Rho GTPases as modulators of the estrogen receptor transcriptional response

The estrogen receptor cu (ER) is a ligand-dependent transcription factor th at plays a critical role in the development and progression of breast cance r, in part, by regulating target genes involved in cellular proliferation. To identify novel components that affect the ER transcriptional response, w e performed a genetic screen in yeast and identified RDI1, a Rho guanine nu cleotide dissociation inhibitor (Rho GDI), as a positive regulator of ER tr ansactivation. Overexpression of the human homologue of RDI1, Rho GDI alpha , increases ER alpha, ER beta, androgen receptor, and glucocorticoid recept or transcriptional activation in mammalian cells but not activation by the unrelated transcription factors serum response factor and Spl, In contrast, expression of constitutively active forms of RhoA, Rad, and Cdc42 decrease ER transcriptional activity, suggesting that Rho GDI increases ER transact ivation by antagonizing Rho function. Inhibition of RhoA by expression of e ither the Clostridium botulinum C3 transferase or a dominant negative RhoA resulted in enhanced ER transcriptional activation, thus phenocopying the e ffect of Rho GDI expression on ER transactivation. Together, these findings establish the Rho GTPases as important modulators of EHL transcriptional a ctivation. Since Rho GTPases regulate actin polymerization, our findings su ggest a link between the major regulators of cellular architecture and ster oid receptor transcriptional response.