Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects
Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects
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DOI：
10.1001/archpsyc.60.3.273
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发表时间：
2003-03-01
影响因子：
--
通讯作者：
Pandey, GN
中科院分区：
文献类型：
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作者：
Dwivedi, Y;Rao, JS;Pandey, GN
背景：环磷酸腺苷反应元件结合蛋白(CREB)是一种转录因子，在蛋白激酶的磷酸化后被激活，并作为响应，调节许多神经元表达基因的转录。鉴于最近观察到自杀受试者(以下简称自杀受试者)死后大脑中许多通过激活CREB来调节其生理反应的激酶的催化性质和/或表达发生改变，我们研究了CREB在自杀行为中的地位。方法：这些研究在26名自杀受试者和20名非精神健康受试者的Brodmann区(BA)和海马区进行。用定量逆转录聚合酶链式反应检测总RNA中CREB和神经元特异性烯醇化酶的信使RNA水平。用Western印迹和环磷酸腺苷反应元件(CRE)-DNA结合活性分别检测核组分中CREB的蛋白水平和功能特性。结果：自杀者BA9和海马区CREB的信使RNA和蛋白水平、CRE-DNA结合活性、基础和环磷酸腺苷刺激的蛋白激酶A活性显著降低，而BA9神经元特异性烯醇化酶的信使RNA水平无明显变化。除蛋白激酶A活性外，所有自杀者的CREB表达和CRE-DNA结合活性均发生改变。这些变化与死后时间、年龄、性别和抗抑郁药物治疗无关。结论：鉴于CREB通过基因转录调节多种生理功能的重要性，我们的研究结果表明，CREB在自杀者死后脑内的表达和功能特征表明，CREB可能在自杀行为中发挥重要作用。
Background: Cyclic adenosine monophosphate response element binding protein (CREB) is a transcription factor that, on phosphorylation by protein kinases, is activated, and in response, regulates the transcription of many neuronally expressed genes. in view of the recent observations that catalytic properties and/or expression of many kinases that mediate their physiological responses through the activation of CREB are altered in the postmortem brain of subjects who commit suicide (hereafter referred to as suicide subjects), we examined the status of CREB in suicidal behavior.Methods: These studies were performed in Brodmann area (BA) 9 and hippocampus obtained from 26 suicide subjects and 20 nonpsychiatric healthy control subjects. Messenger RNA levels of CREB and neuron-specific enolase were determined in total RNA by means of quantitative reverse transcriptase-polymerase chain reaction. Protein levels and the functional characteristics of CREB were determined in nuclear fractions by means of Western blot and cyclic adenosine monophosphate response element (CRE)-DNA binding activity, respectively. In the same nuclear fraction, we determined the catalytic activity of cyclic adenosine monophosphate-stimulated protein kinase A by means of enzymatic assay.Results: We observed a significant reduction in messenger RNA and protein levels of CREB, CRE-DNA binding activity, and basal and cyclic adenosine monophosphate-stimulated protein kinase A activity in BA 9 and hippocampus of suicide subjects, without any change in messenger RNA levels of neuron-specific enolase in BA 9. Except for protein kinase A activity, changes in CREB expression and CRE-DNA binding activity were present in all suicide subjects, irrespective of diagnosis. These changes were unrelated to postmortem intervals, age, sex, or antidepressant treatment.Conclusions: Given the significance of CREB in mediating various physiological functions through gene transcription, our results of decreased expression and functional characteristics of CREB in postmortem brain of suicide subjects suggest that CREB may play an important role in suicidal behavior.