Transcriptional regulation of ARF tumor suppressor

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  • March 22, 2019
Creator
  • Zeng, Yaxue
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • The expression of tumor suppressor ARF is tightly repressed during normal cell growth in human and mouse at young age and is activated by oncogenic insults and during aging, resulting in p53 activation and cell cycle arrest to prevent hyperproliferation. The mechanisms of both transcriptional repression and activation of ARF are not well understood. In my dissertation study, I showed that in mouse, p53 binds to Arf promoter and represses Arf expression and this repression requires the function of both histone deacetylase (HDAC) and polycomb group (PcG) proteins. Conversely, I demonstrated that p53 is required for both HADC and PcG to repress Arf expression. Bindings of both HDAC and PcG to Arf are disrupted by inactivation of p53 and can be restored in p53 null MEFs by the reintroduction of wild-type, but not mutant p53. In the latter part of my study, I found that the regulation of ARF expression is quite different in human. While p53 still represses human ARF, HDAC and PcG are not repressors of ARF, instead, ARF expression can be activated by treatment of DNA demethylation drugs. In addition, my study on the activation of ARF expression in response to oncogenic stress demonstrated a dynamic binding of E2F1 and E2F3 on the ARF locus accompanying the increased ARF transcription.
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  • In Copyright
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  • " ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry and Biophysics."
Advisor
  • Marzluff, William
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access

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