smad2 Protein / metabolism
Transcription Factors / metabolism*
Transcription, Genetic / drug effects
Transforming Growth Factor beta / pharmacology*
Tumor Suppressor Proteins / metabolism*

Substances

Homeodomain Proteins
Neoplasm Proteins
Nuclear Proteins
Pml protein, mouse
Promyelocytic Leukemia Protein
Proto-Oncogene Proteins c-jun
Repressor Proteins
SMAD2 protein, human
Smad2 Protein
TGIF1 protein, human
Transcription Factors
Transforming Growth Factor beta
Tumor Suppressor Proteins
PML protein, human