Programmed cell death, or apoptosis, is a fundamental biological process in development and homeostasis within all multicellular organisms. Disturbances in the regulation of apoptosis may result in multiple diseases, including cancer. Understanding the process and regulation of apoptosis may provide novel clinical approaches to cancer therapy. The susceptibility to apoptosis is regulated by intracellular checkpoints of which the BCL-2 family plays a prominent role. Family members function, at least in part, through protein-protein interactions. The ratio of death agonists (BAX,BAK,BAD,BCL-Xx) and death antagonists (BCL-2, BCL-2-XL,MCL-1,A1) dictate the responses to an apoptotic signal. However, the complete pathway from proximal death signal to distal death effector mechanisms has yet to be elucidated. Toward that end, a new death agonist gene, Bid, has been cloned based on its ability to interact with both the death agonist (BAX) and death antagonist (BCL-2). BID shares with BCL-2 family members only the BH3 domain, which it requires for both protein interaction and function. BID resides in cytosol or membrane locations and may be instrumental in mediating events between cytosol and membrane compartments during apoptosis. To determine the role of BID in normal development and homeostasis, I propose: 1) to generate a Bid loss-of-function model by gene-targeting; 2) to examine BID in human tumors and determine tumor incidence in Bid-deficient mice; 3) to characterize the molecular mechanisms of BID-induced death and define the role of BH3 domain.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Scientist Development Award - Research & Training (K01)
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Subcommittee G - Education (NCI)
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Yin, Xiao-Ming (2006) Bid, a BH3-only multi-functional molecule, is at the cross road of life and death. Gene 369:7-19
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Yi, Xiaolan; Yin, Xiao-Ming; Dong, Zheng (2003) Inhibition of Bid-induced apoptosis by Bcl-2. tBid insertion, Bax translocation, and Bax/Bak oligomerization suppressed. J Biol Chem 278:16992-9
Yin, Xiao-Ming; Ding, Wen-Xing (2003) Death receptor activation-induced hepatocyte apoptosis and liver injury. Curr Mol Med 3:491-508
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Yin, Xiao-Ming; Luo, Yumin; Cao, Guodong et al. (2002) Bid-mediated mitochondrial pathway is critical to ischemic neuronal apoptosis and focal cerebral ischemia. J Biol Chem 277:42074-81
Zhao, Y; Li, S; Childs, E E et al. (2001) Activation of pro-death Bcl-2 family proteins and mitochondria apoptosis pathway in tumor necrosis factor-alpha-induced liver injury. J Biol Chem 276:27432-40
Kim, T H; Zhao, Y; Barber, M J et al. (2000) Bid-induced cytochrome c release is mediated by a pathway independent of mitochondrial permeability transition pore and Bax. J Biol Chem 275:39474-81

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