Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging.
Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging.
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DOI：
10.1161/circresaha.113.300536
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发表时间：
2014-01-17
影响因子：
20.1
通讯作者：
Gupta MP
中科院分区：
文献类型：
--
作者：
Pillai VB;Sundaresan NR;Gupta MP
心脏肥大是一种多因素疾病，其特征在于多种分子改变。这些变化之一是Akt活性的变化，Akt在调节从细胞存活到衰老的各种细胞过程中起着核心作用。Akt活化主要通过其与磷脂酰肌醇3，4，5三磷酸（PIP3）结合来实现。这导致构象变化，其暴露Akt的激酶结构域用于磷酸化并被其在细胞膜中的上游激酶PDK1激活。最近的研究表明，sirtuin亚型SIRT1，SIRT3和SIRT6在调节Akt激活中起着重要作用。SIRT1使Akt去乙酰化以促进PIP3结合和活化，而SIRT3控制ROS介导的Akt活化，SIRT6在染色质水平转录抑制Akt。在本文的第一部分中，我们讨论了sirtuins调节Akt激活的机制，以及它们如何影响Akt的其他翻译后修饰。在评论的后半部分，我们总结了sirtuin依赖性调节Akt信号在控制主要细胞过程中的影响，如细胞生长，血管生成，凋亡，自噬和衰老，这些过程参与了几种疾病的发生和发展。
Cardiac hypertrophy is a multifactorial disease characterized by multiple molecular alterations. One of these alterations is change in activity of Akt, which plays a central role in regulating a variety of cellular processes ranging from cell survival to aging. Akt activation is mainly achieved by its binding to phosphatidylinositol 3,4,5 triphosphate (PIP3). This results in a conformational change that exposes the kinase domain of Akt for phosphorylation and activation by its upstream kinase PDK1 in the cell membrane. Recent studies have shown that sirtuin isoforms SIRT1, SIRT3 and SIRT6 play an essential role in the regulation of Akt activation. While SIRT1 deacetylates Akt to promote PIP3 binding and activation, SIRT3 controls ROS-mediated Akt activation and SIRT6 transcriptionally represses Akt at the level of chromatin. In the first part of this review, we discuss the mechanisms by which sirtuins regulate Akt activation and how they influence other post-translational modifications of Akt. In the latter part of the review, we summarize the implications of sirtuin-dependent regulation of Akt signaling in the control of major cellular processes like cellular growth, angiogenesis, apoptosis, autophagy and aging; which are involved in the initiation and progression of several diseases.