Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis

Xiao Ming Yin, Kun Wang, Atan Gross, Yongge Zhao, Sandra Zinkel, Barbara Klocke, Kevin A. Roth, Stanley J. Korsmeyer

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Abstract

The protein Bid is a participant in the pathway that leads to cell death (apoptosis), mediating the release of cytochrome c from mitochondria in response to signals from 'death' receptors known as TNFR1/Fas on the cell surface. It is a member of the proapoptotic Bcl-2 family and is activated as a result of its cleavage by caspase 8, one of a family of proteolytic cell- death proteins. To investigate the role of Bid in vivo, we have generated mice deficient for Bid. We find that when these mice are injected with an antibody directed against Fas, they nearly all survive, whereas wild-type mice die from hepatocellular apoptosis and haemorrhagic necrosis. About half of the Bid-deficient animals had no apparent liver injury and showed no evidence of activation of the effector caspases 3 and 7, although the initiator caspase 8 had been activated. Other Bid-deficient mice survived with only moderate damage: all three caspases (8 and 37) were activated but their cell nuclei were intact and no mitochondrial cytochrome c was released. We also investigated the effects of Bid deficiency in cultured cells treated with anti-Fas antibody (hepatocytes and thymocytes) or with TNFα. (fibroblasts). In these Bid(-/-) cells, mitochondrial dysfunction was delayed, cytochrome c was not released, effector caspase activity was reduced and the cleavage of apoptosis substrates was altered. This loss-of-function model indicates that Bid is a critical substrate in vivo for signalling by death-receptor agonists, which mediates a mitochondrial amplification loop that is essential for the apoptosis of selected cells.

Original languageEnglish (US)
Pages (from-to)886-891
Number of pages6
JournalNature
Volume400
Issue number6747
DOIs
StatePublished - Aug 26 1999

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    Yin, X. M., Wang, K., Gross, A., Zhao, Y., Zinkel, S., Klocke, B., Roth, K. A., & Korsmeyer, S. J. (1999). Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature, 400(6747), 886-891. https://doi.org/10.1038/23730