A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans

Gareth L. Bond, Wenwei Hu, Elisabeth E. Bond, Harlan Robins, Stuart G. Lutzker, Nicoleta C. Arva, Jill Bargonetti, Frank Bartel, Helge Taubert, Peter Wuerl, Kenan Onel, Linwah Yip, Shih Jen Hwang, Louise C. Strong, Guillermina Lozano, Arnold J. Levine*

*Corresponding author for this work

Research output: Contribution to journalArticle

984 Scopus citations

Abstract

The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.

Original languageEnglish (US)
Pages (from-to)591-602
Number of pages12
JournalCell
Volume119
Issue number5
DOIs
StatePublished - Nov 24 2004

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Bond, G. L., Hu, W., Bond, E. E., Robins, H., Lutzker, S. G., Arva, N. C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., Onel, K., Yip, L., Hwang, S. J., Strong, L. C., Lozano, G., & Levine, A. J. (2004). A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell, 119(5), 591-602. https://doi.org/10.1016/j.cell.2004.11.022