Received for publication May 19, 2004.
Revised August 20, 2004.
Accepted for publication August 23, 2004.

Gz Inhibits Serum Response Factor-Dependent Transcription by Inhibiting Rho GTPase Signaling

Abstract

G12/13 or Gq 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 Gz signals inhibit serum response factor (SRF)-dependent transcription. Gz expression inhibits G12/13-, Gq-, and Rho guanine nucleotide exchange factor (GEF)-induced serum response element (SRE) reporter activation in HEK293T and PC12 cells. Expression of Gz mutants with defective fatty acylation have no inhibitory effect. Expression of Gz, but not Gi, attenuates serum-induced SRE reporter activation, suggesting that Gz can down-regulate endogenous signals leading to SRF. Whereas Gz also blocks SRE reporter induction by the activated mutant RhoAL63, it does not affect G12- or Rho GEF-induced RhoA activation, or RhoAL63-GTP binding in vivo. Moreover, Gz does not inhibit SRE reporter activation by an activated form of Rho-kinase (ROK). Since Gz inhibits RhoAL63/A188-induced reporter activation, phosphorylation of RhoA on serine 188 does not appear to be involved; furthermore, RhoA subcellular localization was not affected. Use of pharmacologic inhibitors implies that Gz-induced reduction of SRE reporter activation occurs via a mechanism other than adenylate cyclase modulation. These findings suggest that Gz signals may attenuate Rho-induced stimulation of SRF-mediated transcription.

Key words: Gi family, Gq/11 family, G12,13;other G's, Cdc42, rho, rac, other small G proteins, Transcription targets

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