MECHANISM OF STEROID ACTION IN LYMPHOID MALIGNANCY

这项竞争性更新申请是为了研究糖皮质激素诱导淋巴瘤和白血病细胞凋亡的机制。 在分子和细胞生物学水平上深入了解这一机制对于了解糖皮质激素如何作为淋巴恶性肿瘤的治疗剂以及淋巴恶性肿瘤如何对糖皮质激素诱导的细胞凋亡产生抗性至关重要。 使用淋巴瘤和白血病细胞系作为模型系统，本研究的重点是两个研究主题，通过在本实验室的工作，在前一个资助期。 一是研究蛋白酶体介导的c-Fos降解在地塞米松（DX）诱导的细胞凋亡中的作用。 这一主题是基于最近的发现，即蛋白酶体介导的c-Fos降解是DX诱导的细胞凋亡中的早期、Bc 1 -2调节的步骤，并且c-FosdeltaC（一种逃避蛋白酶体降解的c-Fos突变体）是半胱天冬酶活化和细胞凋亡的有效抑制剂。 另一个主题是建立在钙从内质网（ER）中的细胞内储库释放参与介导DX诱导的细胞凋亡的证据上。目的1将研究DX诱导的细胞凋亡中c-Fos降解的机制，重点关注糖皮质激素受体和c-Fos - c-Jun相互作用在该过程中的作用。 目的2通过研究稳定的c-Fos突变体c-FosdeltaC抑制细胞凋亡的机制，试图了解c-Fos降解如何促进细胞凋亡。 该目的将研究c-FosdeltaC对糖皮质激素受体活性和AP-1-糖皮质激素受体串扰的影响。 此外，这一目标将确定由c-FosdeltaC调控的基因，其功能为凋亡抑制剂。 目的3研究ER钙释放在DX诱导的细胞凋亡中的作用，探讨ER钙释放如何触发细胞凋亡，以及ER钙释放与细胞凋亡中其他事件的关系，包括蛋白酶体介导的c-Fos降解和caspase激活。

This competing renewal application is for research into the mechanism of glucocorticosteroid induced apoptosis in lymphoma and leukemia cells. An in depth understanding of this mechanism at the molecular and cell biological level is essential to an understanding of how glucocorticoids work as therapeutic agents in lymphoid malignancies and how lymphoid malignancies become resistant to glucocorticoid-induced apoptosis. Using lymphoma and leukemia cell lines as a model system, this research focuses on two research themes that have arisen through work in this laboratory during the preceding funding period. One is focused on the role of proteasome-mediated c-Fos degradation in dexamethasone (DX)-induced apoptosis. This theme is based on the recent discovery that proteasome-mediated degradation of c-Fos is an early, Bc1-2-regulated step in DX induced apoptosis and that c-FosdeltaC, a c-Fos mutant that evades degradation by the proteasome, is a potent inhibitor of caspase activation and apoptosis. The other theme builds on evidence that calcium release from its intracellular reservoir in the endoplasmic reticulum (ER) is involved in mediating DX-induced apoptosis. Aim 1 will investigate the mechanism of c-Fos degradation in DX- induced apoptosis, focusing on the role of the glucocorticoid receptor and c-Fos - c-Jun interaction in this process. Aim 2 seeks to understand how c-Fos degradation contributes to apoptosis by investigating the mechanism by which the stable c- Fos mutant, c-FosdeltaC, inhibits apoptosis. This aim will investigate the effect of c-FosdeltaC on glucocorticoid receptor activity and on AP-1-glucocorticoid receptor crosstalk. Also, this aim will identify genes regulated by c-FosdeltaC that function as apoptosis inhibitors. Aim 3 will investigate the role of ER calcium release in DX induced apoptosis, determining how ER calcium release triggers apoptosis and the relationship between ER calcium release and other events in apoptosis, including proteasome-mediated c-Fos degradation and caspase activation.