Abstract
The estrogen receptor alpha (ER) is a ligand-dependent transcription factor that plays a critical role in the development and progression of breast cancer, in part, by regulating target genes involved in cellular proliferation. To identify novel components that affect the ER transcriptional response, we performed a genetic screen in yeast and identified RDI1, a Rho guanine nucleotide dissociation inhibitor (Rho GDI), as a positive regulator of ER transactivation. Overexpression of the human homologue of RDI1, Rho GDIalpha, increases ERalpha, ERbeta, androgen receptor, and glucocorticoid receptor transcriptional activation in mammalian cells but not activation by the unrelated transcription factors serum response factor and Sp1. In contrast, expression of constitutively active forms of RhoA, Rac1, and Cdc42 decrease ER transcriptional activity, suggesting that Rho GDI increases ER transactivation by antagonizing Rho function. Inhibition of RhoA by expression of either the Clostridium botulinum C3 transferase or a dominant negative RhoA resulted in enhanced ER transcriptional activation, thus phenocopying the effect of Rho GDI expression on ER transactivation. Together, these findings establish the Rho GTPases as important modulators of ER transcriptional activation. Since Rho GTPases regulate actin polymerization, our findings suggest a link between the major regulators of cellular architecture and steroid receptor transcriptional response.
Highlights
The estrogen receptor ␣ (ER)1 is a ligand-dependent transcription factor that transduces the estrogen signal [1]
Our findings indicate that Rho guanine nucleotide dissociation inhibitor (Rho GDI)␣ increases the transcriptional activity of ER␣ and ER as well as the glucocorticoid receptor (GR) and androgen receptor (AR), but not of the unrelated transcription factors serum response factor (SRF) and Sp1, and that this activation is mediated via repression of Rho GTPases
We have demonstrated that Rho GDI␣ enhances the transcriptional activity of the ER␣ as well as ER, GR, and AR but not SRF or Sp1
Summary
This approach has proven successful for investigating various aspects of ER signal transduction [11] Using this system, we have isolated RDI1, the yeast Rho guanine nucleotide dissociation inhibitor (Rho GDI), as a gene product that is capable of increasing both ERAAA and WT ER transcriptional activation when overexpressed. We have isolated RDI1, the yeast Rho guanine nucleotide dissociation inhibitor (Rho GDI), as a gene product that is capable of increasing both ERAAA and WT ER transcriptional activation when overexpressed This gene product is the yeast homologue of the mammalian Rho GDI␣, a cytoplasmic protein originally identified as a negative regulator of the Rho family of GTPbinding proteins [12,13,14,15]. These results further establish the Rho-mediated signaling pathway as an important regulator of ER, GR, and AR transcriptional activity
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