Document Detail

Type I interferons induce apoptosis by balancing cFLIP and caspase-8 independent of death ligands.
MedLine Citation:
PMID:  23230268     Owner:  NLM     Status:  MEDLINE    
Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-γ) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.
Amir Apelbaum; Ganit Yarden; Shira Warszawski; Daniel Harari; Gideon Schreiber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-10
Journal Detail:
Title:  Molecular and cellular biology     Volume:  33     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-28     Completed Date:  2013-03-25     Revised Date:  2013-08-11    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  800-14     Citation Subset:  IM    
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
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MeSH Terms
CASP8 and FADD-Like Apoptosis Regulating Protein / genetics*,  metabolism
Caspase 8 / genetics*,  metabolism
Cell Cycle Checkpoints
Cell Line, Tumor
Enzyme Activation
Gene Expression Regulation
Interferon Type I / metabolism*
Interferon-gamma / metabolism
RNA Interference
RNA, Small Interfering / genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics,  metabolism
Reg. No./Substance:
0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/CFLAR protein, human; 0/Interferon Type I; 0/RNA, Small Interfering; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 82115-62-6/Interferon-gamma; EC 3.4.22.-/Caspase 8

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