MECHANISM OF STEROID ACTION IN LYMPHOID MALIGNANCY

类固醇在淋巴恶性肿瘤中的作用机制

• 批准号: 6475767
• 负责人: CLARK W DISTELHORST
• 金额: $ 28.82万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-11-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475767
• 关键词: AP1 protein; apoptosis; biological signal transduction; calcium flux; calreticulin; corticosteroid receptors; cysteine endopeptidases; dexamethasone; endonuclease; endoplasmic reticulum; enzyme activity; enzyme inhibitors; genetic transcription; hormone regulation /control mechanism; lymphocyte; lymphoma; membrane channels; mitochondria; neoplasm /cancer pharmacology; northern blottings; protooncogene; tissue /cell culture; transfection

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.

这种竞争性的更新应用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在淋巴系统恶性肿瘤中发挥治疗作用以及淋巴系统恶性肿瘤如何对糖皮质激素诱导的细胞凋亡产生抵抗力是至关重要的。以淋巴瘤和白血病细胞系为模型系统，这项研究集中在两个研究主题上，这两个主题是在之前的资助期间在这个实验室的工作中产生的。一种是蛋白酶体介导的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的降解是DX诱导的细胞凋亡中Bc1-2调控的早期步骤，而c-Fos突变体c-FosdeltaC可以逃避蛋白酶体的降解，是caspase激活和凋亡的有效抑制因子。另一个主题建立在内质网(ER)内细胞内钙释放参与介导DX诱导的细胞凋亡的证据之上。目的1探讨c-Fos降解在DX诱导的细胞凋亡中的作用机制，重点探讨糖皮质激素受体和c-Fos-c-Jun相互作用在此过程中的作用。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，探讨c-Fos降解对细胞凋亡的影响。本研究旨在探讨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，这一目标还将确定c-FosdeltaC调控的具有细胞凋亡抑制作用的基因。目的3研究内质网钙释放在DX诱导的细胞凋亡中的作用，确定内质网钙释放如何触发细胞凋亡，以及内质网钙释放与其他细胞凋亡事件的关系，包括蛋白酶体介导的c-Fos降解和caspase激活。