PP-1β and PP-2Aα modulate cAMP response element-binding protein (CREB) functions in aging control and stress response through de-regulation of αB-crystallin gene and p300-p53 signaling axis.
PP-1β and PP-2Aα modulate cAMP response element-binding protein (CREB) functions in aging control and stress response through de-regulation of αB-crystallin gene and p300-p53 signaling axis.
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PP-1β 和 PP-2Aα 通过调节 αB 晶状体蛋白基因和 p300-p53 信号轴来调节 cAMP 反应元件结合蛋白 (CREB) 在衰老控制和应激反应中的功能
作者：
Wang L;Zhang L;Gong XD;Fu JL;Gan YW;Hou M;Nie Q;Xiang JW;Xiao Y;Wang Y;Zheng SY;Yang L;Chen H;Xiang MQ;Liu Y;Li DW
转录因子cAMP反应元件结合蛋白(CREB)的功能是通过PKA等对S133的磷酸化而激活的。关于它的失活，它没有很好的定义。CAMP反应元件结合蛋白在促进细胞增殖、神经元存活和与长时记忆相关的突触可塑性方面发挥着重要作用。我们最近的研究表明，CREB在调节应激反应中起着重要作用。在这里，我们已经证明，CREB通过抑制αB-晶体蛋白和激活p300-P53-BAK/BAX信号轴来调节衰老过程。首先，我们确定了两种特异的蛋白磷酸酶，PP-1β和PP-2Aα，它们可以通过S133去磷酸化来灭活CREB。随后，我们证明了表达S133A-CREB的细胞，一个模拟S133处持续去磷酸化的突变体，抑制了CREB在衰老控制和应激反应中的功能。在机制上，S133A-CREB不仅显著抑制αB-晶状体蛋白基因的CREB调控，而且还抑制CREB介导的P53乙酰化及其下游的BAK/BAX基因的激活。CAMP反应元件结合蛋白抑制αB-晶状体蛋白及其激活P53乙酰化是不同年龄段白内障晶状体中观察到的主要分子事件。综上所述，我们的结果表明，PP-1β和PP-2Aα通过下调αB-晶体蛋白基因和p300-P53-BAX/BAK信号轴来调节CREB在衰老控制和应激反应中的功能，从而调节人类老化晶状体中的白内障发生。该图说明在正常晶状体和白内障晶状体中，PP-1β和PP-2Aα通过抑制α-晶状体蛋白和激活p300-P53-BAX/BAK信号轴，调节CREB在衰老控制和应激反应中的功能。
The function of the transcription factor, cAMP response element‐binding protein (CREB), is activated through S133 phosphorylation by PKA and others. Regarding its inactivation, it is not well defined. cAMP response element‐binding protein plays an essential role in promoting cell proliferation, neuronal survival and the synaptic plasticity associated with long‐term memory. Our recent studies have shown that CREB is an important player in mediating stress response. Here, we have demonstrated that CREB regulates aging process through suppression of αB‐crystallin and activation of the p300‐p53‐Bak/Bax signaling axis. First, we determined that two specific protein phosphatases, PP‐1β and PP‐2Aα, can inactivate CREB through S133 dephosphorylation. Subsequently, we demonstrated that cells expressing the S133A‐CREB, a mutant mimicking constant dephosphorylation at S133, suppress CREB functions in aging control and stress response. Mechanistically, S133A‐CREB not only significantly suppresses CREB control of αB‐crystallin gene, but also represses CREB‐mediated activation of p53 acetylation and downstream Bak/Bax genes. cAMP response element‐binding protein suppression of αB‐crystallin and its activation of p53 acetylation are major molecular events observed in human cataractous lenses of different age groups. Together, our results demonstrate that PP‐1β and PP‐2Aα modulate CREB functions in aging control and stress response through de‐regulation of αB‐crystallin gene and p300‐p53‐Bax/Bak signaling axis, which regulates human cataractogenesis in the aging lens. This figure illustrates that the PP‐1β and PP‐2Aα modulate CREB functions in aging control and stress response through suppression of alphaB‐crystallin and activation of the p300‐p53‐Bax/Bak signaling axis in normal and cataractous lenses.
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