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

Estrogen tightly regulates the levels of circulating gonadotropins, but a direct effect of estrogen receptor alpha (ER alpha) on the mammalian LH beta gene has remained poorly defined. We demonstrate here that ER alpha can associate with the LH beta promoter through interactions with Sf-1 and Pitx1 without requiring an estrogen response element (ERE). We show that gonadotropin-releasing hormone (GnRH) promotes ERa ubiquitylation and also degradation while stimulating expression of ubc4. GnRH also increases the association and lengthens the cycling time of ER alpha on the LH beta promoter. The ERa association and transactivation of the LH beta gene, as well as ER(x degradation, are increased following ubc4 overexpression, while the effects of GnRH are abated following ubc4 knockdown. Our results indicate that ERa ubiquitylation and subsequent transactivation of the LH beta 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.