Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Guillermina Lozano, Ph.D.

Committee Member

Mong-Hong Lee, Ph.D.

Committee Member

Randy J. Legerski, Ph.D.

Committee Member

Shiaw-Yih Lin, Ph.D.

Committee Member

David J. McConkey, Ph.D.


The TP53 tumor suppressor is the most mutated gene in human cancers. Recent studies using genetically modified mouse models have shown that restoring the expression of wild-type p53 has led to tumor growth suppression in various types of tumors lacking p53. Other mechanisms, e.g. upregulation of Mdm2 levels, exist in tumors to inactivate the p53 pathway. Mdm2, an E3 ubiquitin-ligase that targets p53 for proteasomal degradation, is present at high levels in many tumors with wild-type p53. In this study, we probed the effects of restoring p53 activity in Mdm2-overexpressing tumors genetically using animal models. Here we demonstrated high levels of Mdm2 and low levels of p53 act additively to dampen p53 activity in DNA damage response and tumor development, suggesting a dose-dependent tumor-suppressive function of p53. Our data also indicate that restoration of wild-type p53 expression in spontaneous Mdm2-overexpressing angiosarcomas resulted in tumor stasis and regression in some cases. We further showed that the restored p53 suppressed cell proliferation in the Mdm2-overexpressing angiosarcomas but did not elicit apoptosis. Therefore, we conclude that restoration of wild-type p53 expression in tumors with high levels of Mdm2 represents a potential strategy to treat these tumors. This finding is of important clinic relevance since a large number of human tumors have high levels of Mdm2. Our present work suggests that p53 restoration confers therapeutic potentials even to tumors with high levels of Mdm2.


p53, Mdm2 overexpression, animal model, gene therapy



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