Mcl-1 regulation by rBH3 proteins.

rBH3 蛋白对 Mcl-1 的调节。

• 批准号: 9175202
• 负责人: William J. Placzek
• 金额: $ 30.87万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-08 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175202
• 关键词: Affect; Apoptosis; Apoptotic; Attention; BCL-2 Protein; BCL2 gene; Basic Science; Binding; CRISPR/Cas technology; Cancer cell line; Cells; Communication; DNA Damage; Data; Development; Exhibits; Family; Family member; Gene Expression; Goals; Grant; Homeostasis; Human; Internal Ribosome Entry Site; Knowledge; Lead; Light; Link; Luciferases; MCL1 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Mitosis; Mitotic; Mutate; Normal Cell; Normal tissue morphology; Oxidative Stress; Pathway interactions; Platinum; Polypyrimidine Tract-Binding Protein; Post-Transcriptional Regulation; Process; Proteins; Publishing; RNA; RNA Binding; RNA Processing; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Regulation; Reporter; Research; Resistance; Solid Neoplasm; Stress; System; Testing; Tissues; Translation Initiation; Translations; Transportation; Treatment-Related Cancer; Untranslated Regions; Up-Regulation; Variant; Work; anti-cancer therapeutic; base; cancer cell; cancer therapy; docetaxel; genetic regulatory protein; genome editing; improved; inhibitor/antagonist; insight; knock-down; mRNA Stability; novel; overexpression; response; taxane; tumor progression; tumorigenesis

ABSTRACT Apoptosis, a highly regulated process of programmed cell death, is essential for maintaining tissue homeostasis and development. Intrinsic apoptosis is regulated by the competitive interactions between anti- apoptotic and pro-apoptotic BCL-2 family members containing the BH3 helix or BH3 binding groove. MCL1 is an anti-apoptotic BCL-2 protein at the center of the intrinsic apoptotic pathway. Cells require strict control over MCL1 expression to maintain homeostasis. Aberrant MCL1 expression facilitates tumor progression and chemoresistance. Understanding the mechanisms that regulate MCL1 expression will improve MCL1 targeting in anti-cancer therapy. For instance, a growing understanding of the degradation factors affecting MCL1 has provided key insights regarding cellular response to prolonged mitosis. Yet, little is known regarding the regulation of MCL1 mRNA. While searching for putative RNA regulatory proteins we observed that polypyrimidine tract binding protein 1 (PTBP1), a master regulator for post-transcriptional control of gene expression through mRNA splicing, translation, turnover and localization, associated with MCL1. PTBP1 had previously come to our attention as a putative rBH3 containing protein that may directly interact with MCL1. Like MCL1, PTBP1 has been shown to be a critical factor in cellular differentiation, a mitotic regulator, and exhibits significant overexpression across the cancer landscape. Based on these data and our preliminary findings we propose in this grant to: (1) characterize post-transcriptional control of MCL1 mRNA by PTBP1, (2) characterize the direct interaction between PTBP1 and MCL1, and (3) characterize the effect of PTBP1 association with MCL1 protein and mRNA on cellular response to DNA damage and mitotic stress. Understanding the crosstalk between PTBP1 and MCL1 will advance the basic research in the field of apoptosis during normal development and cancer.

摘要 细胞凋亡是细胞程序性死亡的一个高度调控的过程，对维持组织是必不可少的 动态平衡和发展。内源性细胞凋亡受抗肿瘤细胞间竞争性相互作用的调节 含有BH3螺旋或BH3结合槽的凋亡和促凋亡bcl2家族成员。MCL1是 位于固有的细胞凋亡途径中心的抗细胞凋亡的bcl2蛋白。单元格需要严格控制 MCL1的表达维持动态平衡。MCL1异常表达促进肿瘤进展和 化疗耐药。了解调控MCL1表达的机制将提高MCL1的靶向性 在抗癌治疗中。例如，对影响MCL1的退化因素的了解不断加深 提供了关于细胞对长时间有丝分裂的反应的关键见解。然而，人们对此知之甚少 MCL1mRNA的调控。在寻找可能的RNA调节蛋白时，我们观察到 多嘧啶结合蛋白1(PTBP1)--基因转录后调控的主要调控因子 通过mRNA剪接、翻译、周转和定位来表达，与MCL1相关。PTBP1有 以前引起我们注意的是一个假定的含有rBH3的蛋白，它可能直接与MCL1相互作用。 与MCL1一样，PTBP1已被证明是细胞分化的关键因子，是有丝分裂的调节因子，以及 在癌症领域表现出显著的过度表达。基于这些数据和我们初步的 我们在这项资助中提出的发现是：(1)表征PTBP1对MCL1 mRNA的转录后调控，(2) 表征PTBP1和MCL1之间的直接相互作用，以及(3)表征PTBP1的作用 MCL1蛋白和mRNA在细胞对DNA损伤和有丝分裂应激反应中的相关性。 了解PTBP1和MCL1之间的串扰将促进PTBP1和MCL1领域的基础研究 正常发育和癌症过程中的细胞凋亡。