title: Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging.
abstract: Cardiac hypertrophy is a multifactorial disease characterized by multiple molecular alterations. One of these alterations is change in the 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. This results in a conformational change that exposes the kinase domain of Akt for phosphorylation and activation by its upstream kinase, 3-phosphoinositide-dependent protein kinase 1, in the cell membrane. Recent studies have shown that sirtuin isoforms, silent information regulator (SIRT) 1, SIRT3, and SIRT6, play an essential role in the regulation of Akt activation. Although SIRT1 deacetylates Akt to promote phosphatidylinositol (3,4,5)-triphosphate binding and activation, SIRT3 controls reactive oxygen species-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 such as cellular growth, angiogenesis, apoptosis, autophagy, and aging, which are involved in the initiation and progression of several diseases.
authors.affiliation: From Center of Cardiac Cell Biology and Therapeutics, Committee on Molecular Medicine, University of Chicago, Chicago, IL.
authors.forename: Vinodkumar B
authors.initials: VB
authors.lastname: Pillai
authors.forename: Nagalingam R
authors.initials: NR
authors.lastname: Sundaresan
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D042002:Chromatin Assembly and Disassembly; D004789:Enzyme Activation; D006801:Humans; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D037761:Sirtuins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018129:Phosphatidylinositol Phosphates; D017382:Reactive Oxygen Species; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt; D037761:Sirtuins
keywords: aging; cardiac hypertrophy; sirtuins