Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling.
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.
Seo
Su Ryeon
SR
INSERM U673, Hôpital St-Antoine, 184 Rue du Faubourg St-Antoine, 75571 Paris.
Ferrand
Nathalie
N
Faresse
Nourdine
N
Prunier
Céline
C
Abécassis
Lucile
L
Pessah
Marcia
M
Bourgeade
Marie-Francoise
MF
Atfi
Azeddine
A
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C097504:TGIF1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C070576:PML protein, human