肿瘤抑制基因磷酸酶及张力蛋白同源物、Akt1 和 3-磷酸肌醇依赖性激酶 1 的活性和表达的调节：进一步的证据表明自杀者死后大脑中存在磷酸肌醇 3-激酶信号转导异常。
Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subjects.
机构信息
Department of Psychiatry, Psychiatric Institute, University of Illinois at Chicago, Chicago, IL 60612, USA.
出版信息
Biol Psychiatry. 2010 Jun 1;67(11):1017-25. doi: 10.1016/j.biopsych.2009.12.031. Epub 2010 Feb 16.
BACKGROUND
Phosphoinositide 3-kinase (PI3-K) signaling plays a crucial role in neuronal growth and plasticity. Recently, we demonstrated that suicide brain is associated with decreased activation and expression of selective catalytic and regulatory subunits of PI3-K. The present investigation examined the regulation and functional significance of compromised PI3-K in suicide brain at the level of upstream phosphatase and tensin homologue on chromosome ten (PTEN) and downstream substrates 3-phosphoinositide-dependent kinase 1 (PDK1) and Akt.
METHODS
Messenger RNA expression of Akt1, Akt3, PTEN, and PDK1 by competitive reverse transcription polymerase polymerase chain reaction; protein expression of Akt1, Akt3, PTEN, PDK1, phosphorylated Akt1 (Ser473 and Thr308), phosphorylated PDK1, and phosphorylated PTEN by Western blot; and catalytic activities of Akt1, Akt3, and PDK1 by enzymatic assays were determined in prefrontal cortex and hippocampus obtained from suicide subjects and nonpsychiatric control subjects.
RESULTS
No significant changes in the expression of Akt1 or Akt3 were observed; however, catalytic activity of Akt1, but not of Akt3, was decreased in prefrontal cortex and hippocampus of suicide subjects, which was associated with decreased phosphorylation of Akt1 at Ser473 and Thr308. The catalytic activity of PDK1 and the level of phosphorylated PDK1 were also decreased in both brain areas without any change in expression levels of PDK1. On the other hand, messenger RNA and protein expression of PTEN was increased, whereas the level of phosphorylated PTEN was decreased.
CONCLUSIONS
Our study demonstrates abnormalities in PI3-K signaling at several levels in brain of suicide subjects and suggests the possible involvement of aberrant PI3-K/Akt signaling in the pathogenic mechanisms of suicide.
背景
磷酸肌醇 3-激酶 (PI3-K) 信号转导在神经元的生长和可塑性中起着至关重要的作用。最近，我们证明自杀大脑与选择性催化和调节亚基的 PI3-K 的活性和表达降低有关。本研究在 upstream phosphatase 和 tensin homologue on chromosome ten (PTEN) 以及 downstream substrates 3-phosphoinositide-dependent kinase 1 (PDK1) 和 Akt 的水平上检查了自杀大脑中受损的 PI3-K 的调节和功能意义。
方法
竞争性逆转录聚合酶链反应测定 Akt1、Akt3、PTEN 和 PDK1 的信使 RNA 表达；Western blot 测定 Akt1、Akt3、PTEN、PDK1、磷酸化 Akt1（Ser473 和 Thr308）、磷酸化 PDK1 和磷酸化 PTEN 的蛋白表达；通过酶促测定测定 Akt1、Akt3 和 PDK1 的催化活性，从前额叶皮质和海马体获得自杀者和非精神科对照组。
结果
未观察到 Akt1 或 Akt3 的表达有显著变化；然而，自杀者的前额叶皮质和海马体中 Akt1 的催化活性降低，但 Akt3 的催化活性没有降低，这与 Akt1 在 Ser473 和 Thr308 的磷酸化减少有关。PDK1 的催化活性和磷酸化 PDK1 的水平也降低，而 PDK1 的表达水平没有变化。另一方面，PTEN 的信使 RNA 和蛋白表达增加，而磷酸化 PTEN 的水平降低。
结论
我们的研究表明自杀者大脑中的 PI3-K 信号转导在几个水平上存在异常，并表明异常的 PI3-K/Akt 信号转导可能参与了自杀的发病机制。
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