SIRT1 confers protection against UVB- and H2O2-induced cell death via modulation of p53 and JNK in cultured skin keratinocytes.
SIRT1 is a member of a highly conserved gene family (sirtuins) encoding nicotinamide adenine dinucleotide (NAD)(+)-dependent deacetylases, originally found to deacetylate histones leading to increased DNA stability and prolonged survival in yeast and higher organisms, including mammals. SIRT1 has been found to function as a deacetylase for numerous protein targets involved in various cellular pathways, including stress responses, apoptosis and axonal degeneration. However, the role of SIRT1 in ultraviolet (UV) signalling pathways remains unknown. Using cell culture and Western blot analysis in this study we found that SIRT1 is expressed in cultured human skin keratinocytes. Both UV radiation and H(2)O(2), two major inducers of skin cell damage, down-regulate SIRT1 in a time- and dose-dependent manner. We observed that reactive oxygen species-mediated JNK activation is involved in this SIRT1 down-regulation. SIRT1 activator, resveratrol, which has been considered as an important antioxidant, protects against UV- and H(2)O(2)-induced cell death, whereas SIRT inhibitors such as sirtinol and nicotinamide enhance cell death. Activation of SIRT1 negatively regulates UV- and H(2)O(2)-induced p53 acetylation, because nicotinamide and sirtinol as well as SIRT1 siRNA enhance UV- and H(2)O(2)-induced p53 acetylation, whereas SIRT1 activator resveratrol inhibits it. We also found that SIRT1 is involved in UV-induced AMP-activated protein kinase (AMPK) and downstream acetyl-CoA carboxylase (ACC), phosphofructose kinase-2 (PFK-2) phosphorylation. Collectively, our data provide new insights into understanding of the molecular mechanisms of UV-induced skin aging, suggesting that SIRT1 activators such as resveratrol could serve as new anti-skin aging agents.
Cao
Cong
C
Department of Biology, Providence College, Providence, RI 02918-0001, USA.
Lu
Shan
S
Kivlin
Rebecca
R
Wallin
Brittany
B
Card
Elizabeth
E
Bagdasarian
Andrew
A
Tamakloe
Tyrone
T
Wang
Wen-jun
WJ
Song
Xiuzu
X
Chu
Wen-ming
WM
Kouttab
Nicola
N
Xu
Aie
A
Wan
Yinsheng
Y
D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D002478:Cells, Cultured / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D017382:Reactive Oxygen Species; D056564:Sirtuin 1 / Q000378:metabolism*; D012867:Skin / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D048670:MAP Kinase Kinase 4; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1