Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21Cip.
Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21Cip.
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DOI：
10.1007/s00125-012-2465-9
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发表时间：
2012-05
期刊：
影响因子：
8.2
通讯作者：
Bernal-Mizrachi, E.
中科院分区：
文献类型：
--
作者：
Blandino-Rosano, M.;Alejandro, E. U.;Sathyamurthy, A.;Scheys, J. O.;Gregg, B.;Chen, A. Y.;Rachdi, L.;Weiss, A.;Barker, D. J.;Gould, A. P.;Elghazi, L.;Bernal-Mizrachi, E.
关键词：
胰腺β细胞的增殖能力对于正常组织的维持以及胰岛素需求增加的情况都至关重要。 Akt（也称为蛋白激酶 B）在促进多种细胞类型（包括产生胰岛素的 β 细胞）增殖方面发挥着重要作用。我们之前曾报道过，过表达 Akt 组成型活性形式 (caAktTg) 的小鼠表现出增强的 β 细胞增殖，这与细胞周期蛋白 D1、细胞周期蛋白 D2 和细胞周期蛋白依赖性激酶抑制剂 1A (p21Cip) 的蛋白质产量增加有关。在本研究中，我们试图评估 caAktTg 小鼠中 p21Cip 水平增加的机制，并测试 p21Cip 在增殖反应中的作用为了更好地了解 Akt 和 p21Cip 之间的关系，我们评估了 Akt 调节 p21Cip 的机制以及减少的 p21Cip 在 Akt 诱导的增殖反应中的体内作用。我们的实验表明，Akt 信号调节 p21Cip 转录和蛋白质稳定性。与 caAktTg 小鼠相比，葡萄糖耐量测试显示，与 caAktTg 相比，caAktTg/p21Cip+/- 小鼠的葡萄糖耐量有所改善。与 caAktTg 小鼠相比，这些变化是由于 caAktTg/p21Cip+/- 小鼠的增殖、存活和 β 细胞质量增加所致。这些研究表明，p21Cip 可能在胰岛素抵抗等条件下的 β 细胞增殖适应性反应中发挥重要作用。
The ability of pancreatic beta cells to proliferate is critical both for normal tissue maintenance and in conditions where there is an increased demand for insulin. Akt (also known as Protein kinase B) plays a major role in promoting proliferation in many cell types, including the insulin-producing beta cells. We have previously reported that mice overexpressing a constitutively active form of Akt (caAktTg show enhanced beta cell proliferation that is associated with increased protein production of cyclin D1, cyclin D2 and cyclin-dependent kinase inhibitor 1A (p21Cip). In the present study, we sought to assess the mechanisms responsible for augmented p21Cip levels in caAktTg mice and test the role of p21Cip in the proliferative responses induced by activation of Akt signalling. To gain a greater understanding of the relationship between Akt and p21Cip, we evaluated the mechanisms involved in the modulation of p21Cip by Akt and the in vivo role of reduced p21Cip in proliferative responses induced by Akt. Our experiments showed that Akt signalling regulates p21Cip transcription and protein stability. caAktTg/p21Cip+/− mice exhibited fasting and fed hypoglycaemia as well as hyperinsulinaemia when compared with caAktTg mice. Glucose tolerance tests revealed improved glucose tolerance in caAktTg/p21Cip+/− mice compared with caAktTg. These changes resulted from increased proliferation, survival and beta cell mass in caAktTg/p21Cip+/− compared with caAktTg mice. Our data indicate that increased p21Cip levels in caAktTg mice act as a compensatory brake, protecting beta cells from unrestrained proliferation. These studies imply that p21Cip could play important roles in the adaptive responses of beta cells to proliferate in conditions such as in insulin resistance.
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