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P85? deficiency protects ?-cells from endoplasmic reticulum stress-induced apoptosis.


ABSTRACT: In insulin resistant states such as type 2 diabetes, there is a high demand on the ?-cell to synthesize and secrete insulin, which challenges the ability of the endoplasmic reticulum (ER) to synthesize and fold nascent proteins. This creates a state of ER stress that triggers a coordinated program referred to as the unfolded protein response (UPR) that attempts to restore ER homeostasis. We identified a role for the p85? regulatory subunit of PI3K to modulate the UPR by promoting the nuclear localization of X-box binding protein 1, a transcription factor central to the UPR. In the present study we demonstrate that reducing p85? expression in ?-cells can markedly delay the onset and severity of the diabetic phenotype observed in Akita(+/-) mice, which express a mutant insulin molecule. This is due to a decrease in activation of ER stress-dependent apoptotic pathways and a preservation of ?-cell mass and function. These data demonstrate that modulation of p85? can protect pancreatic ?-cells from ER stress, pointing to a potentially therapeutic target in diabetic states.

SUBMITTER: Winnay JN 

PROVIDER: S-EPMC3903202 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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p85α deficiency protects β-cells from endoplasmic reticulum stress-induced apoptosis.

Winnay Jonathon N JN   Dirice Ercument E   Liew Chong Wee CW   Kulkarni Rohit N RN   Kahn C Ronald CR  

Proceedings of the National Academy of Sciences of the United States of America 20140106 3


In insulin resistant states such as type 2 diabetes, there is a high demand on the β-cell to synthesize and secrete insulin, which challenges the ability of the endoplasmic reticulum (ER) to synthesize and fold nascent proteins. This creates a state of ER stress that triggers a coordinated program referred to as the unfolded protein response (UPR) that attempts to restore ER homeostasis. We identified a role for the p85α regulatory subunit of PI3K to modulate the UPR by promoting the nuclear loc  ...[more]

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