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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0017262,
umls-concept:C0018270,
umls-concept:C0030274,
umls-concept:C0185117,
umls-concept:C0202220,
umls-concept:C0227525,
umls-concept:C0521447,
umls-concept:C1414685,
umls-concept:C1998811,
umls-concept:C2911684
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pubmed:issue |
6
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pubmed:dateCreated |
2002-5-28
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pubmed:abstractText |
Maturity-onset diabetes of the young type 3 (MODY3) is characterized by impaired insulin secretion. Heterozygous mutations in the gene encoding hepatocyte nuclear factor (HNF)-1alpha are the cause of MODY3. Transgenic mice overexpressing dominant-negative HNF-1alpha mutant in pancreatic beta-cells and HNF-1alpha knockout mice are animal models of MODY3. These mice exhibit defective glucose-stimulated insulin secretion and have reduced beta-cell mass and beta-cell proliferation rate. Here we examined the effect of HNF-1alpha on beta-cell proliferation by overexpressing a human naturally occurring dominant- negative mutation P291fsinsC in INS-1 cells under the control of doxycycline-induction system. INS-1 cells overexpressing P291fsinsC showed apparent growth impairment. The proliferation rate estimated by [(3)H]thymidine incorporation was significantly reduced in P291fsinsC-expressing INS-1 cells compared with noninduced or wild-type HNF-1alpha-overexpressing INS-1 cells. Growth inhibition occurred at the transition from G1 to S cell cycle phase, with reduced expression of cyclin E and upregulation of p27. cDNA array analysis revealed that the expression levels of IGF-1, a major growth factor for beta-cells, and macrophage migration inhibitory factor (MIF), a cytokine expressed in pancreatic beta-cells, were reduced in P291fsinsC-HNF-1alpha-expressing INS-1 cells. Although MIF seemed to have proliferative function, blockade of MIF action by anti-MIF antibody stimulated INS-1 cell proliferation, excluding its direct role in the growth impairment. However, addition of IGF-1 to P291fsinsC-expressing INS-1 cells rescued the growth inhibition. Our data suggest that HNF-1alpha is critical for modulating pancreatic beta-cell growth by regulating IGF-1 expression. IGF-1 might be a potential therapeutic target for the treatment of MODY3.
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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/Antibodies,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/HNF1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/HNF1B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hepatocyte Nuclear Factor 1,
http://linkedlifedata.com/resource/pubmed/chemical/Hepatocyte Nuclear Factor 1-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Hepatocyte Nuclear Factor 1-beta,
http://linkedlifedata.com/resource/pubmed/chemical/Hnf1a protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Hnf1a protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Hnf1b protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor I,
http://linkedlifedata.com/resource/pubmed/chemical/Macrophage Migration-Inhibitory...,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0012-1797
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pubmed:author |
pubmed-author:BucalaRichardR,
pubmed-author:CaoYangY,
pubmed-author:FukuiKenjiK,
pubmed-author:HanafusaToshiakiT,
pubmed-author:IwahashiHiromiH,
pubmed-author:MatsumuraItaruI,
pubmed-author:MatsuzawaYujiY,
pubmed-author:MiyagawaJun-IchiroJ,
pubmed-author:NammoTakaoT,
pubmed-author:WangHaiyanH,
pubmed-author:WollheimClaes BCB,
pubmed-author:YamagataKazuyaK,
pubmed-author:YangQinQ
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pubmed:issnType |
Print
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1785-92
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:12031966-Animals,
pubmed-meshheading:12031966-Antibodies,
pubmed-meshheading:12031966-Cell Division,
pubmed-meshheading:12031966-DNA-Binding Proteins,
pubmed-meshheading:12031966-Diabetes Mellitus, Type 2,
pubmed-meshheading:12031966-G1 Phase,
pubmed-meshheading:12031966-Gene Expression Regulation,
pubmed-meshheading:12031966-Glucose,
pubmed-meshheading:12031966-Hepatocyte Nuclear Factor 1,
pubmed-meshheading:12031966-Hepatocyte Nuclear Factor 1-alpha,
pubmed-meshheading:12031966-Hepatocyte Nuclear Factor 1-beta,
pubmed-meshheading:12031966-Humans,
pubmed-meshheading:12031966-Insulin,
pubmed-meshheading:12031966-Insulin-Like Growth Factor I,
pubmed-meshheading:12031966-Islets of Langerhans,
pubmed-meshheading:12031966-Macrophage Migration-Inhibitory Factors,
pubmed-meshheading:12031966-Mice,
pubmed-meshheading:12031966-Mutation,
pubmed-meshheading:12031966-Nuclear Proteins,
pubmed-meshheading:12031966-Rats,
pubmed-meshheading:12031966-S Phase,
pubmed-meshheading:12031966-Transcription Factors,
pubmed-meshheading:12031966-Tumor Cells, Cultured
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pubmed:year |
2002
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pubmed:articleTitle |
Hepatocyte nuclear factor-1alpha modulates pancreatic beta-cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells.
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pubmed:affiliation |
Department of Internal Medicine and Molecular Science, Biomedical Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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