SIRT1 and p53, effect on cancer, senescence and beyond

Abstract

NAD + -dependent Class III histone deacetylase SIRT1 is a multiple function protein critically involved in stress responses, cellular metabolism and aging through deacetylating a variety of substrates including p53, forkhead-box transcription factors, PGC-1α, NF-κB, Ku70 and histones. The first discovered non-histone target of SIRT1, p53, is suggested to play a central role in SIRT1-mediated functions in tumorigenesis and senescence. SIRT1 was originally considered to be a potential tumor promoter since it negatively regulates the tumor suppressor p53 and other tumor suppressors. There is new evidence that SIRT1 acts as a tumor suppressor based on its role in negatively regulating β-catenin and survivin. This review provides an overview of current knowledge of SIRT1-p53 signaling and controversies regarding the functions of SIRT1 in tumorigenesis.

Redox regulation of cellular stress response in multiple sclerosis

“…The most studied is the SIRT1, a NAD+ dependent enzyme, involved in deacetylation of different proteins and in the regulation of energy metabolism and redox state. Sirtuins are involved in the regulation of important biological processes, such as apoptosis, cell differentiation, energy transduction, glucose homeostasis [18,65], as well as in mediating enhancement of synaptic plasticity and neurogenesis in response to exercise, dietary energy restriction, and other hormetic environmental factors [15,66]. Because of their roles in cellular stress responses, sirtuins would be expected to play particularly important roles in adaptive responses of neural cells to stress, such as that associated with the MS pathogenesis.…”

Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo

“…SIRT1 deacetylates histone proteins and other key transcriptional regulators such as p53 (6)(7)(8), NF-kB (9), Foxo (10), Ku70 (11), E2F1 (12), PPARg coactivator 1a (PGC-1a; ref. 13), and hypoxia-inducible transcription factors (HIF; [14][15][16].…”

Redox-regulating sirtuins in aging, caloric restriction, and exercise

“…p53 is acetylated by CBP/p300 acetyltransferases at lysine residues, including Lys 370, 372, 382, and 386 at the carboxyterminal region [46,47]. Activated p53 then enhance ROS production through mitochondrial dysfunction and/or increased expression of genes that are involved in redox modulation, such as the p53-upregulated modulator of apoptosis (PUMA), NADPH activator A (NOXA), and p53-induced gene 3 (PIG3) [48,49].…”

“…One of the first proteins for which acetylation was linked to stability was p53 [47,99]. Acetylation of lysine residues prevents ubiquitination of the given residues, thus hampering signaling for proteolytic degradation [98].…”