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Mol Endocrinol. 2014 Sep;28(9):1435-47. doi: 10.1210/me.2014-1024. Epub 2014 Jul 29.

Activated FoxM1 attenuates streptozotocin-mediated β-cell death.

Author information

1
Tennessee Valley Healthcare System Department of Veteran Affairs (M.L.G., M.F.M., J.C.D., G.P., M.A.G.), Nashville, Tennessee 37212; Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism (M.L.G., M.F.M., J.C.D., G.P., M.A.G.), and Departments of Cell and Developmental Biology (M.A.G.) and Molecular Physiology and Biophysics (M.A.G.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Department of Genetics and Institute for Diabetes, Obesity and Metabolism (J.S., K.H.K.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.

Abstract

The forkhead box transcription factor FoxM1, a positive regulator of the cell cycle, is required for β-cell mass expansion postnatally, during pregnancy, and after partial pancreatectomy. Up-regulation of full-length FoxM1, however, is unable to stimulate increases in β-cell mass in unstressed mice or after partial pancreatectomy, probably due to the lack of posttranslational activation. We hypothesized that expression of an activated form of FoxM1 could aid in recovery after β-cell injury. We therefore derived transgenic mice that inducibly express an activated version of FoxM1 in β-cells (RIP-rtTA;TetO-hemagglutinin (HA)-Foxm1(Δ)(NRD) mice). This N-terminally truncated form of FoxM1 bypasses 2 posttranslational controls: exposure of the forkhead DNA binding domain and targeted proteasomal degradation. Transgenic mice were subjected to streptozotocin (STZ)-induced β-cell ablation to test whether activated FoxM1 can promote β-cell regeneration. Mice expressing HA-FoxM1(ΔNRD) displayed decreased ad libitum-fed blood glucose and increased β-cell mass. β-Cell proliferation was actually decreased in RIP-rtTA:TetO-HA-Foxm1(NRD) mice compared with that in RIP-rtTA mice 7 days after STZ treatment. Unexpectedly, β-cell death was decreased 2 days after STZ treatment. RNA sequencing analysis indicated that activated FoxM1 alters the expression of extracellular matrix and immune cell gene profiles, which may protect against STZ-mediated death. These studies highlight a previously underappreciated role for FoxM1 in promoting β-cell survival.

PMID:
25073103
PMCID:
PMC4154244
DOI:
10.1210/me.2014-1024
[Indexed for MEDLINE]
Free PMC Article

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