TY - JOUR
T1 - Negative control of p53 by Sir2α promotes cell survival under stress
AU - Luo, Jianyuan
AU - Nikolaev, Anatoly Y.
AU - Imai, Shin ichiro
AU - Chen, Delin
AU - Su, Fei
AU - Shiloh, Ariel
AU - Guarente, Leonard
AU - Gu, Wei
N1 - Funding Information:
We especially thank R. Baer, B. Tycko, and R. Dalla-Favera for critical comments. We thank Y. Yin and F. Baer for technical expertise, and many colleagues in the field for providing antibodies, cell lines, and plasmids. We also thank H. Vaziri and R.A. Weinberg for sharing unpublished results, and other members of W. Gu's lab for comments. This work was supported in part by grants from NIH, the Ellison Medical Foundation, and the Howard and Linda Stern Fund to L.G.; by grants from Concert for the Cure, Avon Foundation, the Irma T. Hirschl Trust, NIH/NCI (RO1CA85533) to W.G.
PY - 2001/10/19
Y1 - 2001/10/19
N2 - The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2α physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2α, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2α represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2α point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2α. These results have significant implications regarding an important role for Sir2α in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
AB - The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2α physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2α, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2α represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2α point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2α. These results have significant implications regarding an important role for Sir2α in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
UR - http://www.scopus.com/inward/record.url?scp=0035913911&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(01)00524-4
DO - 10.1016/S0092-8674(01)00524-4
M3 - Article
C2 - 11672522
AN - SCOPUS:0035913911
SN - 0092-8674
VL - 107
SP - 137
EP - 148
JO - Cell
JF - Cell
IS - 2
ER -