Gβγ 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 G alpha and G beta gamma subunits regulate specific effectors to transmit signals received by the receptor. Recent data suggest potential nuclear localization or translocation of the G beta gamma subunit. Here, we show that co-expression of the G beta gamma 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 L beta T2 gonadotrope cells. Further, we identify Fos transcription factors as novel interactors of the G beta 1 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. G beta gamma did not interfere with the dimerization of Fos and Jun or their ability to bind DNA. Rather, G beta gamma 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 G beta gamma subunits as transcriptional regulators. (C) 2010 Elsevier Inc. All rights reserved.