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. ? ? ?
| Deng, Hongbin; Zhang, Jingpu; Yoon, Taewon et al. (2011) Phosphorylation of Bcl-associated death protein (Bad) by erythropoietin-activated c-Jun N-terminal protein kinase 1 contributes to survival of erythropoietin-dependent cells. Int J Biochem Cell Biol 43:409-15 |
| Tang, Fangming; Kokontis, John; Lin, Yuting et al. (2009) Androgen via p21 inhibits tumor necrosis factor alpha-induced JNK activation and apoptosis. J Biol Chem 284:32353-8 |
| Liu, Jing; Zhao, Yingming; Eilers, Martin et al. (2009) Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-alpha-induced JNK1 activation. Proc Natl Acad Sci U S A 106:18279-84 |
| Deng, Hongbin; Yu, Fei; Chen, Jianqun et al. (2008) Phosphorylation of Bad at Thr-201 by JNK1 promotes glycolysis through activation of phosphofructokinase-1. J Biol Chem 283:20754-60 |
