Publication Date


Document Type


Committee Members

Steven Berberich (Advisor), Paula Bubulya (Committee Member), Madhavi Kadakia (Committee Member), Michael Leffak (Committee Member), Robert Putnam (Committee Member)

Degree Name

Doctor of Philosophy (PhD)


Mutations in p53 that compromise its function have been reported in approximately half of all human cancers (Vousden et al., 2002). The other half of human tumors that retain wild-type p53 have a dysfunctional p53 pathway through other mechanisms (Wade et al., 2009). Activation of p53 leads to cell cycle arrest, DNA repair, apoptosis and senescence, however, the pathway leading to cellular senescence is the focus of this study. Cellular senescence is a process leading to irreversible arrest of cell division. Under normal physiologic conditions, the activity of p53 is kept in check by its negative regulators, Mdm2 and MdmX. While MdmX overexpression has been linked to human tumor formation, the mechanism has yet to be elucidated. The first part of this thesis describes the ability of HdmX to block oncogenic Ras mediated senescence in human diploid fibroblasts (HDFs) through interactions with Hdm2 and p53, elucidating a potential mechanism for HdmX's contribution to tumor formation. Furthermore, senescence induction was demonstrated when HdmX was reduced in prostate adenocarcinoma cells (mutant Ras, wild-type p53, high HdmX), suggesting that targeting HdmX in tumor cells with this genotype may be a useful anti-cancer therapeutic approach. In part two of this thesis, a novel-p53 target, YPEL3, was described as a senescence inducer in non-transformed and human tumor cell lines. YPEL3, acting downstream of p53, was shown to be required for oncogenic Ras mediated senescence but functions as a senescence inducer independent of p16 or p21 expression in HDFs, suggesting its critical nature to senescence signaling. In accordance with its potential activity as a tumor suppressor protein, YPEL3 expression was found to be differentially regulated in breast tumor versus normal tissue. In the third part of this thesis, I discovered that YPEL3 is down-regulated by ERα signaling in a p53 independent manner. Estrogen depletion of MCF7 cells led to activation of YPEL3 and induction of cellular senescence of this breast carcinoma cell line, suggesting that YPEL3 may be a valid therapeutic target for treating ER+ breast tumors. This study describes novel mechanisms that are involved in the activation of p53 and subsequent downstream targets leading to cellular senescence.

Page Count


Department or Program

Biomedical Sciences

Year Degree Awarded