Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53

Kathleen Forrester, Stefan Ambs, Shawn Lupold, Rachel B. Kapust, Elisa A. Spillare, Wendy C. Weinberg, Emanuela Felley-Bosco, Xin W. Wang, David A. Geller, Edith Tzeng, Timothy R. Billiar, Curtis C. Harris

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2442-2447
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number6
DOIs
StatePublished - Mar 19 1996
Externally publishedYes

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Nitric Oxide Synthase Type II
DNA Damage
Nitric Oxide
Mutagens
Nitric Oxide Donors
Tumor Cell Line
Tumor Suppressor Genes
Down-Regulation
Fibroblasts
Gene Expression
Proteins

Keywords

  • carcinogenesis
  • mutagenesis
  • tumor suppressor gene

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. / Forrester, Kathleen; Ambs, Stefan; Lupold, Shawn; Kapust, Rachel B.; Spillare, Elisa A.; Weinberg, Wendy C.; Felley-Bosco, Emanuela; Wang, Xin W.; Geller, David A.; Tzeng, Edith; Billiar, Timothy R.; Harris, Curtis C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 6, 19.03.1996, p. 2442-2447.

Research output: Contribution to journalArticle

Forrester, K, Ambs, S, Lupold, S, Kapust, RB, Spillare, EA, Weinberg, WC, Felley-Bosco, E, Wang, XW, Geller, DA, Tzeng, E, Billiar, TR & Harris, CC 1996, 'Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53', Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 6, pp. 2442-2447. https://doi.org/10.1073/pnas.93.6.2442
Forrester, Kathleen ; Ambs, Stefan ; Lupold, Shawn ; Kapust, Rachel B. ; Spillare, Elisa A. ; Weinberg, Wendy C. ; Felley-Bosco, Emanuela ; Wang, Xin W. ; Geller, David A. ; Tzeng, Edith ; Billiar, Timothy R. ; Harris, Curtis C. / Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. In: Proceedings of the National Academy of Sciences of the United States of America. 1996 ; Vol. 93, No. 6. pp. 2442-2447.
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AB - 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.

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