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Sci. STKE, 23 July 2002
Vol. 2002, Issue 142, p. tw260
[DOI: 10.1126/stke.2002.142.tw260]


Apoptosis FLIPping the Caspase Switch

c-FLIP is a caspase homolog that lacks protease activity. Expression of the long form of c-FLIP, c-FLIPL, has been reported to inhibit apoptosis; however, FLIP knockout mice have defects similar to animals deficient in caspase 8- or FADD (a death adaptor that activates caspase 8 during apoptosis). Like caspases, cFLIPL is cleaved upon activation of death receptors (such as CD95) and formation of the death-inducing signaling complex (DISC). Chang et al. sought to clarify the role of c-FLIPL in regulating apoptosis. In vitro and in transfected cells, using a forced dimerization method, the addition of c-FLIPL accelerated the rate of caspase 8 activation and promoted cleavage of c-FLIPL. Furthermore, cotransfection of the dimerizing c-FLIPL and caspase 8 proteins promoted cell death in a manner that was dependent on the concentration of c-FLIPL. Cells expressing variable levels of c-FLIPL exhibited distinct effects: (i) Low concentrations of c-FLIPL sensitized cells to CD95-mediated apoptosis and increased complete caspase 8 processing to the fully active fragment. (ii) Intermediate concentrations (but more than endogenous amounts) inhibited CD95-mediated apoptosis and inhibited complete caspase 8 processing. And (iii) very high concentrations stimulated cell death in the absence of CD95. In vitro assays with recombinant proteins showed that c-FLIPL stimulated the enzymatic activity of an uncleavable form of procaspase 8. Thus, c-FLIPL may act to directly stimulate catalytic activity of the procaspase 8 zymogen.

D. W. Chang, Z. Xing, Y. Pan, A. Algeciras-Schimnich, B. C. Barnhart, S. Yaish-Ohad, M. E. Peter, X. Yang, c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 21, 3704-3714 (2002). [Abstract] [Full Text]

Citation: FLIPping the Caspase Switch. Sci. STKE 2002, tw260 (2002).

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