MDM2 as an oncogene

MDM-2 was first regarded as an oncogene when it was realized that cell lines overex-pressing MDM-2 show tumorigenic properties in nude mice. In addition, targeted MDM-2 overexpression in the mammary tissue of mice during lactation has been shown to not only induce cellular changes similar to the pheno-types with inactive or defective p53 but also to progress to the development of mammary gland tumors by the time the mice reach 18 months of age.33

The oncogenic properties of MDM-2 were further suggested in a range of tumor types including breast cancers,22 where overexpression of MDM-2 was found either through gene amplification, increased transcription, or increased translation. In some individuals with Li-Fraumeni syndrome, who have two alleles of p53 without the capacity to express p21, show overexpression of MDM-2 in their normal tissues. Overexpression of MDM-2 in the absence of p21 expression (which is tran-scriptionally induced by p53) suggests that

MDM-2 overexpression is p53 independent and may be a direct cause of the high tumor incidence (including breast cancer) in these families.34

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