TY - JOUR
T1 - Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging
AU - Gambino, Valentina
AU - De Michele, Giulia
AU - Venezia, Oriella
AU - Migliaccio, Pierluigi
AU - Dall'Olio, Valentina
AU - Bernard, Loris
AU - Minardi, Simone Paolo
AU - Fazia, Maria Agnese Della
AU - Bartoli, Daniela
AU - Servillo, Giuseppe
AU - Alcalay, Myriam
AU - Luzi, Lucilla
AU - Giorgio, Marco
AU - Scrable, Heidi
AU - Pelicci, Pier Giuseppe
AU - Migliaccio, Enrica
PY - 2013/6
Y1 - 2013/6
N2 - Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress. We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence. They are selectively down-regulated in cultured fibroblasts after oxidative stress, and, in vivo, in proliferating tissues and during physiological aging. Selectivity is imposed by p66 expression and activation of p44/p53 (also named Delta40p53), a p53 isoform that accelerates aging and prevents mitosis after protein damage. p66 deletion retards aging and increases longevity of p44/p53 transgenic mice. Thus, oxidative stress activates a specific p53 transcriptional response, mediated by p44/p53 and p66, which regulates cellular senescence and aging.
AB - Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress. We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence. They are selectively down-regulated in cultured fibroblasts after oxidative stress, and, in vivo, in proliferating tissues and during physiological aging. Selectivity is imposed by p66 expression and activation of p44/p53 (also named Delta40p53), a p53 isoform that accelerates aging and prevents mitosis after protein damage. p66 deletion retards aging and increases longevity of p44/p53 transgenic mice. Thus, oxidative stress activates a specific p53 transcriptional response, mediated by p44/p53 and p66, which regulates cellular senescence and aging.
KW - Aging genes
KW - Oxydative stress
KW - P53
KW - Senescence
UR - http://www.scopus.com/inward/record.url?scp=84877806331&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877806331&partnerID=8YFLogxK
U2 - 10.1111/acel.12060
DO - 10.1111/acel.12060
M3 - Article
C2 - 23448364
SN - 1474-9718
VL - 12
SP - 435
EP - 445
JO - Aging Cell
JF - Aging Cell
IS - 3
ER -