MDM2 was initially identified and characterized as an oncogene in murine fibroblasts. It was later demonstrated that the mdm2gene was amplified in approximately 30 percentof soft tissue sarcomas, establishing its role in human cancer. The ability of MDM2 to bind, inactivate and facilitate degradation of the p53 tumor suppressor protein has been well characterized; but the transforming phenotype of MDM2 appears to be, at least in part, independent of p53. In contrast to this growth-promoting anti-apoptotic function of MDM2, a growth inhibitory phenotype has also been demonstrated, inconsistent with the action of an oncogene. In addition, novel data presented in this proposal demonstrate an apoptotic function that is also in contrast to its transforming potential. We propose to evaluate, in Aim 1, which domains of the MDM2 protein are necessary for its apoptotic function and whether the oncogenic alternatively spliced isoforms of MDM2 that are often found in human tumors, have deleted these regions.
In Aim 2 we will investigate the mechanism by which MDM2 induces apoptosis and in Aim 3 we will evaluate whether the alternatively spliced isoforms of MDM2 found in tumor cells influence MDM2-induced apoptosis or the cellular response to chemotherapeutic agents. We expect that data generated from this work will resolve some of the conflicting published reports with respect to MDM2 function and will determine the importance of full-length versus alternatively spliced isoforms of MDM2 in the cellular response to chemotherapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092401-04
Application #
6850837
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Blair, Donald G
Project Start
2002-03-05
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
4
Fiscal Year
2005
Total Cost
$213,750
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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Volk, Erin L; Fan, Liying; Schuster, Katja et al. (2009) The MDM2-a splice variant of MDM2 alters transformation in vitro and the tumor spectrum in both Arf- and p53-null models of tumorigenesis. Mol Cancer Res 7:863-9
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