Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis
Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis
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Min6 胰腺 β 细胞中 p35 的过度表达诱导应激性神经元样凋亡
DOI：
10.1016/j.jns.2010.08.067
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发表时间：
2010-12-15
影响因子：
4.4
通讯作者：
Pant, Harish C.
中科院分区：
文献类型：
--
作者：
Zheng, Ya-Li;Hu, Ya-Fang;Pant, Harish C.
Cdk5活性与大脑发育和许多神经元过程的调节有关。最近，已经报道了胰腺β细胞中p35和Cdk5活性的表达。Cdk 5活性降低可增强葡萄糖刺激的胰岛素分泌。这表明Cdk 5可能在调节胰岛素分泌中起重要作用。为了进一步了解Cdk5如何调节葡萄糖刺激的胰腺β细胞中的胰岛素分泌，我们首先证实了胰腺Min6细胞中存在低水平的p35。接下来，在高葡萄糖（25 mM）的时程实验中，我们发现内源性p35逐渐增加，伴随着Cdk5活性的3倍增加，到16 h。胰岛素分泌，但是，增加了一倍，2小时后进行性下调，与Cdk5活性呈负相关。另一方面，在这些细胞中p35的过表达导致Cdk5活性在2小时内增加了3倍以上，在高和低（3 mM）葡萄糖中胰岛素分泌减少了50%。最重要的是，过表达p35的细胞，用高葡萄糖处理4小时，显示诱导p25，p35衍生的截短片段，其在神经元中过度激活Cdk5。结果，胰岛素分泌受到抑制，细胞发生凋亡。Roscovitine或显性负性Cdk5（dnCdk5）与p35的共感染增加胰岛素分泌并抑制细胞凋亡。这些结果表明，神经变性中Cdk5的失调和过度激活的模型可能适用于2型糖尿病（T2DM）中观察到的病理学。这与阿尔茨海默病和T2DM通过Cdk 5以多种方式在代谢和病理上相关联的观点一致。(C)出版社：Elsevier B.V.
Cdk5 activity has been implicated in brain development and the regulation of many neuronal processes. Recently, the expression of p35 and Cdk5 activity has been reported in pancreatic beta cells. Decreased Cdk5 activity enhanced glucose-stimulated insulin secretion. This suggests that Cdk5 may play an important role in the regulation of insulin secretion. To further understand how Cdk5 regulates insulin secretion in glucose-stimulated pancreatic beta cells, we first confirmed the presence of a low level of p35 in pancreatic Min6 cells. Next, in a time-course experiment in high glucose (25 mM) we showed that endogenous p35 increased gradually accompanied by a 3-fold increase in Cdk5 activity by 16 h. Insulin secretion, however, doubled after 2 h followed by progressive downregulation, negatively correlated with Cdk5 activity. On the other hand, overexpression of p35 in these cells resulted in more than a three-fold increase in Cdk5 activity within 2 h coupled to a 50% reduction in insulin secretion in both high and low (3 mM) glucose. Most significantly, cells overexpressing p35, treated with high glucose for 4 h, showed induction of p25, the p35-derived truncated fragment which hyperactivates Cdk5 in neurons. As a result, insulin secretion was inhibited and cells became apoptotic. Roscovitine or co-infection of dominant negative Cdk5 (dnCdk5) with p35 increased insulin secretion and inhibited apoptosis. These results suggest that the model for deregulation and hyperactivation of Cdk5 in neurodegeneration may apply to the pathology seen in type 2 diabetes (T2DM). It is consistent with the view that Alzheimer's disease and T2DM are linked metabolically and pathologically by Cdk5 in a number of ways. (C) 2010 Published by Elsevier B.V.