&amp;beta;-Cell Growth: An Unusual Paradigm of Organogenesis That is Cyclin D2/cdk4 Dependent

Kushner, Jake A.

doi:10.4161/cc.5.3.2399

Cited by 37 publications

(26 citation statements)

References 29 publications

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“…The question of whether loss of G s ␣/cAMP signaling directly leads to cyclin D2 deficiency in ␤ cells requires further study, although recent studies in both lymphocytes and ovarian granulosa cells demonstrated that cAMP induces the Ccnd2 gene promoter via binding of PKA-phosphorylated CREB to a CREB binding site (31,32). Cyclin D2 and its associated cyclin-dependent kinase cdk4 have both been shown to be critical regulators of ␤ cell proliferation and ␤ cell mass (3)(4)(5)(6)(7)33). However, it is unclear to what extent cyclin D2 deficiency contributes to the ␤ cell defect resulting from G s ␣ deficiency, because cyclin D2 knockout mice have been shown to affect ␤ cell mass and proliferation within the early postnatal period in one genetic background (7) but to only affect ␤ cells in later life in another genetic background (4).…”

Section: Discussionmentioning

confidence: 99%

“…␤ cell proliferation is important for maintaining adequate ␤ cell mass under normal and stress conditions, and ␤ cell mass appears to depend on proteins involved in cell cycle regulation (2). In particular, both cyclin D2 and cyclin-dependent kinase 4 (cdk4), which are expressed at high levels in ␤ cells and are critical for G 1 /S phase transition, are required to maintain normal ␤ cell mass (3)(4)(5)(6)(7).…”

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confidence: 99%

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β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

Xie

Chen

Zhang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The G protein ␣-subunit Gs␣ is required for hormone-stimulated cAMP generation. In pancreatic ␤ cells, Gs␣ mediates the signaling of glucagon-like peptide 1 and other incretin hormones, which are implicated as important regulators of ␤ cell survival and insulin release. Studies have suggested that G s␣/cAMP mediates these actions by stimulating insulin receptor substrate 2 (IRS2) expression. Mice with ␤ cell-specific Gs␣ deficiency (␤GsKO) were generated by mating G s␣-floxed mice to rat insulin II promoter-cre recombinase mice. ␤GsKO mice had poor survival and postnatal growth with low serum insulin-like growth factor 1 levels. ␤GsKO mice also developed severe hyperglycemia and glucose intolerance with severe hypoinsulinemia and reduced islet insulin content and glucose-stimulated insulin release. ␤GsKO mice had markedly reduced average islet size and ␤ cell mass, which was partially explained by reduced ␤ cell size. In addition, ␤GsKO mice had significantly reduced ␤ cell proliferation and increased ␤ cell apoptosis and markedly reduced expression of the cell cycle protein cyclin D2. The effects on ␤ cell mass and proliferation, but not apoptosis, were present from birth. Unexpectedly expression of Irs2 and the downstream gene Pdx1 were unaffected. These results show that G s␣/cAMP pathways are critical regulators of ␤ cell function and proliferation that can work through IRS2-independent mechanisms.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

Xie

Chen

Zhang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Increased b-cell mass due to hyperglycemia has been associated with cell-autonomous molecular mechanisms that increase b-cell proliferation such as cell cycle regulators (cycline D family) (48,49), systemic factors such as hormones (insulin and prolactin) (4), and glucose (50). In a mouse model of insulin resistance, it was shown that betatrophin, a newly discovered molecule produced by hepatocytes, could increase b-cell proliferation and normalize blood glucose levels (51).…”

Section: Discussionmentioning

confidence: 99%

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

et al. 2014

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Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for b-cell loss since their b-cell-producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that b-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward b-cells in mouse and human. These effects are dynamic and correlate with functional b-cell regeneration when conditions allow.

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“…Cyclin/CDK and PCNA form a quaternary complex which regulates cell cycle progression. 59 CyclinD2, the dominant D-type cyclin in adult islets, 45 is an essential b-cell replication factor implicated in triggering b-cell entry into the cell cycle 60,61 and regulating b-cell mass. 57 Cdkn1a inhibits CDKs, promoting G1 cell cycle arrest 31 and blocking islet replication in response to growth factors.…”

Section: Discussionmentioning

confidence: 99%

Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

Kauri¹,

Wang²,

Patrick

et al. 2007

Laboratory Investigation

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We reported previously that young BioBreeding diabetes-prone (BBdp) rats display increased neogenic extra-islet insulin þ clusters (EICs, o4 insulin þ cells) without an increase in b-cell mass. Therefore, we investigated the possibility that abnormal islet expansion occurs in BBdp rats before the appearance of islet inflammation. Islet expansion was analyzed in pancreata from 14 to 45 day BBdp and control (BioBreeding control, BBc) rats using immunohistochemistry, morphometry, laser capture microdissection and reverse transcriptase-PCR. mRNA expression for Neurogenin-3, a developmental marker of endocrine progenitors, was three-fold greater in EIC of weanling BBdp and BBc rats compared with islet cells. With increasing age (14-30 days), Neurogenin-3 expression decreased in EIC and increased in islets. In BBdp rats, EIC number and b-cell proliferation within EIC was greater compared with BBc animals; apoptosis did not differ. The area of small and medium islets in BBdp rats was greater than BBc rats between 14 and 30 days, but this did not result in increased total islet area or b-cell mass. In addition, the number and area of very large islets was low at 45 days. The frequency of proliferating b-cells decreased with increasing islet size in BBdp but was constant in BBc rats. Cell cycle analysis of islets revealed more G1 cells and fewer G2 cells in BBdp rats. The ratio of cyclinD2/Cdkn1a, genes that respectively promote or inhibit cell cycle progression, was decreased in BBdp islets. These results suggest that despite increased islet neogenesis, the capacity for islet expansion in diabetes-prone rats is compromised possibly due to decreased proliferative capacity with increasing islet size associated with a partial block at the G1/S cell cycle boundary in islet cells.

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β-Cell Growth: An Unusual Paradigm of Organogenesis That is Cyclin D2/cdk4 Dependent

Cited by 37 publications

References 29 publications

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

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&beta;-Cell Growth: An Unusual Paradigm of Organogenesis That is Cyclin D2/cdk4 Dependent

Cited by 37 publications

References 29 publications

β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

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β-Cell Growth: An Unusual Paradigm of Organogenesis That is Cyclin D2/cdk4 Dependent

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes