GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Stein, Jeffrey A.; Milewski, Wieslawa; Hara, Manami; Steiner, Donald F.; Dey, Arunangsu

doi:10.4161/isl.3.1.14435

Cited by 27 publications

(39 citation statements)

References 56 publications

(103 reference statements)

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“…Indeed, our data dovetail with a previous work showing that the overexpression of a dominant-negative Pkb (also known as Akt) in beta cells leads to impaired insulin secretion [45]. Recent facts have been reported showing that GSK-3β activation is linked to beta cell failure in diabetic mouse models, and is involved in negative regulation of beta cell proliferation and mass [46,47]. Moreover, GSK-3β activity is enhanced in insulin-resistant states, and in skeletal muscle from type 2 diabetic patients [48].…”

Section: Discussionsupporting

confidence: 51%

Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

et al. 2011

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Aims/hypothesis Chronic hyperglycaemia aggravates insulin resistance, at least in part, by increasing the formation of advanced glycation end-products (AGEs). Methylglyoxal (MGO) is the most reactive AGE precursor and its abnormal accumulation participates in damage in various tissues and organs. Here we investigated the ability of MGO to interfere with insulin signalling and to affect beta cell functions in the INS-1E beta cell line. Methods INS-1E cells were incubated with MGO and then exposed to insulin or to glucose. Western blotting was used to study signalling pathways, and real-time PCR to analyse gene expression; insulin levels were determined by radioimmunoassay.Results Non-cytotoxic MGO concentrations inhibited insulin-induced IRS tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway activation independently from reactive oxygen species (ROS) production. Concomitantly, formation of AGE adducts on immunoprecipitated IRS was observed. Aminoguanidine reversed MGO inhibitory effects and the formation of AGE adducts on IRS. Further, the insulin-and glucose-induced expression of Ins1, Gck and Pdx1 mRNA was abolished by MGO. Finally, MGO blocked glucoseinduced insulin secretion and PI3K/PKB pathway activation. These MGO effects were abolished by LiCl, which inhibits glycogen synthase kinase-3 (GSK-3). Conclusions/interpretation MGO exerted major damaging effects on INS-1E cells impairing both insulin action and secretion. An important actor in these noxious MGO effects appears to be GSK-3. In conclusion, MGO participates not only in the pathogenesis of the debilitating complications of type 2 diabetes, but also in worsening of the diabetic state by favouring beta cell failure.

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Section: Discussionsupporting

confidence: 51%

Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

et al. 2011

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“…We found a similar pattern of abundance and localization of GSK-3 in adult mouse islet β-cells (data not shown). Our current and previous data, 9 as well as independent studies, 28 indicate that p27(Kip1) levels are likely stabilized following binding with GSK-3 in adult human and mouse β-cells resulting in maintenance of their quiescence. It’s worth pointing out that GSK-3 can also be present in the nuclei of cells via its nuclear localization signal 24 .…”

Section: Resultssupporting

confidence: 67%

“…Such interactions lead to cancellation of the positive cell cycle regulatory function of cyclinD-CDK/4 complexes. We and others showed substantial levels of cyclin D3 in adult human islets/β-cells and also, found low/undetectable amounts of the other 2 D-type cyclins, D1 and D2 9 , 10 . Next, we examined the abundance and sub-cellular localization of p27(Kip1), p-p27(S10), and p-p27(T187) in α-cells of adult human and mouse pancreatic tissue.…”

Section: Resultsmentioning

confidence: 91%

“…Nonetheless, such studies documented the clear potential of adult human β-cells to proliferate ex vivo. We showed, using isolated adult human islets, marked levels of several critical cell cycle regulators, including p27(Kip1) (a cyclin-dependent kinase [CDK] inhibitor), glycogen synthase kinase-3 (GSK-3) (a serine-threnine protein kinase), cyclin D3 (a member of D-type cyclins) and retinoblastoma (Rb) protein (a tumor suppressor) 9 . Substantial levels of both p27(Kip1) and cyclin D3 in β-cells of adult human pancreatic tissue were also reported 10 .…”

Section: Introductionmentioning

confidence: 99%

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The negative cell cycle regulators, p27^Kip1, p18^Ink4c, and GSK-3, play critical role in maintaining quiescence of adult human pancreaticβ-cells and restrict their ability to proliferate

Stein

Milewski²,

Dey³

2013

Islets

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Adult human pancreatic β-cells are primarily quiescent (G0) yet the mechanisms controlling their quiescence are poorly understood. Here, we demonstrate, by immunofluorescence and confocal microscopy, abundant levels of the critical negative cell cycle regulators, p27(Kip1) and p18(Ink4c), 2 key members of cyclin-dependent kinase (CDK) inhibitor family, and glycogen synthase kinase-3 (GSK-3), a serine-threonine protein kinase, in islet β-cells of adult human pancreatic tissue. Our data show that p27(Kip1) localizes primarily in β-cell nuclei, whereas, p18(Ink4c) is mostly present in β-cell cytosol. Additionally, p-p27(S10), a phosphorylated form of p27(Kip1), which was shown to interact with and to sequester cyclinD-CDK4/6 in the cytoplasm, is present in substantial amounts in β-cell cytosol. Our immunofluorescence analysis displays similar distribution pattern of p27(Kip1), p-p27(S10), p18(Ink4c) and GSK-3 in islet β-cells of adult mouse pancreatic tissue. We demonstrate marked interaction of p27(Kip1) with cyclin D3, an abundant D-type cyclin in adult human islets, and vice versa as well as with its cognate kinase partners, CDK4 and CDK6. Likewise, we show marked interaction of p18(Ink4c) with CDK4. The data collectively suggest that inhibition of CDK function by p27(Kip1) and p18(Ink4c) contributes to human β-cell quiescence. Consistent with this, we have found by BrdU incorporation assay that combined treatments of small molecule GSK-3 inhibitor and mitogen/s lead to elevated proliferation of human β-cells, which is caused partly due to p27(Kip1) downregulation. The results altogether suggest that ex vivo expansion of human β-cells is achievable via increased proliferation for β-cell replacement therapy in diabetes.

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“…GSK3b is a serine/threonine kinase (Aparicio et al, 2010;Jacobs et al, 2012), which plays an important physiological role in the regulation of a wide range of cellular functions, including differentiation, growth, apoptosis, and cell response to stimuli (Dong et al, 2005;Stein et al, 2011;Chen et al, 2012). The GSK3b was inhibited in the PI3K/Akt pathway, Wnt/GSK3 signaling, and ERK pathway (Zhang et al, 2006;Fuentealba et al, 2007;Kiyonari et al, 2010;Wu and Pan, 2010).…”

mentioning

confidence: 98%

WISP3 (CCN6) Regulates Milk Protein Synthesis and Cell Growth Through mTOR Signaling in Dairy Cow Mammary Epithelial Cells

Jiang

Wang

et al. 2015

DNA and Cell Biology

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The mTOR/S6K1 signaling pathway is the primary regulator of milk protein synthesis. While mTOR is known to be regulated at the translational level by amino acids, the mechanism by which mTOR accepts the amino acid signal is not yet clear. In this study, we describe the discovery of WISP3 as a potentially novel signaling factor that connects mTOR and amino acids. Treatment of dairy cow mammary epithelial cells with amino acids (lysine or methionine) increased both cell growth and the expression of β-casein (CSN2), WISP3, mTOR, and phospho-mTOR (p-mTOR). Notably, overexpressing WISP3 in these cells also increased both cell growth and the expression of CSN2, mTOR, and p-mTOR and decreased the expression of glycogen synthase kinase 3β (GSK3β), while repressing WISP3 had the opposite effect. The increase of the expression of CSN2, mTOR, and p-mTOR mediated by amino acid could be inhibited by repressing WISP3. The increase of the expression of CSN2, mTOR, and p-mTOR mediated by WISP3 overexpression could be inhibited by overexpressing GSK3β, and vice versa. Taken together, these results reveal that through its amino acid-mediated regulation of the mTOR pathway, WISP3 is an important regulatory factor involved in the amino acid-mediated regulation of milk protein synthesis and cell growth.

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GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Cited by 27 publications

References 56 publications

Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

The negative cell cycle regulators, p27^Kip1, p18^Ink4c, and GSK-3, play critical role in maintaining quiescence of adult human pancreaticβ-cells and restrict their ability to proliferate

WISP3 (CCN6) Regulates Milk Protein Synthesis and Cell Growth Through mTOR Signaling in Dairy Cow Mammary Epithelial Cells

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GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Cited by 27 publications

References 56 publications

Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

The negative cell cycle regulators, p27Kip1, p18Ink4c, and GSK-3, play critical role in maintaining quiescence of adult human pancreaticβ-cells and restrict their ability to proliferate

WISP3 (CCN6) Regulates Milk Protein Synthesis and Cell Growth Through mTOR Signaling in Dairy Cow Mammary Epithelial Cells

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The negative cell cycle regulators, p27^Kip1, p18^Ink4c, and GSK-3, play critical role in maintaining quiescence of adult human pancreaticβ-cells and restrict their ability to proliferate