Targeting BAD by JNK for Cell Survival

JNK 靶向 BAD 以促进细胞存活

• 批准号: 7093230
• 负责人: ANNING LIN
• 金额: $ 29.13万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093230
• 关键词: BCL2 gene /protein; JUN kinase; affinity chromatography; apoptosis; biological signal transduction; carcinogenesis; enzyme activity; genetic regulation; genetically modified animals; glycolysis; interleukin 3; laboratory mouse; mitogen activated protein kinase; molecular oncology; phosphorylation; protein purification; proteomics; small interfering RNA; yeast two hybrid system

DESCRIPTION (provided by applicant): The mitogen-activated protein kinase JNK (c-Jun-N-terminal protein kinase) has been implicated in many biological activities, including programmed cell death (apoptosis). In addition to playing a critical role in apoptosis, genetic and biochemical evidence suggests that JNK is also involved in cell survival. However, the molecular mechanism by which JNK promotes or inhibits apoptosis remains largely unknown. Using both genetic and biochemical approaches, we recently found that JNK activation is required for survival of IL- 3 (interleukin 3)-dependent cells. Specifically, JNK suppresses apoptosis in IL-3-dependent cells via phosphorylation and inactivation of the pro-apoptotic Bcl-2 family protein BAD. This proposal is novel, as it will delineate the signaling pathway that leads to JNK activation by a group of hematopoietic cytokines, reveal the molecular mechanism by which JNK inhibits the pro-apoptotic activity of BAD, and determine the role of JNK-mediated phosphorylation of BAD in physiological and/or pathological events, such as apoptosis, glycolysis, and tumorigenesis. Three hypothesis-driven specific aims will be pursued to determine how JNK suppresses the pro-apoptotic activity of BAD. This study should shed light on our understanding of the biology of JNK signaling pathway and may provide information that is critical to the development of novel strategies for targeting the apoptotic process in prevention and treatment of human diseases and cancer.

描述（由申请人提供）：有丝分裂原激活的蛋白激酶JNK（C-Jun-N-末端蛋白激酶）与许多生物学活性有关，包括程序性细胞死亡（凋亡）。除了在凋亡中发挥关键作用外，遗传和生化证据表明，JNK也参与了细胞存活。然而，JNK促进或抑制凋亡的分子机制在很大程度上尚不清楚。使用遗传和生化方法，我们最近发现，IL-3（白介素3）依赖性细胞的生存需要JNK激活。具体而言，JNK通过磷酸化和促凋亡Bcl-2家族蛋白不良的磷酸化和失活而抑制IL-3依赖性细胞的凋亡。该提议是新颖的，因为它将描述导致一组造血细胞因子激活JNK激活的信号传导途径，揭示了JNK抑制坏蛋的促凋亡活性的分子机制，并确定JNK介导的不良磷酸化的作用，例如生理和/或/或或病理学中的apopopoptigcoptississ，诸如apopopopopopticsiss，例如apopopopopoptigtississ和apopopopoptigtississ。将追求三个假设驱动的特定目标，以确定JNK如何抑制不良的凋亡活性。这项研究应阐明我们对JNK信号通路的生物学的理解，并可能提供有关针对预防和治疗人类疾病和癌症的凋亡过程的新型策略至关重要的信息。