Using Genetic Means to Identify Factors That Affect Estrogen Receptor Function

摘要

To identify novel components that affect the ER transcriptional response, we performed a genetic screen in yeast and identified RDIl, a Rho guanine nucleotide dissociation inhibitor, as a positive regulator of ER transactivation. In contrast, expression of constitutively active forms of RhoA, Racl, and Cdc42 decreases ER transcriptional activity, suggesting that Rho GDI increases ER transactivation by antagonizing ER inhibition by Rho GTpases. Our recent results indicate that the Rho GDI signal is transduced to ER by CBP/p300 through GRIPl- dependent and -independent pathways. Together, these findings establish Rho GTPases as important modulators of ER transcriptional activation by regulating of GRIPl and CPB coactivator activity. Our data suggest a complex relationship between ER transactivation and the Rho signaling pathways through modulation of receptor cofactors, which may have evolved to coordinate receptor- dependent gene expression with Rho-regulated events, such as cell migration. Our results also suggest that dysregulation of the Rho-ER axis may participate in cancer progression.