Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

21 (14): 3704-3714

Copyright © 2002 by the European Molecular Biology Organization.

c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis

David W. Chang1, Zheng Xing1,2, Yi Pan1, Alicia Algeciras-Schimnich3, Bryan C. Barnhart3, Shoshanit Yaish-Ohad1, Marcus E. Peter3, and Xiaolu Yang1,4

1 Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 and 3 The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637, USA 2 Present address: Department of Molecular and Cell Biology, University of California at Berkley, Berkley, CA 94720, USA 4 Corresponding author e-mail: xyang{at}mail.med.upenn.eduD.W.Chang, Z.Xing and Y.Pan contributed equally to this work

Abstract: Activation of the caspase cascade is a pivotal step in apoptosis and can occur via death adaptor-mediated homo-oligomerization of initiator procaspases. Here we show that c-FLIPL, a protease-deficient caspase homolog widely regarded as an apoptosis inhibitor, is enriched in the CD95 death-inducing signaling complex (DISC) and potently promotes procaspase-8 activation through hetero-dimerization. c-FLIPL exerts its effect through its protease-like domain, which associates efficiently with the procaspase-8 protease domain and induces the enzymatic activity of the zymogen. Ectopic expression of c-FLIPL at physiologically relevant levels enhances procaspase-8 processing in the CD95 DISC and promotes apoptosis, while a decrease of c-FLIPL expression results in inhibition of apoptosis. c-FLIPL acts as an apoptosis inhibitor only at high ectopic expression levels. Thus, c-FLIPL defines a novel type of caspase regulator, distinct from the death adaptors, that can either promote or inhibit apoptosis.

Key Words: Keywords: apoptosis/caspase activation/caspase-8/CD95 (Fas/APO-1)/c-FLIP

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882