Journal Article


Jochen H M Prehn
Maria M Byrne
Claes B Wollheim
Caoimhín G Concannon
Kristine C Nyhan
Manus W Ward
Caroline Bonner
Angela M Farrelly
Seán M Kilbride



reverse transcriptase polymerase chain reaction hypoglycemic agents energy metabolism ribonucleotides amp activated protein kinases drug effects flow cytometry mice transgenic genetics metabolism adenosine triphosphate protein subunits hnf1a protein rat aminoimidazole carboxamide rna interference gene expression regulation neoplastic hepatocyte nuclear factor 1 alpha pathology physiology blotting western pharmacology rats doxycycline mice inbred c57bl cell line tumor analogs derivatives insulinoma animals apoptosis enzyme activation adaptor proteins signal transducing mice aica ribonucleotide bmf protein rat

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. (2010)

Abstract 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 apoptosis activation following HNF1A inactivation. This study employed single cell fluorescent microscopy, flow cytometry, gene expression analysis, and gene silencing to study the effects of overexpression of dominant-negative (DN)-HNF1A expression on cellular bioenergetics and apoptosis in INS-1 cells. Induction of DN-HNF1A expression led to reduced ATP levels and diminished the bioenergetic response to glucose. This was coupled with activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), which preceded the onset of apoptosis. Pharmacological activation of AMPK using aminoimidazole carboxamide ribonucleotide (AICAR) was sufficient to induce apoptosis in naive cells. Conversely, inhibition of AMPK with compound C or AMPKα gene silencing protected against DN-HNF1A-induced apoptosis. Interestingly, AMPK mediated the induction of the pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor). Bmf expression was also elevated in islets of DN-HNF1A transgenic mice. Furthermore, knockdown of Bmf expression in INS-1 cells using siRNA was sufficient to protect against DN-HNF1A-induced apoptosis. Our study suggests that overexpression of DN-HNF1A induces bioenergetic stress and activation of AMPK. This in turn mediates the transcriptional activation of the pro-apoptotic Bcl-2-homology protein BMF, coupling prolonged energy stress to apoptosis activation.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jochen H M Prehn, Maria M Byrne, Claes B Wollheim, Caoimhín G Concannon, Kristine C Nyhan, Manus W Ward, Caroline Bonner, Angela M Farrelly, Seán M Kilbride

Experts in our system

Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
Caoimhín G Concannon
Royal College of Surgeons in Ireland
Total Publications: 46