Participation of Akt, Menin, and p21 in Pregnancy-Induced β-Cell Proliferation
Participation of Akt, Menin, and p21 in Pregnancy-Induced β-Cell Proliferation
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DOI：
10.1210/en.2010-1250
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发表时间：
2011-03-01
期刊：
影响因子：
4.8
通讯作者：
Huang, Carol
中科院分区：
文献类型：
--
作者：
Hughes, Elizabeth;Huang, Carol
怀孕期间β细胞质量增加，以适应胰岛素抵抗。这种增加主要是由于β细胞增殖，这是一个需要完整的催乳素受体（Prlr）信号传导的过程。已知调节β细胞增殖的信号分子包括Jak 2、Akt、肿瘤抑制因子menin和细胞周期蛋白。这些途径是否参与催乳素介导的β细胞增殖尚不清楚。使用杂合子催乳素受体缺失（Prlr（+/+））小鼠，我们从妊娠d 0和15的Prlr（+/+）和Prlr（+/+）小鼠中分离胰岛，并检测这些信号分子的表达水平。在野生型小鼠（Prlr（+/+））中，胰腺胰岛中磷酸化-Jak 2和磷酸化-Akt表达在妊娠期间增加，这在妊娠Prlr（+/+）小鼠中减弱。在妊娠期间，menin表达在Prlr（+/+）和Prlr（+/+）小鼠中分别减少50%和20%，并且妊娠Prlr（+/+）小鼠的胰岛p18水平高于Prlr（+/+）小鼠。有趣的是，在妊娠d 0和15之间，周期蛋白抑制蛋白p21 cip在Prlr（+/+）小鼠中的表达增加，但这种增加在Prlr（+/+）小鼠中被钝化。最后，我们没有发现怀孕的Prlr（+/+）和Prlr（+/+）小鼠之间的细胞周期蛋白D1，D2和抑制性激酶的表达水平有任何差异。因此，我们得出结论，在怀孕期间，胎盘激素通过催乳素受体通过参与Jak 2，Akt，menin/ p18和p21上调β细胞增殖来增加β细胞质量。未来的研究将确定这些分子在维持妊娠期间正常葡萄糖稳态中的相对贡献。（内分泌学152：847-855，2011）
beta-Cell mass increases during pregnancy to accommodate for insulin resistance. This increase is mainly due to beta-cell proliferation, a process that requires intact prolactin receptor (Prlr) signaling. Signaling molecules that are known to regulate beta-cell proliferation include Jak2, Akt, the tumor suppressor menin, and cell cycle proteins. Whether these pathways are involved in prolactin-mediated beta-cell proliferation is unknown. Using the heterozygous prolactin receptor-null (Prlr(+/+)) mice, we isolated pancreatic islets from both Prlr(+/+) and Prlr(+/+) mice on d 0 and 15 of pregnancy and examined the expression levels of these signaling molecules. In the wild-type mice (Prlr(+/+)), both phospho-Jak2 and phospho-Akt expression in pancreatic islets increased during pregnancy, which were attenuated in the pregnant Prlr(+/+) mice. During pregnancy, menin expression was reduced by 50 and 20% in the Prlr(+/+) and the Prlr(+/+) mice, respectively, and the pregnant Prlr(+/+) mice had higher islet p18 levels than the Prlr(+/+) mice. Interestingly, between d 0 and 15 of pregnancy, expression of cyclin inhibitory protein p21cip was increased in the Prlr(+/+) mice, but this increase was blunted in the Prlr(+/+) mice. Lastly, we did not find any difference in the expression levels of cyclins D1, D2, and inhibitory kinases between the pregnant Prlr(+/+) and Prlr(+/+) mice. Therefore, we conclude that during pregnancy, placental hormones act through the prolactin receptor to increase beta-cell mass by up regulating beta-cell proliferation by engaging Jak2, Akt, menin/ p18, and p21. Future studies will determine the relative contribution of these molecules in maintaining normal glucose homeostasis during pregnancy. (Endocrinology 152: 847-855, 2011)