Document Detail


IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression.
MedLine Citation:
PMID:  17878376     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
IFN regulatory factor 8 (IRF8) is a transcription factor that was originally identified in myeloid cells and has been shown to be essential for differentiation and function of hemopoietic cells. Mice with a null mutation of IRF8 exhibit uncontrolled expansion of the granulocytic and monocytic lineages that progress into a phenotype resembling human chronic myelogenous leukemia. In human patients with chronic myelogenous leukemia, IRF8 transcript levels are frequently diminished. Therefore, IRF8 is a key regulator of myeloid tumor development. In this study, we report that IRF8 is a critical regulator of apoptosis in nonhemopoietic tumor cells. Disruption of IRF8 function with IRF8 dominant-negative mutants diminished Fas-mediated apoptosis in sarcoma tumor cells. Both constitutively expressed and IFN-gamma-activated IRF8 were involved in regulation of apoptosis. Furthermore, it was found that constitutively expressed IRF8 is associated with the Fas promoter to activate Fas transcription. In addition, disruption of constitutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFN-gamma-initiated induction of STAT1 phosphorylation, which in turn, blocked IFN-gamma-induced Fas up-regulation. Interestingly, the constitutively expressed IRF8 was also essential for TNF-alpha sensitization of Fas-mediated apoptosis because disruption of IRF8 function also inhibited TNF-alpha-sensitized and Fas-mediated apoptosis. Taken together, our data suggest that IRF8 is an essential mediator of Fas-mediated apoptosis and that IRF8 mediates apoptosis through regulation of Fas expression in nonhemopoietic tumor cells.
Authors:
Dafeng Yang; Muthusamy Thangaraju; Darren D Browning; Zheng Dong; Borys Korchin; Dina C Lev; Vadivel Ganapathy; Kebin Liu
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  179     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-09-19     Completed Date:  2007-11-06     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4775-82     Citation Subset:  AIM; IM    
Affiliation:
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD95 / genetics,  metabolism*
Apoptosis* / drug effects
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Interferon Regulatory Factors / genetics,  metabolism*
Interferon-gamma / pharmacology
Mice
Promoter Regions, Genetic / genetics
Protein Binding
STAT1 Transcription Factor / metabolism
Sarcoma / genetics,  metabolism*,  pathology*
Tumor Necrosis Factor-alpha / pharmacology
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/Interferon Regulatory Factors; 0/STAT1 Transcription Factor; 0/Tumor Necrosis Factor-alpha; 0/interferon regulatory factor-8; 82115-62-6/Interferon-gamma

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