Function and dysfunction of the human oncoprotein MDM2.
The protein MDM2 coded by the human homologue of mouse double minute-2 (mdm2) gene frequently overexpresses in malignant human breast and other tumors. Artificial amplification of mouse mdm2 gene derived from a transformed murine cell line enhances tumorigenic potential of murine cells. These evidences suggest oncogenic properties of human or mouse MDM2. The tumorigenic property of MDM2 is not unexpected as MDM2 can inactivate several functions of the tumor suppressor p53. The protein also interacts with several cell cycle regulatory proteins that may contribute to its tumorigenic ability. Several spliced forms of MDM2 have been detected in cells that overexpress MDM2. The function of the proteins coded by these spliced forms is not well understood. Overexpression of full-length MDM2 from its cDNA arrests G1 to S phase transition of normal human or murine cells. Elimination of the growth inhibitory domains of the oncoprotein induces tumorigenesis. Some cancer-derived cell lines are partially insensitive to MDM2-mediated growth arrest. Normal cells can induce MDM2 in response to oncogenic challenges such as UV irradiation or estrogen treatment. Normal cells may induce full-length MDM2 in response to oncogenic challenges to protect against premature cell cycle progression. If the oncoprotein is defective in growth arrest or if the cells are insensitive to MDM2 mediated growth arrest, premature progression of cell cycle may lead to tumorigenesis. Elucidation of the growth regulatory functions of MDM2 may help develop new drug design for cancer treatment.
Deb
Swati Palit
SP
Department of Biochemistry and Molecular Biophysics and the Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA. Spdeb@hsc.vcu.edu
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2