Journal
BIOCHEMICAL JOURNAL
Volume 444, Issue -, Pages 239-247Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20111606
Keywords
B55 alpha regulatory subunit; diabetes; forkhead box O1 (FOXO1); oxidative stress; pancreatic beta-cell; protein phosphatase 2A (PP2A)
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Funding
- National Institutes of Health [R01CA92498, 5R01DK050203]
- Hope Street Kids Foundation
- Juvenile Diabetes Research Foundation
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The FOXO1 (forkhead box O1) transcription factor influences many key cellular processes, including those important in metabolism, proliferation and cell death. Reversible phosphorylation of FOXO1 at Thr(24) and Ser(256) regulates its subcellular localization, with phosphorylation promoting cytoplasmic localization, whereas dephosphorylation triggers nuclear import and transcriptional activation. In the present study, we used biochemical and molecular approaches to isolate and link the serine/threonine PP2A (protein phosphatase 2A) holoenzyme containing the B55 alpha regulatory subunit, with nuclear import of FOXO1 in pancreatic islet beta-cells under oxidative stress, a condition associated with cellular dysfunction in Type 2 diabetes. The mechanism of FOXO1 dephosphorylation and nuclear translocation was investigated in pancreatic islet INS-I and beta TC-3 cell lines subjected to oxidative stress. A combined chemical cross-linking and MS strategy revealed the association of FOXO1 with a PP2A holoenzyme composed of the catalytic C, structural A and B55 alpha regulatory subunits. Knockdown of B55 alpha in INS-1 cells reduced FOXO1 dephosphorylation, inhibited FOXO1 nuclear translocation and attenuated oxidative stress-induced cell death. Furthermore, both B55 alpha and nuclear FOXO1 levels were increased under hyperglycaemic conditions in db/db mouse islets, an animal model of Type 2 diabetes. We conclude that B55 alpha-containing PP2A is a key regulator of FOX01 activity in vivo.
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