Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Mar 19;93(6):2442–2447. doi: 10.1073/pnas.93.6.2442

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

K Forrester 1, S Ambs 1, S E Lupold 1, R B Kapust 1, E A Spillare 1, W C Weinberg 1, E Felley-Bosco 1, X W Wang 1, D A Geller 1, E Tzeng 1, T R Billiar 1, C C Harris 1
PMCID: PMC39816  PMID: 8637893

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.

Full text

PDF
2442

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agoff S. N., Hou J., Linzer D. I., Wu B. Regulation of the human hsp70 promoter by p53. Science. 1993 Jan 1;259(5091):84–87. doi: 10.1126/science.8418500. [DOI] [PubMed] [Google Scholar]
  2. Ames B. N., Gold L. S., Willett W. C. The causes and prevention of cancer. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5258–5265. doi: 10.1073/pnas.92.12.5258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arroyo P. L., Hatch-Pigott V., Mower H. F., Cooney R. V. Mutagenicity of nitric oxide and its inhibition by antioxidants. Mutat Res. 1992 Mar;281(3):193–202. doi: 10.1016/0165-7992(92)90008-6. [DOI] [PubMed] [Google Scholar]
  4. Baker S. J., Markowitz S., Fearon E. R., Willson J. K., Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990 Aug 24;249(4971):912–915. doi: 10.1126/science.2144057. [DOI] [PubMed] [Google Scholar]
  5. Boughton-Smith N. K., Evans S. M., Hawkey C. J., Cole A. T., Balsitis M., Whittle B. J., Moncada S. Nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Lancet. 1993 Aug 7;342(8867):338–340. doi: 10.1016/0140-6736(93)91476-3. [DOI] [PubMed] [Google Scholar]
  6. Chartrain N. A., Geller D. A., Koty P. P., Sitrin N. F., Nussler A. K., Hoffman E. P., Billiar T. R., Hutchinson N. I., Mudgett J. S. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem. 1994 Mar 4;269(9):6765–6772. [PubMed] [Google Scholar]
  7. Chu S. C., Wu H. P., Banks T. C., Eissa N. T., Moss J. Structural diversity in the 5'-untranslated region of cytokine-stimulated human inducible nitric oxide synthase mRNA. J Biol Chem. 1995 May 5;270(18):10625–10630. doi: 10.1074/jbc.270.18.10625. [DOI] [PubMed] [Google Scholar]
  8. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  9. Cobbs C. S., Brenman J. E., Aldape K. D., Bredt D. S., Israel M. A. Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res. 1995 Feb 15;55(4):727–730. [PubMed] [Google Scholar]
  10. Cui S., Reichner J. S., Mateo R. B., Albina J. E. Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or -independent mechanisms. Cancer Res. 1994 May 1;54(9):2462–2467. [PubMed] [Google Scholar]
  11. Fehsel K., Jalowy A., Qi S., Burkart V., Hartmann B., Kolb H. Islet cell DNA is a target of inflammatory attack by nitric oxide. Diabetes. 1993 Mar;42(3):496–500. doi: 10.2337/diab.42.3.496. [DOI] [PubMed] [Google Scholar]
  12. Fehsel K., Kröncke K. D., Meyer K. L., Huber H., Wahn V., Kolb-Bachofen V. Nitric oxide induces apoptosis in mouse thymocytes. J Immunol. 1995 Sep 15;155(6):2858–2865. [PubMed] [Google Scholar]
  13. Fritsche M., Haessler C., Brandner G. Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene. 1993 Feb;8(2):307–318. [PubMed] [Google Scholar]
  14. Funk W. D., Pak D. T., Karas R. H., Wright W. E., Shay J. W. A transcriptionally active DNA-binding site for human p53 protein complexes. Mol Cell Biol. 1992 Jun;12(6):2866–2871. doi: 10.1128/mcb.12.6.2866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Geller D. A., Lowenstein C. J., Shapiro R. A., Nussler A. K., Di Silvio M., Wang S. C., Nakayama D. K., Simmons R. L., Snyder S. H., Billiar T. R. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3491–3495. doi: 10.1073/pnas.90.8.3491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ginsberg D., Mechta F., Yaniv M., Oren M. Wild-type p53 can down-modulate the activity of various promoters. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9979–9983. doi: 10.1073/pnas.88.22.9979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  18. Görsdorf S., Appel K. E., Engeholm C., Obe G. Nitrogen dioxide induces DNA single-strand breaks in cultured Chinese hamster cells. Carcinogenesis. 1990 Jan;11(1):37–41. doi: 10.1093/carcin/11.1.37. [DOI] [PubMed] [Google Scholar]
  19. Hollander M. C., Alamo I., Jackman J., Wang M. G., McBride O. W., Fornace A. J., Jr Analysis of the mammalian gadd45 gene and its response to DNA damage. J Biol Chem. 1993 Nov 15;268(32):24385–24393. [PubMed] [Google Scholar]
  20. Horikoshi N., Usheva A., Chen J., Levine A. J., Weinmann R., Shenk T. Two domains of p53 interact with the TATA-binding protein, and the adenovirus 13S E1A protein disrupts the association, relieving p53-mediated transcriptional repression. Mol Cell Biol. 1995 Jan;15(1):227–234. doi: 10.1128/mcb.15.1.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jackson P., Bos E., Braithwaite A. W. Wild-type mouse p53 down-regulates transcription from different virus enhancer/promoters. Oncogene. 1993 Mar;8(3):589–597. [PubMed] [Google Scholar]
  22. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed] [Google Scholar]
  23. Kastan M. B., Zhan Q., el-Deiry W. S., Carrier F., Jacks T., Walsh W. V., Plunkett B. S., Vogelstein B., Fornace A. J., Jr A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992 Nov 13;71(4):587–597. doi: 10.1016/0092-8674(92)90593-2. [DOI] [PubMed] [Google Scholar]
  24. Kobzik L., Bredt D. S., Lowenstein C. J., Drazen J., Gaston B., Sugarbaker D., Stamler J. S. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol. 1993 Oct;9(4):371–377. doi: 10.1165/ajrcmb/9.4.371. [DOI] [PubMed] [Google Scholar]
  25. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  26. Liu R. H., Jacob J. R., Hotchkiss J. H., Cote P. J., Gerin J. L., Tennant B. C. Woodchuck hepatitis virus surface antigen induces nitric oxide synthesis in hepatocytes: possible role in hepatocarcinogenesis. Carcinogenesis. 1994 Dec;15(12):2875–2877. doi: 10.1093/carcin/15.12.2875. [DOI] [PubMed] [Google Scholar]
  27. Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  28. Lowenstein C. J., Alley E. W., Raval P., Snowman A. M., Snyder S. H., Russell S. W., Murphy W. J. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9730–9734. doi: 10.1073/pnas.90.20.9730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lu X., Lane D. P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell. 1993 Nov 19;75(4):765–778. doi: 10.1016/0092-8674(93)90496-d. [DOI] [PubMed] [Google Scholar]
  30. Mack D. H., Vartikar J., Pipas J. M., Laimins L. A. Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53. Nature. 1993 May 20;363(6426):281–283. doi: 10.1038/363281a0. [DOI] [PubMed] [Google Scholar]
  31. Marletta M. A. Mammalian synthesis of nitrite, nitrate, nitric oxide, and N-nitrosating agents. Chem Res Toxicol. 1988 Sep-Oct;1(5):249–257. doi: 10.1021/tx00005a001. [DOI] [PubMed] [Google Scholar]
  32. Messmer U. K., Ankarcrona M., Nicotera P., Brüne B. p53 expression in nitric oxide-induced apoptosis. FEBS Lett. 1994 Nov 21;355(1):23–26. doi: 10.1016/0014-5793(94)01161-3. [DOI] [PubMed] [Google Scholar]
  33. Middleton S. J., Shorthouse M., Hunter J. O. Increased nitric oxide synthesis in ulcerative colitis. Lancet. 1993 Feb 20;341(8843):465–466. doi: 10.1016/0140-6736(93)90211-x. [DOI] [PubMed] [Google Scholar]
  34. Miyashita T., Harigai M., Hanada M., Reed J. C. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994 Jun 15;54(12):3131–3135. [PubMed] [Google Scholar]
  35. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  36. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  37. Nathan C., Xie Q. W. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994 Sep 23;78(6):915–918. doi: 10.1016/0092-8674(94)90266-6. [DOI] [PubMed] [Google Scholar]
  38. Nguyen T., Brunson D., Crespi C. L., Penman B. W., Wishnok J. S., Tannenbaum S. R. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3030–3034. doi: 10.1073/pnas.89.7.3030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nordeen S. K. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed] [Google Scholar]
  40. Okamoto K., Beach D. Cyclin G is a transcriptional target of the p53 tumor suppressor protein. EMBO J. 1994 Oct 17;13(20):4816–4822. doi: 10.1002/j.1460-2075.1994.tb06807.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pfeifer A. M., Cole K. E., Smoot D. T., Weston A., Groopman J. D., Shields P. G., Vignaud J. M., Juillerat M., Lipsky M. M., Trump B. F. Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5123–5127. doi: 10.1073/pnas.90.11.5123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Seto E., Usheva A., Zambetti G. P., Momand J., Horikoshi N., Weinmann R., Levine A. J., Shenk T. Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12028–12032. doi: 10.1073/pnas.89.24.12028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sherman P. A., Laubach V. E., Reep B. R., Wood E. R. Purification and cDNA sequence of an inducible nitric oxide synthase from a human tumor cell line. Biochemistry. 1993 Nov 2;32(43):11600–11605. doi: 10.1021/bi00094a017. [DOI] [PubMed] [Google Scholar]
  44. Subler M. A., Martin D. W., Deb S. Inhibition of viral and cellular promoters by human wild-type p53. J Virol. 1992 Aug;66(8):4757–4762. doi: 10.1128/jvi.66.8.4757-4762.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Thomsen L. L., Lawton F. G., Knowles R. G., Beesley J. E., Riveros-Moreno V., Moncada S. Nitric oxide synthase activity in human gynecological cancer. Cancer Res. 1994 Mar 1;54(5):1352–1354. [PubMed] [Google Scholar]
  46. Thomsen L. L., Miles D. W., Happerfield L., Bobrow L. G., Knowles R. G., Moncada S. Nitric oxide synthase activity in human breast cancer. Br J Cancer. 1995 Jul;72(1):41–44. doi: 10.1038/bjc.1995.274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tzeng E., Billiar T. R., Robbins P. D., Loftus M., Stuehr D. J. Expression of human inducible nitric oxide synthase in a tetrahydrobiopterin (H4B)-deficient cell line: H4B promotes assembly of enzyme subunits into an active dimer. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11771–11775. doi: 10.1073/pnas.92.25.11771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  49. Wang X. W., Forrester K., Yeh H., Feitelson M. A., Gu J. R., Harris C. C. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2230–2234. doi: 10.1073/pnas.91.6.2230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wang X. W., Yeh H., Schaeffer L., Roy R., Moncollin V., Egly J. M., Wang Z., Freidberg E. C., Evans M. K., Taffe B. G. p53 modulation of TFIIH-associated nucleotide excision repair activity. Nat Genet. 1995 Jun;10(2):188–195. doi: 10.1038/ng0695-188. [DOI] [PubMed] [Google Scholar]
  51. Weinberg W. C., Azzoli C. G., Chapman K., Levine A. J., Yuspa S. H. p53-mediated transcriptional activity increases in differentiating epidermal keratinocytes in association with decreased p53 protein. Oncogene. 1995 Jun 15;10(12):2271–2279. [PubMed] [Google Scholar]
  52. Weinberg W. C., Azzoli C. G., Kadiwar N., Yuspa S. H. p53 gene dosage modifies growth and malignant progression of keratinocytes expressing the v-rasHa oncogene. Cancer Res. 1994 Nov 1;54(21):5584–5592. [PubMed] [Google Scholar]
  53. Wink D. A., Kasprzak K. S., Maragos C. M., Elespuru R. K., Misra M., Dunams T. M., Cebula T. A., Koch W. H., Andrews A. W., Allen J. S. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991 Nov 15;254(5034):1001–1003. doi: 10.1126/science.1948068. [DOI] [PubMed] [Google Scholar]
  54. Xie Q. W., Whisnant R., Nathan C. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med. 1993 Jun 1;177(6):1779–1784. doi: 10.1084/jem.177.6.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. de Vera M. E., Shapiro R. A., Nussler A. K., Mudgett J. S., Simmons R. L., Morris S. M., Jr, Billiar T. R., Geller D. A. Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1054–1059. doi: 10.1073/pnas.93.3.1054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. el-Deiry W. S., Harper J. W., O'Connor P. M., Velculescu V. E., Canman C. E., Jackman J., Pietenpol J. A., Burrell M., Hill D. E., Wang Y. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed] [Google Scholar]
  57. el-Deiry W. S., Kern S. E., Pietenpol J. A., Kinzler K. W., Vogelstein B. Definition of a consensus binding site for p53. Nat Genet. 1992 Apr;1(1):45–49. doi: 10.1038/ng0492-45. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES