Type

Other / n/a

Authors

Jochen HM Prehn
Maria M Byrne
Claes B Wollheim
Claus Reimertz
Haiyan Wang
Donat Kögel
Heiko Düssmann
Hella Wobser

Subjects

Biochemistry

Topics
doxycycline bcl x protein hepatocyte nuclear factor 1 alpha transcriptional activation cell death insulinoma transcription factors suppression physiology mitochondria tumor cells rats pancreatic neoplasms dna binding proteins diabetes mellitus type 2 hepatocyte nuclear factor 1 apoptosis proto oncogene proteins c bcl 2 genetic animals glucose transfection nuclear proteins cell line diabetes mellitus humans tumor cells cultured suppression genetic recombinant proteins cultured mutation type 2 hepatocyte nuclear factor 1 beta physics

Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. (2002)

Abstract Maturity onset diabetes of the young (MODY) 3 is a monogenic form of diabetes caused by mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha. We investigated the involvement of apoptotic events in INS-1 insulinoma cells overexpressing wild-type HNF-1 alpha (WT-HNF-1 alpha) or a dominant-negative mutant (DN-HNF-1 alpha) under control of a doxycycline-dependent transcriptional activator. Forty-eight h after induction of DN-HNF-1 alpha, INS-1 cells activated caspase-3 and underwent apoptotic cell death, while cells overexpressing WT-HNF-1 alpha remained viable. Mitochondrial cytochrome c release and activation of caspase-9 accompanied DN-HNF-1 alpha-induced apoptosis, suggesting the involvement of the mitochondrial apoptosis pathway. Activation of caspases was preceded by mitochondrial hyperpolarization and decreased expression of the anti-apoptotic protein Bcl-xL. Transient overexpression of Bcl-xL was sufficient to rescue INS-1 cells from DN-HNF-1 alpha-induced apoptosis. Both WT- and DN-HNF-1 alpha-expressing cells demonstrated similar increases in apoptosis when cultured at high glucose (25 mm). In contrast, induction of DN-HNF-1 alpha highly sensitized cells to ceramide toxicity. In cells cultured at low glucose, DN-HNF-1 alpha induction also caused up-regulation of the cell cycle inhibitor p27(KIP1). Therefore, our data indicate that increased sensitivity to the mitochondrial apoptosis pathway and decreased cell proliferation may account for the progressive loss of beta-cell function seen in MODY 3 subjects.
Collections Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Jochen HM Prehn, Maria M Byrne, Claes B Wollheim, Claus Reimertz, Haiyan Wang, Donat Kögel, Heiko Düssmann, Hella Wobser

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Donat Kögel
Royal College of Surgeons in Ireland
Total Publications: 14
 
3
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45