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Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress.
PLoS One. 2013; 8(9):e73875.Plos

Abstract

Excessive reactive oxygen species (ROS) induce apoptosis and are associated with various diseases and with aging. SIRT1 (sirtuin-1), an NAD+-dependent protein deacetylase, decreases ROS levels and participates in cell survival under oxidative stress conditions. SIRT1 modulates the transcription factors p53, a tumor suppressor and inducer of apoptosis, and the forkhead O (FOXO) family, both of which play roles for cell survival and cell death. In this study, we aimed to know which is working greatly among p53 and FOXOs transcription factors in SIRT1's cell protective functions under oxidative stress conditions. The antimycin A-induced increase in ROS levels and apoptosis was enhanced by SIRT1 inhibitors nicotinamide and splitomicin, whereas it was suppressed by a SIRT1 activator, resveratrol, and a SIRT1 cofactor, NAD+. SIRT1-siRNA abolished the effects of splitomicin and resveratrol. p53-knockdown experiment in C2C12 cells and experiment using p53-deficient HCT116 cells showed that splitomicin and resveratrol modulated apoptosis by p53-dependent and p53-independent pathways. In p53-independent cell protective pathway, we found that FOXO1, FOXO3a, and FOXO4 were involved in SOD2's upregulation by resveratrol. The knockdown of these three FOXOs by siRNAs completely abolished the SOD2 induction, ROS reduction, and anti-apoptotic function of resveratrol. Our results indicate that FOXO1, FOXO3a and FOXO4, are indispensable for SIRT1-dependent cell survival against oxidative stress, although deacetylation of p53 has also some role for cell protective function of SIRT1.

Authors+Show Affiliations

Department of Pharmacology, School of Medicine, Sapporo Medical University, Sapporo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24040102

Citation

Hori, Yusuke S., et al. "Regulation of FOXOs and P53 By SIRT1 Modulators Under Oxidative Stress." PloS One, vol. 8, no. 9, 2013, pp. e73875.
Hori YS, Kuno A, Hosoda R, et al. Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS One. 2013;8(9):e73875.
Hori, Y. S., Kuno, A., Hosoda, R., & Horio, Y. (2013). Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PloS One, 8(9), e73875. https://doi.org/10.1371/journal.pone.0073875
Hori YS, et al. Regulation of FOXOs and P53 By SIRT1 Modulators Under Oxidative Stress. PLoS One. 2013;8(9):e73875. PubMed PMID: 24040102.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. AU - Hori,Yusuke S, AU - Kuno,Atsushi, AU - Hosoda,Ryusuke, AU - Horio,Yoshiyuki, Y1 - 2013/09/11/ PY - 2013/03/08/received PY - 2013/07/24/accepted PY - 2013/9/17/entrez PY - 2013/9/17/pubmed PY - 2014/6/16/medline SP - e73875 EP - e73875 JF - PloS one JO - PLoS One VL - 8 IS - 9 N2 - Excessive reactive oxygen species (ROS) induce apoptosis and are associated with various diseases and with aging. SIRT1 (sirtuin-1), an NAD+-dependent protein deacetylase, decreases ROS levels and participates in cell survival under oxidative stress conditions. SIRT1 modulates the transcription factors p53, a tumor suppressor and inducer of apoptosis, and the forkhead O (FOXO) family, both of which play roles for cell survival and cell death. In this study, we aimed to know which is working greatly among p53 and FOXOs transcription factors in SIRT1's cell protective functions under oxidative stress conditions. The antimycin A-induced increase in ROS levels and apoptosis was enhanced by SIRT1 inhibitors nicotinamide and splitomicin, whereas it was suppressed by a SIRT1 activator, resveratrol, and a SIRT1 cofactor, NAD+. SIRT1-siRNA abolished the effects of splitomicin and resveratrol. p53-knockdown experiment in C2C12 cells and experiment using p53-deficient HCT116 cells showed that splitomicin and resveratrol modulated apoptosis by p53-dependent and p53-independent pathways. In p53-independent cell protective pathway, we found that FOXO1, FOXO3a, and FOXO4 were involved in SOD2's upregulation by resveratrol. The knockdown of these three FOXOs by siRNAs completely abolished the SOD2 induction, ROS reduction, and anti-apoptotic function of resveratrol. Our results indicate that FOXO1, FOXO3a and FOXO4, are indispensable for SIRT1-dependent cell survival against oxidative stress, although deacetylation of p53 has also some role for cell protective function of SIRT1. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24040102/Regulation_of_FOXOs_and_p53_by_SIRT1_modulators_under_oxidative_stress_ L2 - https://dx.plos.org/10.1371/journal.pone.0073875 DB - PRIME DP - Unbound Medicine ER -