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J. Biol. Chem., Vol. 279, Issue 31, 32737-32750, July 30, 2004

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RhoA/ROCK Activation by Growth Hormone Abrogates p300/Histone Deacetylase 6 Repression of Stat5-mediated Transcription^*

Ling Ling and Peter E. Lobie¶

From the Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Republic of Singapore and Liggins Institute, University of Auckland, 2-6 Park Avenue, Private Bag 92019, Auckland, New Zealand

We demonstrate here that growth hormone (GH) stimulates the activation of RhoA and its substrate Rho kinase (ROCK) in NIH-3T3 cells. GH-stimulated formation of GTP-bound RhoA requires JAK2-dependent dissociation of RhoA from its negative regulator p190 RhoGAP. Inactivation of RhoA does not affect GH-stimulated JAK2 tyrosine phosphorylation nor p44/42 MAPK activity. However, RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. RhoA-dependent enhancement of GH-stimulated, Stat5-mediated transcription is due to repression of histone deacetylase 6 activity recruited by transcription cofactor p300 that negatively regulates GH-stimulated, Stat5-mediated transcription. We also demonstrate that RhoA is the pivot for cAMP-dependent protein kinase inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of cAMP-dependent protein kinase inactivation of RhoA through serine residue 188 of RhoA. We have therefore provided a novel mechanism by which a Ras-like small GTPase, RhoA, can regulate Stat5-mediated transcription.

Received for publication, January 20, 2004 , and in revised form, April 5, 2004.

^* This work was supported by grants from the National Science and Technology Board of Singapore (to P. E. L.), the School of Medicine Foundation, University of Auckland (to P. E. L.), and The National Research Centre for Growth and Development, New Zealand (Theme 2). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Liggins Institute, University of Auckland, 2-6 Park Ave., Private Bag 92019, Auckland, New Zealand. Tel.: 64-9-3737599 (ext. 82125); Fax: 64-9-3737497; E-mail: p.lobie{at}auckland.ac.nz.

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