Document Detail

The interferon consensus sequence-binding protein (ICSBP/IRF8) represses PTPN13 gene transcription in differentiating myeloid cells.
MedLine Citation:
PMID:  18195016     Owner:  NLM     Status:  MEDLINE    
The interferon consensus sequence-binding protein (ICSBP/IRF8) is an interferon regulatory factor that is expressed in myeloid and B-cells. ICSBP-deficient mice develop a myeloproliferative disorder characterized by cytokine hypersensitivity and apoptosis resistance. To identify ICSBP target genes involved in these effects, we screened a CpG island microarray with chromatin that co-immunoprecipitated with ICSBP from myeloid cells. Using this technique, we identified PTPN13 as an ICSBP target gene. PTPN13 encodes Fas-associated phosphatase 1 (Fap-1), a ubiquitously expressed protein-tyrosine phosphatase. This was of interest because interaction of Fap-1 with Fas results in Fas dephosphorylation and inhibition of Fas-induced apoptosis. In this study, we found that ICSBP influenced Fas-induced apoptosis in a Fap-1-dependent manner. We also found that ICSBP interacted with a cis element in the proximal PTPN13 promoter and repressed transcription. This interaction increased during myeloid differentiation and was regulated by phosphorylation of conserved tyrosine residues in the interferon regulatory factor domain of ICSBP. ICSBP deficiency was present in human myeloid malignancies, including chronic myeloid leukemia. Therefore, these studies identified a mechanism for increased survival of mature myeloid cells in the ICSBP-deficient murine model and in human myeloid malignancies with decreased ICSBP expression.
Weiqi Huang; Chunliu Zhu; Hao Wang; Elizabeth Horvath; Elizabeth A Eklund
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Publication Detail:
Type:  Journal Article     Date:  2008-01-14
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-17     Completed Date:  2008-05-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7921-35     Citation Subset:  IM    
The Feinberg School of Medicine and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA.
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MeSH Terms
Antigens, CD95 / genetics,  metabolism
Apoptosis / genetics
B-Lymphocytes / metabolism
Cell Differentiation* / genetics
CpG Islands / genetics
Gene Expression Profiling
Gene Expression Regulation, Enzymologic / genetics
Interferon Regulatory Factors / genetics,  metabolism*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics,  metabolism
Mice, Knockout
Myeloid Cells / metabolism*
Oligonucleotide Array Sequence Analysis
Protein Tyrosine Phosphatase, Non-Receptor Type 13 / biosynthesis*,  genetics,  metabolism*
Repressor Proteins / genetics,  metabolism*
Transcription, Genetic* / genetics
U937 Cells
Reg. No./Substance:
0/Antigens, CD95; 0/Interferon Regulatory Factors; 0/Repressor Proteins; 0/interferon regulatory factor-8; EC protein, human; EC Tyrosine Phosphatase, Non-Receptor Type 13; EC protein, mouse

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