The FLIP Side of Life

Sci. Signal., 15 January 2013
Vol. 6, Issue 258, p. pe2
DOI: 10.1126/scisignal.2003845

The FLIP Side of Life

  1. John Silke1,2,* and
  2. Andreas Strasser1,2,*
  1. 1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
  2. 2Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
  1. *Corresponding author. E-mail: silke{at}wehi.edu.au (J.S.); strasser{at}wehi.edu.au (A.S.)

Abstract

The anti-apoptotic protein c-FLIP, a catalytically inactive homolog of caspase-8, is an important regulator of death receptor signaling. Death receptors constitute a subgroup of the tumor necrosis factor receptor (TNFR) superfamily, which includes TNFR1, Fas, DR4, and DR5. When activated by their respective ligands, TNF, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL), these receptors cause caspase-8–mediated apoptosis. If caspase-8 activity is blocked, however, then these receptors promote death by necroptosis (programmed necrosis), which requires the kinases receptor-interacting kinase 1 (RIPK1) and RIPK3, as well as mixed-lineage kinase-like protein. Necroptosis has become the subject of intense research because it promotes inflammation, and inhibiting this pathway can limit extensive tissue damage and even lethality in inflammatory syndromes. A study now reports on the role of c-FLIP in vivo from experiments with a range of conditional knockout mice and demonstrates that c-FLIP plays a critical role in inhibiting both apoptotic and necroptotic cell death within the whole mouse.

Citation:

J. Silke and A. Strasser, The FLIP Side of Life. Sci. Signal. 6, pe2 (2013).
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