Bcl-2 family proteins in Shiga Toxin Induced Apoptosis

志贺毒素诱导细胞凋亡中的 Bcl-2 家族蛋白

• 批准号: 7085427
• 负责人: GREGORY H FOSTER
• 金额: $ 5.2万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-09 至 2007-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085427
• 关键词: BCL2 gene /protein; Bax gene /protein; Escherichia coli; SDS polyacrylamide gel electrophoresis; apoptosis; autoradiography; bioterrorism /chemical warfare; cysteine endopeptidases; cytochrome c; epithelium; gene expression; genetic regulation; mitochondria; mitogens; pathologic process; phosphorylation; postdoctoral investigator; shiga toxin; tissue /cell culture

DESCRIPTION (provided by applicant): The purpose of this research proposal is to investigate mechanisms involved in the Shiga toxin 2 induced apoptosis in the human kidney epithelial cell line HK-2. Infection with Shiga toxin producing E. coli may lead to the development of bloody diarrhea and hemolytic-uremic syndrome (HUS). The development of HUS has been attributed to Shiga toxin induced renal tissue injury. Shiga toxins are known to inhibit eukaryotic protein synthesis and cause cell death by apoptosis or necrosis. To investigate Shiga toxin induced apoptosis we propose to examine the phosphorylation of the anti-apoptotic Bcl-2 family members Bcl-2 and BcI-XL. In many cell systems these phosphorylation events are associated with the inhibition of the antiapoptotic function of these proteins and may lead to cell death. In addition, we also propose to examine the phosphorylation status and trafficking of the pro-apoptotic protein Bad, which when dephosphorylated, undergoes transport from the cytoplasm to the mitochondria to induce apoptosis. Finally, since Shiga toxins can inhibit protein synthesis, we wish to examine if Shiga toxin interferes with mRNA transcript stability and translation of a variety of pro- and anti-apoptotic genes as a novel mechanism of apoptosis regulation.

描述（由申请人提供）：本研究计划的目的是研究志贺毒素2诱导人肾上皮细胞系HK-2凋亡的机制。感染产生志贺毒素的大肠杆菌可能会导致血性腹泻和溶血尿毒症综合征 (HUS)。 HUS 的发生归因于志贺毒素引起的肾组织损伤。已知志贺毒素会抑制真核蛋白质合成并通过凋亡或坏死导致细胞死亡。为了研究志贺毒素诱导的细胞凋亡，我们建议检查抗细胞凋亡 Bcl-2 家族成员 Bcl-2 和 Bcl-XL 的磷酸化。在许多细胞系统中，这些磷酸化事件与这些蛋白质的抗凋亡功能的抑制有关，并可能导致细胞死亡。此外，我们还建议检查促凋亡蛋白 Bad 的磷酸化状态和运输，当该蛋白去磷酸化时，会从细胞质转运到线粒体以诱导细胞凋亡。最后，由于志贺毒素可以抑制蛋白质合成，我们希望检查志贺毒素是否干扰 mRNA 转录稳定性以及各种促凋亡和抗凋亡基因的翻译，作为细胞凋亡调节的新机制。