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

doi:10.1016/j.cell.2004.11.022

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

Pathology

Research output: Contribution to journal › Article › peer-review

1075 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 language	English (US)
Pages (from-to)	591-602
Number of pages	12
Journal	Cell
Volume	119
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2004.11.022
State	Published - Nov 24 2004

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2004.11.022

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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

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

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.",

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

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Bond, GL, Hu, W, Bond, EE, Robins, H, Lutzker, SG, Arva, NC, Bargonetti, J, Bartel, F, Taubert, H, Wuerl, P, Onel, K, Yip, L, Hwang, SJ, Strong, LC, Lozano, G & Levine, AJ 2004, 'A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans', Cell, vol. 119, no. 5, pp. 591-602. https://doi.org/10.1016/j.cell.2004.11.022

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T1 - A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans

AU - Bond, Gareth L.

AU - Hu, Wenwei

AU - Bond, Elisabeth E.

AU - Robins, Harlan

AU - Lutzker, Stuart G.

AU - Arva, Nicoleta C.

AU - Bargonetti, Jill

AU - Bartel, Frank

AU - Taubert, Helge

AU - Wuerl, Peter

AU - Onel, Kenan

AU - Yip, Linwah

AU - Hwang, Shih Jen

AU - Strong, Louise C.

AU - Lozano, Guillermina

AU - Levine, Arnold J.

PY - 2004/11/24

Y1 - 2004/11/24

N2 - 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.

AB - 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.

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JO - Cell

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

Abstract

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UN SDGs

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