MDM2 is classified as an oncogene due to its malignant behaviors in tumors. The over-expression of MDM2 has been observed in a wide variety of human tumors, including sarcoma, leukemia, breast carcinoma, melanoma, and glioblastoma. As a critical negative regulator of p53, high expression levels of MDM2 decrease p53 protein levels and function, which lead to increased cancer risk and/or accelerated tumor formation and progression. In human tumors, the over-expression of MDM2 and p53 mutation are often mutually exclusive. This observation strongly supports the notion that inactivation of p53 by MDM2 contributes to the effect of MDM2 on tumor development. Studies in mice and cultured cells have shown that MDM2 also has p53- independent oncogenic functions, which control proliferation, apoptosis, and tumor invasion and metastasis. For example, MDM2 transgenic mice with increased MDM2 expression levels in p532/2 background developed an altered tumor spectrum with an increased incidence of sarcomas. In cells, MDM2 can interact with and inhibit the function of tumor suppressor retinoblastoma protein (RB) in regulation of cell cycle and proliferation. Foxo3A, which regulates cell cycle, is a target of MDM2 for ubiquitination and proteasomal degradation. E-cadherin, which plays a crucial role in cancer metastasis, is also a target of MDM2. MDM2 is a positive regulator of E2F-1, which plays an important role in cell cycle, and XIAP, an anti-apoptotic protein. Therefore, MDM2 is a key player in human cancers and an important cancer therapeutic target.
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