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Involvement of Caspase-Dependent Activation of Cytosolic Phospholipase A2 in Tumor Necrosis Factor-Induced Apoptosis

Dorte Wissing, Helle Mouritzen, Mikala Egeblad, Guy G. Poirier and Marja Jäättelä
Proceedings of the National Academy of Sciences of the United States of America
Vol. 94, No. 10 (May 13, 1997), pp. 5073-5077
Stable URL: http://www.jstor.org/stable/42451
Page Count: 5
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Involvement of Caspase-Dependent Activation of Cytosolic Phospholipase A2 in Tumor Necrosis Factor-Induced Apoptosis
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Abstract

Tumor necrosis factor (TNF)-induced apoptosis is mediated by caspases, which are cysteine proteases related to interleukin 1β -converting enzyme. We report here that TNF-induced activation of caspases results in the cleavage and activation of cytosolic phospholipase A2 (cPLA2) and that activated cPLA2 contributes to apoptosis. Inhibition of caspases by expression of a cowpox virus-derived inhibitor, CrmA, or by a specific tetrapeptide inhibitor of CPP32/caspase-3, acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), inhibited TNF-induced activation of cPLA2 and apoptosis. TNF-induced activation of cPLA2 was accompanied by a cleavage of the 100-kDa cPLA2 to a 70-kDa proteolytic fragment. This cleavage was inhibited by Ac-DEVD-CHO in a similar manner as that of poly(ADP)ribose polymerase, a known substrate of CPP32/caspase-3. Interestingly, specific inhibition of cPLA2 enzyme activity by arachidonyl trifluoromethylketone (AACOCF3) partially inhibited TNF-induced apoptosis without inhibition of caspase activity. Thus, our results suggest a novel caspase-dependent activation pathway for cPLA2 during apoptosis and identify cPLA2 as a mediator of TNF-induced cell death acting downstream of caspases.

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