Gbetagamma is a negative regulator of AP-1 mediated transcription.
Following stimulation of G protein-coupled receptors (GPCRs) at the cell surface, heterotrimeric G proteins are activated. Both Galpha and Gbetagamma subunits regulate specific effectors to transmit signals received by the receptor. Recent data suggest potential nuclear localization or translocation of the Gbetagamma subunit. Here, we show that co-expression of the Gbetagamma dimer decreased phorbol 12-myristate 13-acetate (PMA)-stimulated AP-1 gene reporter activity in HEK293 cells as well as the AP-1 dependent gonadotropin-releasing hormone-stimulated human follicle-stimulating hormone beta reporter activity in LbetaT2 gonadotrope cells. Further, we identify Fos transcription factors as novel interactors of the Gbeta1 subunit, using protein fragment complementation assays, as well as co-immunoprecipitation in vivo and in vitro. Fos proteins dimerize with Jun proteins to form activator protein-1 (AP-1) transcription factor complexes, which regulate target gene expression. Gbetagamma did not interfere with the dimerization of Fos and Jun or their ability to bind DNA. Rather, Gbetagamma co-localized with the AP-1 complex in the nucleus and recruited histone deacetylases (HDACs) to inhibit AP-1 transcriptional activity. Our data indicate a novel role for Gbetagamma subunits as transcriptional regulators.
Robitaille
Mélanie
M
Département de Biochimie, Université de Montréal, Montréal, Québec, Canada.
Gora
Sarah
S
Wang
Ying
Y
Goupil
Eugénie
E
Pétrin
Darlaine
D
Del Duca
Danny
D
Villeneuve
Louis R
LR
Allen
Bruce G
BG
Laporte
Stéphane A
SA
Bernard
Daniel J
DJ
Hébert
Terence E
TE
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D044387:GTP-Binding Protein beta Subunits / Q000032:analysis / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic
C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1