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题名:High glucose exposure promotes activation of protein phosphatase 2A in rodent islets and INS-1 832/13 beta-cells by increasing the posttranslational carboxylmethylation of its catalytic subunit.
作者:ARORA DK; MACHHADIEH B; MATTI A; WADZINSKI BE; RAMANADHAM S; KOWLURU A;
来源:Endocrinology. 2014 Feb;155(2):380-91. doi: 10.1210/en.2013-1773. Epub 2013 Nov [ IF= 4.72 ] ]
URL :10.1210/en.2013-1773
日期:20140317
摘要:Existing evidence implicates regulatory roles for protein phosphatase 2A (PP2A)
in a variety of cellular functions, including cytoskeletal remodeling, hormone
secretion, and apoptosis. We report here activation of PP2A in normal rat islets
and insulin-secreting INS-1 832/13 cells under the duress of hyperglycemic (HG)
conditions. Small interfering RNA-mediated knockdown of the catalytic subunit of
PP2A (PP2Ac) markedly attenuated glucose-induced activation of PP2A. HG, but not
nonmetabolizable 3-O-methyl glucose or mannitol (osmotic control), significantly
stimulated the methylation of PP2Ac at its C-terminal Leu-309, suggesting a novel
role for this posttranslational modification in glucose-induced activation of
PP2A. Moreover, knockdown of the cytosolic leucine carboxymethyl transferase 1
(LCMT1), which carboxymethylates PP2Ac, significantly attenuated PP2A activation
under HG conditions. In addition, HG conditions, but not 3-O-methyl glucose or
mannitol, markedly increased the expression of LCMT1. Furthermore, HG conditions
significantly increased the expression of B55alpha, a regulatory subunit of PP2A,
which has been implicated in islet dysfunction under conditions of oxidative
stress and diabetes. Thapsigargin, a known inducer of endoplasmic reticulum
stress, failed to exert any discernible effects on the carboxymethylation of
PP2Ac, expression of LCMT1 and B55alpha, or PP2A activity, suggesting no clear
role for endoplasmic reticulum stress in HG-induced activation of PP2A. Based on
these findings, we conclude that exposure of the islet beta-cell to HG leads to
accelerated PP2A signaling pathway, leading to loss in glucose-induced insulin
secretion.

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