Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth
Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth
复制标题
DOI：
10.1128/mcb.25.9.3752-3762.2005
复制
发表时间：
2005-05-01
影响因子：
5.3
通讯作者：
White, MF
中科院分区：
文献类型：
--
作者：
Kushner, JA;Ciemerych, MA;White, MF
胰岛成人p细胞质量的调节对于维持足够的胰岛素分泌以适当调节葡萄糖稳态至关重要。在许多组织中，有丝分裂原通过刺激d型细胞周期蛋白（D1、D2或D3）和激活细胞周期蛋白依赖性激酶（CDK4或CDK6）来影响发育，从而导致细胞周期的G期进展。我们发现细胞周期蛋白D2和D1对出生后胰岛的正常生长至关重要。在成年小鼠胰岛中，cyclin D2 mRNA的基础表达很容易被检测到，而cyclin D1的表达水平较低，而cyclin D3几乎无法检测到。细胞周期蛋白D2（-/-）或细胞周期蛋白D1(+/-) D2（-/-）小鼠的产前胰岛发育正常。然而，成年周期蛋白D2（-/-）小鼠的β细胞增殖、成体质量和葡萄糖耐量下降，导致葡萄糖耐受不良，并在12个月大时发展为糖尿病。虽然细胞周期蛋白D1（-/-）小鼠从未发生糖尿病，但3个月大的细胞周期蛋白D1(-/+) D2（-/-）小鼠由于出生后β细胞质量下降而发生危及生命的糖尿病。因此，细胞周期蛋白D2和D1对于成年小鼠的β细胞扩增至关重要。严格调节β细胞中d型细胞周期蛋白活性的策略可以预防或治疗糖尿病。
Regulation of adult P-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G, phase of the cell cycle. Here we show that cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2(-/-) or cyclin D1(+/-) D2(-/-) mice. However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1(-/-) mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1(-/+) D2(-/-) mice as beta-cell mass decreased after birth. Thus, cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.