Cross talk in hormonally regulated gene transcription through induction of estrogen receptor ubiquitylation

Abstract

Estrogen tightly regulates the levels of circulating gonadotropins, but a direct effect of estrogen receptor alpha (ERα) on the mammalian LHβ gene has remained poorly defined. We demonstrate here that ERα can associate with the LHβ promoter through interactions with Sf-1 and Pitx1 without requiring an estrogen response element (ERE). We show that gonadotropin-releasing hormone (GnRH) promotes ERα ubiquitylation and also degradation while stimulating expression of ubc4. GnRH also increases the association and lengthens the cycling time of ERα on the LHβ promoter. The ERα association and transactivation of the LHβ gene, as well as ERα degradation, are increased following ubc4 overexpression, while the effects of GnRH are abated following ubc4 knockdown. Our results indicate that ERα ubiquitylation and subsequent transactivation of the LHβ gene can be induced by increasing the levels of the E2 enzyme as a result of signaling by an extracellular hormone, thus providing a new form of cross talk in hormonally stimulated regulation of gene expression. Copyright © 2005, American Society for Microbiology. All Rights Reserved.