Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53.
The tumor suppressor gene product p53 plays an important role in the cellular response to DNA damage from exogenous chemical and physical mutagens. Therefore, we hypothesized that p53 performs a similar role in response to putative endogenous mutagens, such as nitric oxide (NO). We report here that exposure of human cells to NO generated from an NO donor or from overexpression of inducible nitric oxide synthase (NOS2) results in p53 protein accumulation. In addition, expression of wild-type (WT) p53 in a variety of human tumor cell lines, as well as murine fibroblasts, results in down-regulation of NOS2 expression through inhibition of the NOS2 promoter. These data are consistent with the hypothesis of a negative feedback loop in which endogenous NO-induced DNA damage results in WT p53 accumulation and provides a novel mechanism by which p53 safeguards against DNA damage through p53-mediated transrepression of NOS2 gene expression, thus reducing the potential for NO-induced DNA damage.
Forrester
K
K
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Ambs
S
S
Lupold
S E
SE
Kapust
R B
RB
Spillare
E A
EA
Weinberg
W C
WC
Felley-Bosco
E
E
Wang
X W
XW
Geller
D A
DA
Tzeng
E
E
Billiar
T R
TR
Harris
C C
CC
D000818:Animals; D002478:Cells, Cultured; D003106:Colon / Q000201:enzymology; D004249:DNA Damage; D015536:Down-Regulation; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase