It's not over until the FAT lady sings

Marco J Herold, Andreas Strasser

Author Affiliations

  1. Marco J Herold (herold{at} 1,2 and
  2. Andreas Strasser1,2
  1. 1The Walter and Eliza Hall Institute, Melbourne, Australia
  2. 2Department of Medical Biology, University of Melbourne, Melbourne, Australia
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The death receptors FAS, TRAIL‐Rs and TNFR1 play critical roles in programmed cell death, particularly in the immune system. Upon ligation of death receptors, caspase‐8 is activated within the so‐called ‘Death Induced Signalling Complex’ (DISC) but the mechanisms that mediate and modulate the activation of caspase‐8 are still not fully understood. This is an important issue because caspase‐8 is essential for apoptosis induced by death receptors. In this issue of The EMBO Journal, Kranz and Boutros (2014) describe their findings from a whole genome siRNA screen for the identification of novel regulators of death receptor induced apoptosis signalling. They identified the atypical cadherin FAT1 as a negative regulator of TRAIL‐R‐mediated caspase‐8 activation and consequent induction of apoptosis, although it had no impact on NF‐κB activation. The authors also show that FAT1 depletion substantially increased TRAIL‐induced killing of glioblastoma‐derived cell lines, suggesting a potential novel approach for treatment of this highly aggressive cancer.

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