The role of BH3-only protein Bmf in the pathogenesis of dominant negative hepatocyte nuclear factor-1 –induced mature-onset diabetes of the young in transgenic mice
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چکیده
Introduction Maturity Onset Diabetes of the Young 3 (MODY3) is the most common monogenic form of diabetes, characterized by early age of onset (before the age of 25), autosomal dominant transmission and severe defect in insulin secretion [1,2]. MODY accounts for 2-5% of Non-Insulin Dependent Diabetes Mellitus (NIDDM) cases, with MODY3 identified as the most common and severe form, accounting for 65% of all MODY cases and results from loss of function mutations of the transcription factor Hepatocyte Nuclear Factor1 a (HNF1a). As a result of this, pancreatic islets show reduction in glucose-stimulated insulin secretion response and in beta cell mass, hallmarks of MODY3. Previous work in this laboratory has shown that induction of dominant negative mutant-HNF1a expression results in bioenergetic stress, activation of AMPK and induction of pro-apoptotic BH3-only family protein, Bmf [3].
منابع مشابه
AMP-activated protein kinase mediates apoptosis in response to bioenergetic stress through activation of the pro-apoptotic Bcl-2 homology domain-3-only protein BMF.
Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in the pathogenesis of maturity-onset diabetes-of-the-young type 3, (HNF1A-MODY). This disorder is characterized by a primary defect in metabolism-secretion coupling and decreased beta cell mass, attributed to excessive beta cell apoptosis. Here, we investigated the link between energy stress and apo...
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Mutations in the transcription factor hepatocyte nuclear factor-1 (HNF-1 ) cause maturity-onset diabetes of the young 3, a severe form of diabetes characterized by pancreatic -cell dysfunction. We have used targeted expression of a dominantnegative mutant of HNF-1 to specifically suppress HNF-1 function in -cells of transgenic mice. We show that males expressing the mutant protein became overtl...
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Six monogenic forms of maturity-onset diabetes of the young (MODY) have been identified to date. Except for MODY2 (glucokinase), all other MODY subtypes have been linked to transcription factors. We have established a MODY3 transgenic model through the beta-cell-targeted expression of dominant-negative HNF-1alpha either constitutively (rat insulin II promoter) or conditionally (Tet-On system). ...
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We studied islet function in mice with beta-cell-targeted expression of a dominant-negative mutant of hepatocyte nuclear factor (HNF)-1alpha. At age 2-3 months, anesthetized transgenic and wild-type male mice underwent an intravenous glucose (1 g/kg) tolerance test (IVGTT). It was found that transgenic mice had an abolished insulin response in association with severe glucose intolerance. In oth...
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Members of the Bcl-2 protein family play crucial roles in the maintenance of tissue homeostasis by regulating apoptosis in response to developmental cues or exogenous stress. Proapoptotic BH3-only members of the Bcl-2 family are essential for initiation of cell death, and they function by activating the proapoptotic Bcl-2 family members Bax and/or Bak, either directly or indirectly through bind...
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