The identification of anti-apoptotic signaling mechanisms has provided an experimental framework for understanding how pre-malignant and malignant cells can escape environmental signals that would normally initiate programmed cell death in human mammary epithelial cells (MECs). we have recently defined a novel glucocorticoid receptor (GR)-mediated anti-apoptotic signaling pathway that is induced by physiological concentrations of glucocorticoid and inhibited by GR-specific antagonists (anti-glucocorticoids). Although it is well established that glucocorticoids activate the glucocorticoid receptor (GR) and in turn regulate transcription, the precise mechanism of glucocorticoid-mediated survival signaling in epithelial cells is not known. Recently, our laboratory has found that ectopic expression of a GR-transactivated gene, serum and glucocorticoid-inducible kinase (SGK), inhibits apoptosis in MECs. This finding suggests that SGK, a putative serinethreonine kinase, is a bona fide transcriptional target of GR activation that orchestrates UR-initiated survival signaling. In addition to transcriptional activation by the GR and post-translational phosphorylation by upstream kinases, we have discovered that SGK protein expression is regulated via proteasome-mediated degradation, revealing yet another level of regulation of SGK activity. The overall goal of this grant is to understand the extent and manner through which OR-induced SGK expression contributes to MEC survival. To this end, we will first determine the specific steps in the apoptotic cascade that are inhibited by glucocorticoids and then determine whether or not SGK activity can substitute for GR activation. Second, we will examine the role of OR activation and PI3-K/PDK-l.2 signaling in activating SOK's kinase activity and in subsequently inhibiting apoptosis. Finally, we will characterize the proteasome-mediated mechanism underlying wild type SGK's rapid proteolysis. Together these studies are likely to lead to a detailed understanding of the mechanisms regulating the GR-SGK anti-apoptotic pathway.
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