|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
5
|
|
pubmed:dateCreated |
2001-8-24
|
|
pubmed:abstractText |
The Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and genotoxic effects of cross-linking agents. FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase. Because not all FANCC mutations affect STAT1 activation, the hypothesis was considered that cross-linker resistance function of FANCC depends on structural elements that differ from those required for the cytokine signaling functions of FANCC. Structure-function studies were designed to test this notion. Six separate alanine-substituted mutations were generated in 3 highly conserved motifs of FANCC. All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells. However, 2 of the mutants, S249A and E251A, failed to correct defective STAT1 activation. FA-C lymphoblasts carrying these 2 mutants demonstrated a defect in recruitment of STAT1 to the interferon gamma (IFN-gamma) receptor and GST-fusion proteins bearing S249A and E251A mutations were less efficient binding partners for STAT1 in stimulated lymphoblasts. These same mutations failed to complement the characteristic hypersensitive apoptotic responses of FA-C cells to tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Cells bearing a naturally occurring FANCC mutation (322delG) that preserves this conserved region showed normal STAT1 activation but remained hypersensitive to MMC. The conclusion is that a central highly conserved domain of FANCC is required for functional interaction with STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to cross-linking agents. Preservation of signaling capacity of cells bearing the del322G mutation may account for the reduced severity and later onset of bone marrow failure associated with this mutation.
|
|
pubmed:grant |
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
AIM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/FANCC protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Fanconi Anemia Complementation...,
http://linkedlifedata.com/resource/pubmed/chemical/Fanconi Anemia Complementation...,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Mitomycin,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/STAT1 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/STAT1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Sep
|
|
pubmed:issn |
0006-4971
|
|
pubmed:author |
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
1
|
|
pubmed:volume |
98
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
1392-401
|
|
pubmed:dateRevised |
2008-11-21
|
|
pubmed:meshHeading |
pubmed-meshheading:11520787-Amino Acid Motifs,
pubmed-meshheading:11520787-Amino Acid Sequence,
pubmed-meshheading:11520787-Amino Acid Substitution,
pubmed-meshheading:11520787-Apoptosis,
pubmed-meshheading:11520787-Cell Cycle Proteins,
pubmed-meshheading:11520787-Cell Line, Transformed,
pubmed-meshheading:11520787-DNA-Binding Proteins,
pubmed-meshheading:11520787-Fanconi Anemia,
pubmed-meshheading:11520787-Fanconi Anemia Complementation Group C Protein,
pubmed-meshheading:11520787-Fanconi Anemia Complementation Group Proteins,
pubmed-meshheading:11520787-Genetic Complementation Test,
pubmed-meshheading:11520787-Humans,
pubmed-meshheading:11520787-Interferon-gamma,
pubmed-meshheading:11520787-Mitomycin,
pubmed-meshheading:11520787-Molecular Sequence Data,
pubmed-meshheading:11520787-Mutagenesis, Site-Directed,
pubmed-meshheading:11520787-Nuclear Proteins,
pubmed-meshheading:11520787-Phosphorylation,
pubmed-meshheading:11520787-Protein Processing, Post-Translational,
pubmed-meshheading:11520787-Proteins,
pubmed-meshheading:11520787-Recombinant Fusion Proteins,
pubmed-meshheading:11520787-STAT1 Transcription Factor,
pubmed-meshheading:11520787-Sequence Alignment,
pubmed-meshheading:11520787-Sequence Homology, Amino Acid,
pubmed-meshheading:11520787-Signal Transduction,
pubmed-meshheading:11520787-Structure-Activity Relationship,
pubmed-meshheading:11520787-Trans-Activators,
pubmed-meshheading:11520787-Tumor Necrosis Factor-alpha
|
|
pubmed:year |
2001
|
|
pubmed:articleTitle |
The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality.
|
|
pubmed:affiliation |
Oregon Cancer Center, Department of Medicine (Division of Hematology and Medical Oncology), Oregon Health Sciences University, Portland, OR 97201, USA.
|
|
pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
|
