The Role of E2F3 Phosphorylation in Rb-mediated Tumorigenesis and Embryonic Development

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Title: The Role of E2F3 Phosphorylation in Rb-mediated Tumorigenesis and Embryonic Development
Creators: Gruenzel, Andrew
Advisor: Leone, Gustavo
Issue Date: 2011-06
Abstract: Defects in the regulation of cellular replication are some of the primary causes of cancer in humans. The E2F3 protein, a member of the E2F transcription factor family, acts to control progression past the G1/S-checkpoint during cellular replication. One way that E2F3 is regulated is via phosphorylation. The phosphorylated form of this protein is often found in tumor cell lines and is thought to be linked to cancer. However, the exact pathways and interactions of this protein are not well characterized in vivo. The purpose of this study is to better understand how E2F3 phosphorylation controls the cell cycle in vivo and thus how it affects development as well as tumor incidence, growth, and metastases in mice. The retinoblastoma gene, which promotes pituitary and thyroid cancer when one copy is knocked out, was combined with E2F3 mutations mimicking either the phosphorylated (E2F3S390D) or non-phosphorylated (E2F3S390A) form of the protein. We observed tumor incidence and size, as well as metastases to other organs in these mice at 11 months of age. Our data shows that a lack of E2F3 phosphorylation increases thyroid cancer incidence in female mice. Interestingly, both phospho-mimicking and non-phosphorylatable mutants of E2F3 appear to decrease pituitary tumor size, but not incidence, compared with wild type E2F3. Developmentally, mice lacking the retinoblastoma gene typically die between the embryonic ages of 13.5 and 15.5 days. We observed survival at E11.5 and E13.5 days in Rb-null mice combined with one of the aforementioned E2F3 mutations. We show that embryos with the phospho-mimicking mutant of E2F3 have decreased viability compared to wild-type and non-phosphorylatable mutants at E11.5. Since phosphorylation is an alteration at the chemical level, understanding this pathway could lead to novel forms of chemotherapy that help fight cancer associated with E2F3.
Embargo: No embargo
Series/Report no.: The Ohio State University. Department of Molecular Genetics Honors Theses; 2011
Keywords: E2F3 Rb Phosphorylation E2F Retinoblastoma
Sponsors: Mayer's Summer Scholarship from The Ohio State University
Pelotonia Fellowship
Undergraduate Research Scholarship from the College of Arts and Sciences
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