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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
21
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pubmed:dateCreated |
2007-5-21
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pubmed:abstractText |
We previously showed that inositol hexakisphosphate kinase 2 (IHPK2) functions as a growth-suppressive and apoptosis-enhancing kinase during cell stress. Overexpression of IHPK2 sensitized ovarian carcinoma cell lines to the growth-suppressive and apoptotic effects of interferon beta (IFN-beta), IFN-alpha2, and gamma-irradiation. Expression of a kinase-dead mutant abrogated 50% of the apoptosis induced by IFN-beta. Because the kinase-dead mutant retained significant response to cell stressors, we hypothesized that a portion of the death-promoting function of IHPK2 was independent of its kinase activity. We now demonstrate that IHPK2 binds to tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2 and interferes with phosphorylation of transforming growth factor beta-activated kinase 1 (TAK1), thereby inhibiting NF-kappaB signaling. IHPK2 contains two sites required for TRAF2 binding, Ser-347 and Ser-359. Compared with wild type IHPK2-transfected cells, cells expressing S347A and S359A mutations displayed 3.5-fold greater TAK1 activation following TNF-alpha. This mutant demonstrated a 6-10-fold increase in NF-kappaB DNA binding following TNF-alpha compared with wild type IHPK2-expressing cells in which NF-kappaB DNA binding was inhibited. Cells transfected with wild type IHPK2 or IHPK2 mutants that lacked S347A and S359A mutations displayed enhanced terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining following TNF-alpha. We believe that IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappaB-mediated signaling and is partially responsible for the apoptotic activity of IHPK2.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-10047546,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-10206649,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-10449775,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-10485710,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-10795740,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-10914035,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11030616,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11337497,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11359906,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11479302,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11520989,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11864612,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11896621,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-11927604,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-12391334,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-13678580,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-15150344,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-15533939,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-15604408,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-16260493,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-16260598,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-16953224,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-2359136,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-9252186,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-9275204,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-9390693,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-9390694,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-9721103,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-9744859,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17379600-9892468
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
25
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pubmed:volume |
282
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
15349-56
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:17379600-Amino Acid Substitution,
pubmed-meshheading:17379600-Animals,
pubmed-meshheading:17379600-Apoptosis,
pubmed-meshheading:17379600-Cell Line, Tumor,
pubmed-meshheading:17379600-Gamma Rays,
pubmed-meshheading:17379600-Gene Expression,
pubmed-meshheading:17379600-Humans,
pubmed-meshheading:17379600-Interferon-alpha,
pubmed-meshheading:17379600-Interferon-beta,
pubmed-meshheading:17379600-MAP Kinase Kinase Kinases,
pubmed-meshheading:17379600-MAP Kinase Signaling System,
pubmed-meshheading:17379600-Mice,
pubmed-meshheading:17379600-Mutation, Missense,
pubmed-meshheading:17379600-NF-kappa B,
pubmed-meshheading:17379600-Phosphotransferases (Phosphate Group Acceptor),
pubmed-meshheading:17379600-Protein Binding,
pubmed-meshheading:17379600-TNF Receptor-Associated Factor 2
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pubmed:year |
2007
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pubmed:articleTitle |
Effect of inositol hexakisphosphate kinase 2 on transforming growth factor beta-activated kinase 1 and NF-kappaB activation.
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pubmed:affiliation |
Center for Hematology and Oncology Molecular Therapeutics, Taussig Cancer Center, and Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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