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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 ,
Gerald Verhaegh ,
Marie-Jeanne Richard  and
Pierre Hainaut
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.

Keywords

Tumour suppresser protein p53ZincCadmiumCarcinogenesis
Type
Symposium on ‘Functionality of nutrients and food safety’
Information
Proceedings of the Nutrition Society , Volume 58 , Issue 3 , August 1999 , pp. 565 - 571
Copyright
Copyright © The Nutrition Society 1999

Footnotes

*

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

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