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rdf:type |
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lifeskim:mentions |
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0023467,
umls-concept:C0038866,
umls-concept:C0080090,
umls-concept:C0205266,
umls-concept:C0301625,
umls-concept:C0332285,
umls-concept:C1301771,
umls-concept:C1335875,
umls-concept:C1367307,
umls-concept:C1705050,
umls-concept:C1706395
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pubmed:issue |
3
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pubmed:dateCreated |
2004-7-21
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pubmed:abstractText |
Truncated granulocyte colony-stimulating factor receptors (G-CSF-Rs) are implicated in severe congenital neutropenia (SCN) and the consecutive development of acute myeloid leukemia (AML). Mice expressing G-CSF-R truncation mutants (gcsfr-d715) show defective receptor internalization, an increased signal transducer and activator of transcription 5 (STAT5)/STAT3 activation ratio, and hyperproliferative responses to G-CSF treatment. We determined whether a lack of negative feedback by suppressor of cytokine signaling (SOCS) proteins contributes to the signaling abnormalities of G-CSF-R-d715. Expression of SOCS3 transcripts in bone marrow cells from G-CSF-treated gcsfr-d715 mice was approximately 60% lower than in wild-type (WT) littermates. SOCS3 efficiently suppressed STAT3 and STAT5 activation by WT G-CSF-R in luciferase reporter assays. In contrast, while SOCS3 still inhibited STAT3 activation by G-CSF-R-d715, STAT5 activation was no longer affected. This was due mainly to loss of the SOCS3 recruitment site Tyr729, with an additional contribution of the internalization defects of G-CSF-R-d715. Because Tyr729 is also a docking site for the Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2), which binds to and inactivates STAT5, we suggest a model in which reduced SOCS3 expression, combined with the loss of recruitment of both SOCS3 and SHP-2 to the activated receptor complex, determine the increased STAT5/STAT3 activation ratio and the resulting signaling abnormalities projected by truncated G-CSF-R mutants.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Milk Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Granulocyte...,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/SOCS3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/STAT3 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/STAT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/STAT5 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Socs3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Stat3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Suppressor of Cytokine Signaling...,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0006-4971
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
104
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
667-74
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:15069015-Amino Acid Sequence,
pubmed-meshheading:15069015-Animals,
pubmed-meshheading:15069015-Binding Sites,
pubmed-meshheading:15069015-DNA-Binding Proteins,
pubmed-meshheading:15069015-Disease Models, Animal,
pubmed-meshheading:15069015-Humans,
pubmed-meshheading:15069015-Leukemia, Myeloid, Acute,
pubmed-meshheading:15069015-Mice,
pubmed-meshheading:15069015-Mice, Mutant Strains,
pubmed-meshheading:15069015-Milk Proteins,
pubmed-meshheading:15069015-Neutropenia,
pubmed-meshheading:15069015-Receptors, Granulocyte Colony-Stimulating Factor,
pubmed-meshheading:15069015-Repressor Proteins,
pubmed-meshheading:15069015-STAT3 Transcription Factor,
pubmed-meshheading:15069015-STAT5 Transcription Factor,
pubmed-meshheading:15069015-Sequence Deletion,
pubmed-meshheading:15069015-Signal Transduction,
pubmed-meshheading:15069015-Suppressor of Cytokine Signaling Proteins,
pubmed-meshheading:15069015-Trans-Activators,
pubmed-meshheading:15069015-Transcription Factors,
pubmed-meshheading:15069015-Tyrosine,
pubmed-meshheading:15069015-src Homology Domains
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pubmed:year |
2004
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pubmed:articleTitle |
G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact.
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pubmed:affiliation |
Institute of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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