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A Single Nucleotide Polymorphism in the MDM2 Gene Disrupts the Oscillation of p53 and MDM2 Levels in Cells

¹ Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey; ² IBM T.J. Watson Research Center, Yorktown Heights, New York; and ³ School of Natural Sciences, Institute for Advanced Study, Princeton, New Jersey

Requests for reprints: Arnold J. Levine, School of Natural Sciences, The Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540-0631. Phone: 609-734-8005; Fax: 609-924-7592; E-mail: alevine{at}ias.edu.

Oscillations of both p53 and MDM2 proteins have been observed in cells after exposure to stress. A mathematical model describing these oscillations predicted that oscillations occur only at selected levels of p53 and MDM2 proteins. This model prediction suggests that oscillations will disappear in cells containing high levels of MDM2 as observed with a single nucleotide polymorphism in the MDM2 gene (SNP309). The effect of SNP309 upon the p53-MDM2 oscillation was examined in various human cell lines and the oscillations were observed in the cells with at least one wild-type allele for SNP309 (T/T or T/G) but not in cells homozygous for SNP309 (G/G). Furthermore, estrogen preferentially stimulated the transcription of MDM2 from SNP309 G allele and increased the levels of MDM2 protein in estrogen-responsive cells homozygous for SNP309 (G/G). These results suggest the possibility that SNP309 G allele may contribute to gender-specific tumorigenesis through further elevating the MDM2 levels and disrupting the p53-MDM2 oscillation. Furthermore, using the H1299-HW24 cells expressing wild-type p53 under a tetracycline-regulated promoter, the p53-MDM2 oscillation was observed only when p53 levels were in a specific range, and DNA damage was found to be necessary for triggering the p53-MDM2 oscillation. This study shows that higher levels of MDM2 in cells homozygous for SNP309 (G/G) do not permit coordinated p53-MDM2 oscillation after stress, which might contribute to decreased efficiency of the p53 pathway and correlates with a clinical phenotype (i.e., the development of cancers at earlier age of onset in female). [Cancer Res 2007;67(6):2757–65]

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