TY - JOUR T1 - Gαz Inhibits Serum Response Factor-Dependent Transcription by Inhibiting Rho Signaling JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1508 LP - 1516 DO - 10.1124/mol.104.002949 VL - 66 IS - 6 AU - Parmesh Dutt AU - Aron B. Jaffe AU - Keith D. Merdek AU - Alan Hall AU - Deniz Toksoz Y1 - 2004/12/01 UR - http://molpharm.aspetjournals.org/content/66/6/1508.abstract N2 - Gα12/13 or Gαq signals induce activation of Rho GTPase, leading to serum response factor (SRF)-mediated gene transcription and actin cytoskeletal organization; however, less is known regarding how Rho pathway signals are down-regulated. Here we report that Gαz signals inhibit serum response factor (SRF)-dependent transcription. Gαz expression inhibits Gα12/13-, Gαq-, and Rho guanine nucleotide exchange factor (GEF)-induced serum response element (SRE) reporter activation in human embryonic kidney 293T and PC-12 cells. Expression of Gαz mutants with defective fatty acylation has no inhibitory effect. Expression of Gαz, but not Gαi, attenuates serum-induced SRE reporter activation, suggesting that Gαz can down-regulate endogenous signals leading to SRF. Whereas Gαz also blocks SRE reporter induction by the activated mutant RhoAL63, it does not affect Gα12- or Rho GEF-induced RhoA activation or RhoAL63-GTP binding in vivo. Moreover, Gαz does not inhibit SRE reporter induction by an activated form of Rho kinase. Because Gαz inhibits RhoAL63/A188-induced reporter activation, phosphorylation of RhoA on serine 188 does not seem to be involved; furthermore, RhoA subcellular localization was not affected. Use of pharmacologic inhibitors implies that Gαz-induced reduction of SRE reporter activation occurs via a mechanism other than adenylate cyclase modulation. These findings suggest that Gαz signals may attenuate Rho-induced stimulation of SRF-mediated transcription. ER -