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

来自 EBSCO

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141

作者：

XM Yin，K Wang，A Gross，Y Zhao，S Zinkel，B Klocke，KA Roth，SJ Korsmeyer

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摘要：

The protein Bid is a participant in the pathway that leads to celldeath (apoptosis), mediating the release of cytochromefrom mitochondria in response to signals from 'death' receptors known as TNFR1/Fas on the cell surface. It is a member of the pro-apoptotic Bcl-2 familyand 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, 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-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 cytochromewas 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 thesecells, mitochondrial dysfunction was delayed, cytochromewas 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 substratefor signalling by death-receptor agonists, which mediates a mitochondrial amplification loop that is essential for the apoptosis of selected cells.

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关键词：

gene targeting fertilization ovulation prostanoids gonadotropins

DOI：

10.1038/23730

被引量：

2660