RGD Reference Report - Molecular targets of a human HNF1 alpha mutation responsible for pancreatic beta-cell dysfunction. - Rat Genome Database

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Molecular targets of a human HNF1 alpha mutation responsible for pancreatic beta-cell dysfunction.

Authors: Wang, H  Antinozzi, P A  Hagenfeldt, K A  Maechler, P  Wollheim, C B 
Citation: Wang H, etal., EMBO J. 2000 Aug 15;19(16):4257-64. doi: 10.1093/emboj/19.16.4257.
RGD ID: 150540301
Pubmed: PMID:10944108   (View Abstract at PubMed)
PMCID: PMC302029   (View Article at PubMed Central)
DOI: DOI:10.1093/emboj/19.16.4257   (Journal Full-text)

The reverse tetracycline-dependent transactivator system was employed in insulinoma INS-1 cells to achieve controlled inducible expression of hepatocyte nuclear factor-1 alpha (HNF1 alpha)-P291fsinsC, the most common mutation associated with subtype 3 of maturity-onset diabetes of the young (MODY3). Nuclear localized HNF1 alpha-P291fsinsC protein exerts its dominant-negative effects by competing with endogenous HNF1 alpha for the cognate DNA-binding site. HNF1 alpha controls multiple genes implicated in pancreatic beta-cell function and notably in metabolism- secretion coupling. In addition to reduced expression of the genes encoding insulin, glucose transporter-2, L-pyruvate kinase, aldolase B and 3-hydroxy-3-methylglutaryl coenzyme A reductase, induction of HNF1 alpha-P291fsinsC also significantly inhibits expression of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) E1 subunit mRNA and protein. OGDH enzyme activity and [(14)C]pyruvate oxidation were also reduced. In contrast, the mRNA and protein levels of mitochondrial uncoupling protein-2 were dramatically increased by HNF1 alpha-P291fsinsC induction. As predicted from this altered gene expression profile, HNF1 alpha-P291fsinsC also inhibits insulin secretory responses to glucose and leucine, correlated with impaired nutrient-evoked mitochondrial ATP production and mitochondrial membrane hyperpolarization. These unprecedented results suggest the molecular mechanism of HNF1 alpha-P291fsinsC causing beta-cell dysfunction.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of insulin secretion  IEP 150540301 RGD 
positive regulation of mitochondrial membrane potential  IMP 150540301 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hnf1a  (HNF1 homeobox A)


Additional Information