RT Journal Article
SR Electronic
T1 Gαz Inhibits Serum Response Factor-Dependent Transcription by Inhibiting Rho Signaling
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1508
OP 1516
DO 10.1124/mol.104.002949
VO 66
IS 6
A1 Dutt, Parmesh
A1 Jaffe, Aron B.
A1 Merdek, Keith D.
A1 Hall, Alan
A1 Toksoz, Deniz
YR 2004
UL http://molpharm.aspetjournals.org/content/66/6/1508.abstract
AB 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.