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Metal ions as regulators of the conformation and function of the tumour suppressor protein p53: implications for carcinogenesis

Published online by Cambridge University Press:  28 February 2007

Catherine Méplan
Affiliation:
International Agency for Research on Cancer, 150 Cours Albert Thomas, F69372 Lyon Cedex 08, France
Gerald Verhaegh
Affiliation:
International Agency for Research on Cancer, 150 Cours Albert Thomas, F69372 Lyon Cedex 08, France
Marie-Jeanne Richard
Affiliation:
Laboratoire de Biochimie, Centre Hospitalier et Universitaire Albert Michalon, F38043 Grenoble Cedex 9, France
Pierre Hainaut*
Affiliation:
International Agency for Research on Cancer, 150 Cours Albert Thomas, F69372 Lyon Cedex 08, France
*
Corresponding Author: Dr Pierre Hainaut, fax +33 4 72 73 83 21, email [email protected]
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Abstract

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The p53 protein is a multi-function nuclear factor that is activated in response to multiple forms of stress and controls the proliferation, survival, DNA repair and differentiation of cells exposed to potentially genotoxic DNA damage. Loss of p53 function by mutation is a frequent event in human cancer, and is thought to result in the capacity of cells to acquire and accumulate oncogenic mutations during the progression of neoplasia. The p53 protein is a metal-binding transcription factor that is inactivated by metal chelation and by oxidation in vitro. In intact cells, p53 protein activity is crucially dependent on the availability of Zn ions and is impaired by exposure to Cd, a metal which readily substitutes for Zn in a number of transcription factors. Inactivation by Cd suppresses the p53-dependent responses to DNA damage. Overall, these findings indicate that regulation by metals plays an important role in the control of p53, and that perturbation of this control may explain the carcinogenic potential of several metal compounds. Résumé La protéine p53 est un facteur nucléaire multi-fonctionnel qui est activé en réponse à de multiples formes de stress et qui contrôle la prolifération, la survie, la réparation de l’ADN et la différenciation de cellules exposées à des agents génotoxiques. La perte de la fonction de p53 par mutation est un évènement fréquent dans les cancers chez l’homme, et l’on considère que cette inactivation a pour conséquence de rendre la cellule susceptible d’accumuler rapidement des mutations oncogéniques au cours de la progression du cancer. La protéine p53 est un facteur de transcription qui lie les métaux et qui peut être inactivée in vitro par chélation des métaux ainsi que par oxydation. Dans des cellules en culture, l’activité biologique de la p53 dépend de la bio-disponibilité en Zn, et est altérée par l’exposition des cellules au Cd, un métal qui se substitue facilement au Zn dans nombre de facteurs de transcription Zn-dépendants. L’inactivation de p53 par le Cd inhibe les réponses p53-dépendantes suite à la formation de lésions de l’ADN. Globalement, ces données suggèrent que la régulation par les métaux joue un rôle important dans le contrôle de la p53, et que des perturbations de ce contrôle pourraient contribuer à expliquer le potentiel carcinogénique de certains composés métalliques.

Type
Symposium on ‘Functionality of nutrients and food safety’
Copyright
Copyright © The Nutrition Society 1999

Footnotes

*

Urological Research Laboratory, Academic Hospital, Nijmegen, 6500 HB Nijmegen, The Netherlands

References

Agarwal, ML, Taylor, WR, Chernov, MV, Chernova, OB & Stark, GR (1998) The p53 network. Journal of Biological Chemistry 273, 14.CrossRefGoogle ScholarPubMed
An, WG, Kanekal, M, Simon, MC, Maltepe, E, Blagosklonny, MV & Neckers, LM (1998) Stabilization of wild-type p53 by hypoxia-inducible factor 1 alpha. Nature 392, 405408.CrossRefGoogle Scholar
Calmels, S, Hainaut, P & Ohshima, H (1997) Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. Cancer Research 57, 33653369.Google ScholarPubMed
Cho, Y, Gorina, S, Jeffrey, PD & Pavletich, NP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265, 346355.CrossRefGoogle ScholarPubMed
Fong, LY, Lau, KM, Huebner, K & Magee, PN (1997) Induction of esophageal tumors in zinc-deficient rats by single low doses of N-nitrosomethylbenzylamine (NMBA): analysis of cell proliferation, and mutations in H-ras and p53 genes. Carcinogenesis 18, 14771484.CrossRefGoogle ScholarPubMed
Funk, WD, Pak, DT, Karas, RH, Wright, WE & Shay, JW (1992) A transcriptionally active DNA-binding site for human p53 protein complexes. Molecular and Cellular Biology 12, 28662871.Google ScholarPubMed
Graeber, TG, Osmanian, C, Jacks, T, Housman, DE, Koch, CJ, Lowe, SW & Giaccia, AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 8891.CrossRefGoogle ScholarPubMed
Greenblatt, MS, Bennett, WP, Hollstein, M & Harris, CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Research 54, 48554878.Google ScholarPubMed
Gu, W & Roeder, RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595606.CrossRefGoogle ScholarPubMed
Hainaut, P, Hernandez, T, Robinson, A, Rodriguez-Tome, P, Flores, T, Hollstein, M, Harris, CC & Montesano, R (1998) IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools. Nucleic Acids Research 26, 205213.CrossRefGoogle ScholarPubMed
Hainaut, P & Hollstein, M (1999) p53 and human cancer: the first ten thousand mutations. Advances in Cancer Research 77, 81137.CrossRefGoogle Scholar
Hainaut, P & Milner, J (1993 a) A structural role for metal ions in the ‘wild-type’ conformation of the tumor suppressor protein p53. Cancer Research 53, 17391742.Google ScholarPubMed
Hainaut, P & Milner, J (1993 b) Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. Cancer Research 53, 44694473.Google ScholarPubMed
Hainaut, P, Rolley, N, Davies, M & Milner, J (1995) Modulation by copper of p53 conformation and sequence-specific DNA binding: role for Cu(II)/Cu(I) redox mechanism. Oncogene 10, 2732.Google Scholar
Haupt, Y, Maya, R, Kazaz, A & Oren, M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387, 296299.CrossRefGoogle ScholarPubMed
Hernandez, TM & Hainaut, P (1998) Tumor-specific mutation spectra in the human p53 gene: from carcinogen ‘fingerprints’ to functional consequences. Environmental Carcinogenesis and Ecotoxicology Reviews C16, 3145.CrossRefGoogle Scholar
International Agency for Cancer Research (1993) IARC Monographs on the Evaluation of Carcinogenic Risks no. 58. Beryllium, Cadmium, Mercury and Exposures in the Glass Manufacturing Industry. Lyon: IARC.Google Scholar
Jayaraman, L, Murthy, KG, Zhu, C, Curran, T, Xanthoudakis, S & Prives, C (1997) Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes and Development 11, 558570.CrossRefGoogle ScholarPubMed
Knudson, AGJ (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences USA 68, 820823.CrossRefGoogle ScholarPubMed
Kubbutat, MH, Jones, SN & Vousden, KH (1997) Regulation of p53 stability by Mdm2. Nature 387, 299303.CrossRefGoogle ScholarPubMed
Lane, DP (1992) Cancer. p53, guardian of the genome. Nature 358, 1516.CrossRefGoogle ScholarPubMed
Levine, AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88, 323331.CrossRefGoogle ScholarPubMed
Oliner, JD, Pietenpol, JA, Thiagalingam, S, Gyuris, J, Kinzler, KW & Vogelstein, B (1993) Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 362, 857860.CrossRefGoogle ScholarPubMed
Polyak, K, Xia, Y, Zweier, JL, Kinzler, KW & Vogelstein, B (1997) A model for p53-induced apoptosis. Nature 389, 300305.CrossRefGoogle Scholar
Shieh, SY, Ikeda, M, Taya, Y & Prives, C (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91, 325334.CrossRefGoogle ScholarPubMed
Siliciano, JD, Canman, CE, Taya, Y, Sakaguchi, K, Appella, E & Kastan, MB (1997) DNA damage induces phosphorylation of the amino terminus of p53. Genes and Development 11, 34713481.CrossRefGoogle ScholarPubMed
Vallee, BL (1991) Introduction to metallothionein. Methods in Enzymology 205, 37.CrossRefGoogle ScholarPubMed
Verhaegh, GW, Parat, MO, Richard, MJ & Hainaut, P (1998) Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc. Molecular Carcinogenesis 21, 205214.3.0.CO;2-K>CrossRefGoogle ScholarPubMed
Verhaegh, GW, Richard, MJ & Hainaut, P (1997) Regulation of p53 by metal ions and by antioxidants: dithiocarbamate down-regulates p53 DNA-binding activity by increasing the intracellular level of copper. Molecular and Cellular Biology 17, 56995706.CrossRefGoogle ScholarPubMed
Wahrendorf, J, Munoz, N, Lu, JB, Thurnham, DI, Crespi, M & Bosch, FX (1988) Blood, retinol and zinc riboflavin status in relation to precancerous lesions of the esophagus: findings from a vitamin intervention trial in the People’s Republic of China. Cancer Research 48, 22802283.Google ScholarPubMed
Waterman, MJ, Stavridi, ES, Waterman, JL & Halazonetis, TD (1998) ATM-dependent activation of p53 involves dephosphorylation and association with 14–3–3 proteins. Nature Genetics 19, 175178.CrossRefGoogle ScholarPubMed
Woo, RA, McLure, KG, Lees-Miller, SP, Rancourt, DE & Lee, PW (1998) DNA-dependent protein kinase acts upstream of p53 in response to DNA damage Nature 394, 700704.CrossRefGoogle ScholarPubMed
Wu, J, Forbes, JR, Chen, HS & Cox, DW (1994) The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene. Nature Genetics 7, 541545.CrossRefGoogle Scholar