Glucocorticoid Mediated Signaling in Breast Cancer

描述（由申请人提供）：抗凋亡的鉴定 信号机制提供了一个实验框架， 癌前和恶性细胞如何逃避环境信号， 通常会引发人类乳腺上皮细胞的程序性细胞死亡 （MEC）。我们最近定义了一种新的糖皮质激素受体（GR）介导的 抗凋亡信号通路，其由生理性 浓度的糖皮质激素和GR特异性拮抗剂抑制 （抗糖皮质激素）。虽然糖皮质激素 激活糖皮质激素受体（GR）并反过来调节转录， 糖皮质激素介导的存活信号传导的确切机制 上皮细胞未知。最近，我们的实验室发现， GR反式激活基因的表达，血清和糖皮质激素诱导 激酶（SGK）抑制MEC中的凋亡。这一发现表明，SGK， 一种假定的丝氨酸苏氨酸激酶，是GR真正的转录靶点 激活，协调UR启动的生存信号。除了 转录激活的GR和翻译后磷酸化， 上游激酶，我们已经发现SGK蛋白的表达受到调节， 通过蛋白酶体介导的降解，揭示了另一个调节水平 SGK活动。这项补助金的总体目标是了解程度和 OR诱导的SGK表达有助于MEC存活的方式。到 为此，我们将首先确定凋亡级联反应的具体步骤， 然后确定SGK是否 活性可以替代GR激活。第二，我们将研究 OR激活和PI 3-K/PDK-1.2信号通路在SOK激酶活性激活中的作用 并随后抑制细胞凋亡。最后，我们将描述 蛋白酶体介导的野生型SGK的快速蛋白水解机制。 这些研究很可能会导致详细了解 调节GR-SGK抗凋亡途径的机制。

DESCRIPTION (provided by applicant): 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.