The cell cycle inhibitory protein p21cip is not-essential for maintaining β-cell cycle arrest or β-cell function in vivo
The cell cycle inhibitory protein p21cip is not-essential for maintaining β-cell cycle arrest or β-cell function in vivo
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DOI：
10.2337/db06-0627
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发表时间：
2006-12-01
期刊：
影响因子：
7.7
通讯作者：
Stewart, Andrew F.
中科院分区：
文献类型：
--
作者：
Cozar-Castellano, Irene;Haught, Marcia;Stewart, Andrew F.
p21（cip1）是检查点G上游的调节分子，在β细胞中响应有丝分裂刺激而增加。尽管p21（cip1）可以不同程度地刺激或抑制细胞周期进程，但体外研究表明，p21（cip1）在胰腺β细胞中起抑制剂的作用。为了确定P21（cip1）在体内的功能作用，我们研究了P21缺失的小鼠。令人惊讶的是，p21缺失小鼠的胰岛质量、β细胞复制率和功能都正常。接下来，我们试图通过将p21-nuH小鼠与大鼠胰岛素11启动子小鼠PL-1（胰岛靶向胎盘乳原转基因）小鼠杂交来驱动p21-nuH小鼠的β细胞复制。即使有这种额外的PL复制刺激，p21null胰岛也没有表现出额外的刺激。G（1/S）蛋白质组扫描显示，p21（cip1）的缺失与其他细胞周期抑制剂（pRb、p107、p130、p16、p19和p27）的代偿性增加无关，尽管p57的轻度增加很明显。令人惊讶的是，预期会增加的p18明显减少。总之，分离的p21（cip1）缺失，与pRb、p53、p18、p27和其他抑制剂一样，会导致正常的β细胞发育和功能，要么是因为它不是必需的，要么是因为它的功能是由另一种蛋白质提供或补充的。这些研究强调了显著的抑制压力以及抑制β细胞复制的抑制途径的复杂性和可塑性。
p21(cip1), a regulatory molecule upstream of the G,, checkpoint, is increased in beta-cells in response to mitogenic stimulation. Whereas p21(cip1) can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that P21(cip1) acts as an inhibitor in the pancreatic beta-cell. To determine the functional role of P21(cip1) in vivo, we studied p21-null mice. Surprisingly, islet mass, beta-cell replication rates, and function were normal in p21-null mice. We next attempted to drive beta-cell replication in p21-nuH mice by crossing them with rat insulin 11 promoter-murine PL-1 (islet-targeted placental lactogen transgenic) mice. Even with this added replicative stimulus of PL, p21null islets showed no additional stimulation. A G(1/S) proteome scan demonstrated that p21(cip1) loss was not associated with compensatory increases in other cell cycle inhibitors (pRb, p107, p130, p16, p19, and p27), although mild increases in p57 were apparent. Surprisingly, p18, which had been anticipated to increase, was markedly decreased. In summary, isolated p21(cip1) loss, as for pRb, p53, p18, and p27 and other inhibitors, results in normal beta-cell development and function, either because it is not essential or because its function is subserved or complimented by another protein. These studies underscore marked inhibitory pressure and the complexity and plasticity of inhibitory pathways that restrain beta-cell replication.