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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

Authors
 Eun-Woo Lee  ;  Jung-Hoon Kim  ;  Ye-Hyeon Ahn  ;  Jinho Seo  ;  Aram Ko  ;  Manhyung Jeong  ;  Seok-Jun Kim  ;  Jae Y. Ro  ;  Ki-Moon Park  ;  Han-Woong Lee  ;  Eun Jung Park  ;  Kyung-Hee Chun  ;  Jaewhan Song 
Citation
 Nature Communications, Vol.3 : 978-978, 2012 
Journal Title
 Nature Communications 
ISSN
 2041-1723 
Issue Date
2012
Abstract
Fas-associated protein with death domain (FADD) is a pivotal component of death receptor-mediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by Makorin Ring Finger Protein 1 (MKRN1) E3 ligase-mediated ubiquitination and proteasomal degradation. MKRN1 knockdown results in FADD protein stabilization and formation of the rapid death-inducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that MKRN1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of MKRN1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using MDA-MB-231 breast cancer cells. Suppression of tumour growth by MKRN1 depletion is relieved by simultaneous FADD knockdown. Our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/91502
DOI
10.1038/ncomms1981
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실)
Yonsei Authors
김석준(Kim, Seok Jun)
전경희(Chun, Kyung Hee)
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Full Text
http://www.nature.com/ncomms/journal/v3/n7/full/ncomms1981.html
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