Overexpression of ST5, an activator of Ras, has no effect on β-cell proliferation in adult mice.
Overexpression of ST5, an activator of Ras, has no effect on β-cell proliferation in adult mice.
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DOI：
10.1016/j.molmet.2018.03.009
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发表时间：
2018-05
影响因子：
8.1
通讯作者：
Kaestner KH
中科院分区：
文献类型：
--
作者：
Ou K;Zhang J;Jiao Y;Wang ZV;Scherer P;Kaestner KH
I 型和 II 型糖尿病都是由功能性 β 细胞量不足引起的。作为恢复β细胞质量的手段而增加β细胞增殖的努力取得了有限的成功。在表皮生长因子 (EGF) 存在的情况下，抑制致瘤性 5 (ST5) 会激活 Ras/Erk 信号传导。在胰岛中，妊娠期间增强 β 细胞增殖需要 Ras/Erk 信号传导，这表明 ST5 是增强成人 β 细胞增殖的有吸引力的候选者。我们的目的是检验 ST5 过度表达驱动成人 β 细胞增殖的假设。我们利用多西环素诱导的双转基因小鼠模型在成年小鼠中随意激活人类 ST5 的 β 细胞特异性表达。在基础和两种刺激代谢状态下：妊娠和链脲佐菌素 (STZ) 诱导的 β 细胞损失，通过免疫荧光染色分析对照和 ST5 过表达 (ST5 OE) 动物的胰岛形态、β 细胞增殖和 β 细胞质量。与对照组相比，多西环素处理导致 12-16 周龄 ST5 OE 动物的胰岛中 ST5 强烈过度表达，且不影响胰岛形态和 β 细胞的特性。在基础和代谢刺激的妊娠状态下，ST5 OE 和对照动物的 β 细胞增殖和质量相当。此外，对于 STZ 诱导的 β 细胞损失，ST5 OE 和对照动物之间的 β 细胞增殖没有可检测到的差异。我们成功地衍生了一种可诱导的双转基因小鼠模型，以在 β 细胞中特异性过度表达 ST5。然而，我们的研究结果表明，ST5 过度表达本身对基础和代谢挑战状态下的成体 β 细胞没有促有丝分裂作用。假设 ST5 的过度表达会由于其激活 MAPK/ERK 的作用而驱动成人 β 细胞增殖。生成了强力霉素诱导的双转基因小鼠模型，以激活 ST5 的 β 细胞特异性表达。 ST5 过表达对基础状态和代谢挑战状态下的成人 β 细胞没有促有丝分裂作用。
Both Type I and Type II diabetes mellitus result from insufficient functional β-cell mass. Efforts to increase β-cell proliferation as a means to restore β-cell mass have been met with limited success. Suppression of Tumorigenicity 5 (ST5) activates Ras/Erk signaling in the presence of Epidermal Growth Factor (EGF). In the pancreatic islet, Ras/Erk signaling is required for augmented β-cell proliferation during pregnancy, suggesting that ST5 is an appealing candidate to enhance adult β-cell proliferation. We aimed to test the hypothesis that overexpression of ST5 drives adult β-cell proliferation. We utilized a doxycycline-inducible bitransgenic mouse model to activate β-cell-specific expression of human ST5 in adult mice at will. Islet morphology, β-cell proliferation, and β-cell mass in control and ST5-overexpressing (ST5 OE) animals were analyzed by immunofluorescent staining, under basal and two stimulated metabolic states: pregnancy and streptozotocin (STZ)-induced β-cell loss. Doxycycline treatment resulted in robust ST5 overexpression in islets from 12-16 week-old ST5 OE animals compared to controls, without affecting the islet morphology and identity of the β-cells. Under both basal and metabolically stimulated pregnancy states, β-cell proliferation and mass were comparable in ST5 OE and control animals. Furthermore, there was no detectable difference in β-cell proliferation between ST5 OE and control animals in response to STZ-induced β-cell loss. We successfully derived an inducible bitransgenic mouse model to overexpress ST5 specifically in β-cells. However, our findings demonstrate that ST5 overexpression by itself has no mitogenic effect on the adult β-cell under basal and metabolically challenged states. Hypothesized that overexpression of ST5 would drive adult β-cell proliferation due to its role in activating MAPK/ERK. Generated a doxycycline-inducible bitransgenic mouse model to activate β-cell-specific expression of ST5. ST5 overexpression has no mitogenic effect on adult β-cellsunder basal and metabolically challenged states.
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影响因子：
29
作者：
Le Lay J;Tuteja G;White P;Dhir R;Ahima R;Kaestner KH
通讯作者：
Kaestner KH
影响因子：
7.7
作者：
Kulkarni RN;Mizrachi EB;Ocana AG;Stewart AF
通讯作者：
Stewart AF
影响因子：
10.5
作者：
Gupta, Rana K.;Gao, Nan;Kaestner, Klaus H.
通讯作者：
Kaestner, Klaus H.
影响因子：
7.7
作者：
Stewart AF;Hussain MA;García-Ocaña A;Vasavada RC;Bhushan A;Bernal-Mizrachi E;Kulkarni RN
通讯作者：
Kulkarni RN
影响因子：
29.4
作者：
Means, AL;Ray, KC;Leach, SD
通讯作者：
Leach, SD