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Title page for ETD etd-05242010-175410


Type of Document Dissertation
Author Eby, Kathryn Grace
URN etd-05242010-175410
Title Identification and Characterization of p53 Target Genes
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Jennifer Pietenpol Committee Chair
Bruce Carter Committee Member
Larry Marnett Committee Member
Sandra Zinkel Committee Member
Scott Hiebert Committee Member
Keywords
  • ISG20L1
  • p53
  • autophagy
Date of Defense 2010-05-21
Availability unrestricted
Abstract
After 30 years of research, p53 is recognized as one of the most frequently mutated genes in human cancer (Baker et al, 1989; Nigro et al, 1989; Momand et al, 2000; Daujat et la, 2001). To accomplish its tumor suppressive role, p53 transcriptionally regulates a multitude of genes involved in cell cycle progression, genomic stability, cellular senescence, apoptosis, angiogenesis, cell migration, and autophagy. To date approximately 150 genes are documented as direct p53 target genes. The goal of this dissertation research was to identify novel p53 family transcriptional targets and determine their functions in biologically-relevant processes downstream of the p53 family signaling axis.

In Chapter III of this dissertation, I describe the use of statistical and bioinformatic tools to perform genomic analyses and identify a subset of novel putative p53 transcriptional targets. With the overlay of genomic datasets and predictive mathematical models, I developed a panel of high-confidence p53 transcriptional targets. I describe current and future plans to analyze these target genes, in a high-throughput manner, and identify the contribution of each target gene to p53-regulated processes such as cell cycle arrest, apoptosis, and autophagy, among others.

In Chapter IV of this dissertation, I describe the identification of ISG20L1 as a target gene of p53 as well as family members p63 and p73. Ectopic expression of ISG20L1 decreased clonogenic survival, but changes in ISG20L1 protein levels did not alter apoptosis. Thus, we investigated the role of ISG20L1 in autophagy, a process commonly associated with type II cell death, and found that ISG20L1 knockdown decreased levels of autophagic vacuoles and LC3-II after genotoxic stress as assessed by electron microscopy, biochemical and immunohistochemical measurements of LC3-II.

Investigation of genes and signaling pathways involved in cell death associated with autophagy is critical given the keen interest in targeting autophagy as an anticancer therapeutic approach in tumor cells that are defective in apoptosis.

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