Regulation of GRIP1 and CBP Coactivator activity by Rho GDI modulates estrogen receptor transcriptional enhancement.
Estrogen receptor alpha (ER) coordinates gene expression with cellular physiology in part by controlling receptor- cofactor interactions in response to extracellular signals. We have previously shown that the Rho signaling pathway modulates ER transcriptional activation. We now demonstrate that Rho GDI-dependent increase in ER transactivation is dependent on the ER AF-2 coactivator binding site, prompting us to examine regulation of receptor coactivators by Rho GDI. Indeed, Rho GDI cooperates with GRIP1 to increase ER ligand-independent and ligand-dependent transactivation and also enhances GRIP1 transcriptional activity when GRIP1 is tethered to DNA. The GRIP1 activation domain 1 (AD1), which binds CBP/p300, is necessary for Rho GDI to modulate GRIP1 activity. Using E1A to inhibit the endogenous CBP/p300 and a Gal4-CBP fusion protein to assay CBP activity, we find that the effect of Rho GDI on ER transactivation is CBP/p300-dependent. Importantly, the ability of CBP/p300 to transduce the Rho GDI signal to ER occurs through both GRIP1-dependent and -independent pathways. These data suggest a complex interplay between ER transcriptional activation and the Rho signaling pathways through modulation of receptor cofactors, which may have evolved to coordinate receptor-dependent gene expression with Rho-regulated events, such as cell migration. We speculate that dysregulation of the Rho-ER axis may participate in cancer progression.
Department of Microbiology, The Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016, USA.
Laura F
LF
Su
Zhen
Z
Wang
Michael J
MJ
Garabedian
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D000431:Ethanol / Q000494:pharmacology; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D051958:Nuclear Receptor Coactivator 2; D012516:Osteosarcoma; D011960:Receptors, Estrogen / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014981:Xenopus; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D002352:Carrier Proteins; D047628:Estrogen Receptor alpha; D020730:Guanine Nucleotide Dissociation Inhibitors; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C020723:citrate-binding transport protein; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D013629:Tamoxifen; D000431:Ethanol; D004958:Estradiol; D020741:rho GTP-Binding Proteins