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

Physiology Department, Tufts University School of Medicine, Boston, Massachusetts (P.D., K.D.M., D.T.); and Medical Research Council Laboratory for Molecular Cell Biology, Cancer Research UK Oncogene and Signal Transduction Group, University College London, London, United Kingdom (A.B.J., A.H.)

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 human embryonic kidney 293T and PC-12 cells. Expression of Gz mutants with defective fatty acylation has 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 induction by an activated form of Rho kinase. Because Gz 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 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.

Address correspondence to:Dr. Keith D. Merdek, Physiology Department, Tufts University School of Medicine, Boston, MA 02111. E-mail: keith.merdek{at}tufts.edu

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