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  • Title: Calpain activates caspase-8 in neuron-like differentiated PC12 cells via the amyloid-beta-peptide and CD95 pathways.
    Author: Vaisid T, Barnoy S, Kosower NS.
    Journal: Int J Biochem Cell Biol; 2009 Dec; 41(12):2450-8. PubMed ID: 19646546.
    Abstract:
    The neurotoxic amyloid-beta-peptide (Abeta) is important in the pathogenesis of Alzheimer's disease (AD). Calpain (Ca(2+)-dependent protease) and caspase-8 (the initiating caspase for the extrinsic, receptor-mediated apoptosis pathway) have been implicated in AD/Abeta toxicity. We previously found that Abeta promoted degradation of calpastatin (the specific endogenous calpain inhibitor); calpastatin degradation was prevented by inhibitors of either calpain or caspase-8. The results implied a cross-talk between the two proteases and suggested that one protease was responsible for the activity of the other one. We now report on the previously unrecognized caspase-8 activation by calpain. In neuron-like differentiated PC12 cells, calpain promotes active caspase-8 formation from procaspase-8 via the Abeta and CD95 pathways, along with degradation of the procaspase-8 processing inhibitor caspase-8 (FLICE)-like inhibitory protein, short isoform (FLIP(S)). Inhibition of calpain (by pharmacological inhibitors and by overexpression of calpastatin) prevents the cleavage of procaspase-8 to mature, active caspase-8, and inhibits FLIP(S) degradation in the Abeta-treated and CD95-triggered cells. Increased cellular Ca(2+) per se results in calpain activation but does not lead to caspase-8 activation or FLIP(S) degradation. The results suggest that procaspase-8 and FLIP(S) association with cell membrane receptor complexes is required for calpain-induced caspase-8 activation. The results presented here add to the understanding of the roles of calpain, caspase-8, and CD95 pathway in AD/Abeta toxicity. Calpain-promoted activation of caspase-8 may have implications for other types of CD95-induced cell damage, and for nonapoptotic functions of caspase-8. Inhibition of calpain may be useful for modulating certain caspase-8-dependent processes.
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