Cdk5r1 Overexpression Induces Primary β-Cell Proliferation.
Cdk5r1 Overexpression Induces Primary β-Cell Proliferation.
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DOI：
10.1155/2016/6375804
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发表时间：
2016
影响因子：
4.3
通讯作者：
Tessem JS
中科院分区：
文献类型：
--
作者：
Draney C;Hobson AE;Grover SG;Jack BO;Tessem JS
β 细胞量减少是 1 型和 2 型糖尿病的标志。胰岛移植作为糖尿病治疗的一种方法因缺乏可移植的胰岛而受到阻碍。了解控制胰岛增殖的途径可用于通过移植或增强内源性 β 细胞的生长来增加功能性 β 细胞量。我们已经证明转录因子 Nkx6.1 通过上调孤儿核激素受体 Nr4a1 和 Nr4a3 来诱导 β 细胞增殖。使用表达分析来定义 Nr4a1 和 Nr4a3 诱导 β 细胞增殖的 Nkx6.1 独立机制，我们证明细胞周期蛋白依赖性激酶 5 调节亚基 1 (Cdk5r1) 被 Nr4a1 和 Nr4a3 上调，但不被 Nkx6.1 上调。 Cdk5r1 的过度表达足以诱导原代大鼠 β 细胞增殖，同时维持葡萄糖刺激的胰岛素分泌。 β 细胞中 Cdk5r1 的过度表达可以防止依托泊苷和毒胡萝卜素诱导的细胞凋亡，但不能防止喜树碱诱导的细胞凋亡。 Cdk5 激酶复合物抑制剂 roscovitine 可阻断胰岛增殖，表明 Cdk5r1 介导的 β 细胞增殖是激酶依赖性事件。 Cdk5r1 的过度表达会导致 pRb 磷酸化，而这种磷酸化可被 roscovitine 处理所抑制。这些数据表明，Cdk5激酶复合物的激活足以诱导β细胞增殖，同时维持葡萄糖刺激的胰岛素分泌。
Decreased β-cell mass is a hallmark of type 1 and type 2 diabetes. Islet transplantation as a method of diabetes therapy is hampered by the paucity of transplant ready islets. Understanding the pathways controlling islet proliferation may be used to increase functional β-cell mass through transplantation or by enhanced growth of endogenous β-cells. We have shown that the transcription factor Nkx6.1 induces β-cell proliferation by upregulating the orphan nuclear hormone receptors Nr4a1 and Nr4a3. Using expression analysis to define Nkx6.1-independent mechanisms by which Nr4a1 and Nr4a3 induce β-cell proliferation, we demonstrated that cyclin-dependent kinase 5 regulatory subunit 1 (Cdk5r1) is upregulated by Nr4a1 and Nr4a3 but not by Nkx6.1. Overexpression of Cdk5r1 is sufficient to induce primary rat β-cell proliferation while maintaining glucose stimulated insulin secretion. Overexpression of Cdk5r1 in β-cells confers protection against apoptosis induced by etoposide and thapsigargin, but not camptothecin. The Cdk5 kinase complex inhibitor roscovitine blocks islet proliferation, suggesting that Cdk5r1 mediated β-cell proliferation is a kinase dependent event. Overexpression of Cdk5r1 results in pRb phosphorylation, which is inhibited by roscovitine treatment. These data demonstrate that activation of the Cdk5 kinase complex is sufficient to induce β-cell proliferation while maintaining glucose stimulated insulin secretion.