Page 18 - G. Cell differentiation. division. and death

[G. Cell differentiation, division, and death-13]

Regulation of death receptor-mediated apoptosis via USP8

post-translation modification of c-FLIPL

Chi Hyun Hwang¹˙#, Manhyung Jeong¹˙#, Eun-Woo Lee², Daehyeon Seong¹, Jinho Seo³, Jaewhan Song¹

¹Department of Biochemistry, College of Life science and Biotechnology, Yonsei University, Seoul 120-749, Korea,

²Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon
34141, Korea, ³Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology

(KRIBB), Daejeon 34141, Korea

Apoptosis can be induced by various stimuli including anti-Fas, TRAIL and TNFα induced activation of death

receptors. Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like
regulator of death ligand-induced apoptosis based on observations that c-FLIP impedes death ligand-induced
apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion.c-FLIP is a family of

alternatively spliced variants that primarily exists in human cells as long (c-FLIPL) and short (c-FLIPs) splice variants.
Here, we demonstrated that ubiquitin-specific peptidase 8 (USP8), a c-FLIPL deubiquitinase, has a regulatory

mechanism for c-FLIPL de-ubiquitination and protein level up-regulation. USP8 depletion accelerates death ligand-
induced extrinsic apoptosis due to FLIPL destabilization. Additionaly, we found a correlation between elevated c-

FLIPL protein levels and melanoma and cervical cancers, due to up-regulation of USP8 mRNA and protein levels.
Therefore, we used the ME-180 cervical cancer xenograft model to show that USP8 depletion attenuated tumor

growth upon TRAIL injection. These finding indicate that pharmacological regulation of USP8 may provide an
effective strategy to treat various cancers.