Increasing levels of wild-type CREB up-regulates several activity-regulated inhibitor of death (AID) genes and promotes neuronal survival.
Increasing levels of wild-type CREB up-regulates several activity-regulated inhibitor of death (AID) genes and promotes neuronal survival.
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DOI：
10.1186/1471-2202-13-48
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发表时间：
2012-05-18
期刊：
影响因子：
2.4
通讯作者：
Bading H
中科院分区：
文献类型：
--
作者：
Tan YW;Zhang SJ;Hoffmann T;Bading H
CREB （camp反应元件结合蛋白）是典型的信号调节转录因子。在神经元中，它是突触活动诱导的核钙-钙/钙调蛋白依赖蛋白激酶（CaMK） IV信号通路的靶点，该信号通路控制获得性神经保护以及神经系统中其他长期适应过程的重要基因的表达。CREB作为转录激活因子的功能受其丝氨酸133上的磷酸化控制，该磷酸化可被CaMKIV催化并导致共激活因子CREB结合蛋白（CBP）的募集。通过细胞核钙- camkiv信号激活CBP功能是CREB/CBP介导转录所需的第二个调控步骤。在这里，我们使用重组腺相关病毒（rAAV）来增加野生型CREB的水平，或者在小鼠海马神经元氨基酸133位过度表达含有丝氨酸到丙氨酸突变的CREB突变版本（mCREB）。即使在基础条件下（即在没有刺激突触活动的情况下），增加CREB水平也足以增强神经保护活性。相反，mCREB的过表达增加了细胞死亡。在未受刺激的海马神经元中，内源性CREB和过表达的野生型CREB中，磷酸（丝氨酸133）CREB与CREB免疫反应性的比例相似，正如预期的那样，过表达的mCREB显著降低。一项基因表达分析显示，海马神经元中CREB而非mCREB的表达增加导致bdnf以及先前表征的一组活性调节的死亡抑制剂（AID）基因的几个成员的表达水平升高，这些基因包括atf3、btg2、gadd45β和gadd45γ。我们的研究结果表明，野生型CREB的表达水平是海马神经元在有害条件下生存能力的关键决定因素。增加野生型CREB水平，即使不诱导突触活动，也可以增加促存活基因的表达，增强神经元的神经保护屏蔽。在NMDA处理海马神经元后，CREB蛋白的降解表明，已知的与突触外NMDA受体诱导的兴奋性毒性相关的CREB关闭随后是CREB蛋白水解。
CREB (cAMP-response element binding protein) is the prototypical signal-regulated transcription factor. In neurons, it is the target of the synaptic activity-induced nuclear calcium-calcium/calmodulin dependent protein kinase (CaMK) IV signaling pathway that controls the expression of genes important for acquired neuroprotection as well as other long-lasting adaptive processes in the nervous system. The function of CREB as a transcriptional activator is controlled by its phosphorylation on serine 133, which can be catalyzed by CaMKIV and leads to the recruitment of the co-activator, CREB binding protein (CBP). Activation of CBP function by nuclear calcium-CaMKIV signaling is a second regulatory step required for CREB/CBP-mediated transcription. Here we used recombinant adeno-associated virus (rAAV) to increase the levels of wild type CREB or to overexpress a mutant version of CREB (mCREB) containing a serine to alanine mutation at position amino acid 133 in mouse hippocampal neurons. Increasing the levels of CREB was sufficient to boost neuroprotective activity even under basal conditions (i.e., in the absence of stimulation of synaptic activity). In contrast, overexpression of mCREB increased cell death. The ratio of phospho(serine 133)CREB to CREB immunoreactivity in unstimulated hippocampal neurons was similar for endogenous CREB and overexpressed wild type CREB and, as expected, dramatically reduced for overexpressed mCREB. A gene expression analysis revealed that increased expression of CREB but not that of mCREB in hippocampal neurons led to elevated expression levels of bdnf as well as that of several members of a previously characterized set of Activity-regulated Inhibitor of Death (AID) genes, which include atf3, btg2, gadd45β, and gadd45γ. Our findings indicate that the expression levels of wild type CREB are a critical determinant of the ability of hippocampal neurons to survive harmful conditions. Increasing the levels of wild type CREB can, even without inducing synaptic activity, increase pro-survival gene expression and strengthen the neurons’ neuroprotective shield. The observed degradation of CREB protein following NMDA treatment of hippocampal neurons suggests that the known CREB shut-off associated with extrasynaptic NMDA receptor-induced excitotoxicity is followed by CREB proteolysis.
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