Targeting BAD by JNK for Cell Survival

描述(申请人提供)：丝裂原活化蛋白激酶JNK(c-Jun-N末端蛋白激酶)与许多生物学活动有关，包括细胞程序性死亡(细胞凋亡)。除了在细胞凋亡中发挥关键作用外，遗传和生化证据表明，JNK也参与了细胞生存。然而，JNK促进或抑制细胞凋亡的分子机制在很大程度上仍不清楚。使用遗传和生化方法，我们最近发现JNK激活是IL-3(白介素3)依赖的细胞生存所必需的。具体地说，JNK通过磷酸化和失活促凋亡的Bcl-2家族蛋白BAD来抑制IL-3依赖的细胞的凋亡。这一建议是新颖的，因为它将描绘导致一组造血细胞因子激活JNK的信号通路，揭示JNK抑制BAD促凋亡活性的分子机制，并确定JNK介导的BAD磷酸化在生理和/或病理事件中的作用，如细胞凋亡、糖酵解和肿瘤发生。将追求三个假说驱动的特定目标来确定JNK如何抑制BAD的促凋亡活性。这项研究将有助于我们对JNK信号通路生物学的理解，并可能为开发新的针对人类疾病和癌症治疗中的凋亡过程的策略提供关键信息。

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.