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Title page for ETD etd-03282011-011755

Type of Document Dissertation
Author Boone, David Nelson
Author's Email Address david.n.boone@vanderbilt.edu
URN etd-03282011-011755
Title Transcriptional regulation of Myc by the tumor suppressor ARF
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Stephen R. Hann Committee Chair
Steven R. Hanks Committee Co-Chair
Antonis Hatzopoulos Committee Member
Ethan Lee Committee Member
Scott Hiebert Committee Member
  • transcription
  • Egr1
  • ARF
  • Myc
  • apoptosis
Date of Defense 2011-03-22
Availability unrestricted
c-Myc is frequently deregulated in human cancers. While deregulated c-Myc leads to tumor growth, it also triggers apoptosis in partnership with tumor suppressors such as ARF and p53. Apoptosis induced by c-Myc is a critical fail-safe mechanism for the cell to protect against unrestrained proliferation. Despite the plethora of information on c-Myc, the molecular mechanism of how c-Myc induces both transformation and apoptosis is unclear. Oncogenic c-Myc can indirectly induce the expression of the tumor suppressor ARF, which leads to apoptosis through the stabilization of p53, but both c-Myc and ARF have apoptotic activities that are independent of p53. In cells without p53, ARF directly binds to c-Myc protein and inhibits c-Myc-induced hyperproliferation and transformation with a concomitant inhibition of canonical c-Myc target gene induction. However, ARF is an essential cofactor for p53-independent c-Myc-induced apoptosis. Here we show that ARF is necessary for c-Myc to drive transcription of a novel noncanonical target gene, Egr1. In contrast, c-Myc induces another family member, Egr2, through a canonical mechanism that is inhibited by ARF. We further demonstrate that Egr1 is essential for p53-independent c-Myc-induced apoptosis, but not ARF-independent c-Myc-induced apoptosis. Therefore, ARF binding switches the inherent activity of c-Myc from a proliferative to apoptotic protein without p53 through a novel noncanonical transcriptional mechanism. These findings also provide evidence that cofactors can differentially regulate specific transcriptional programs of c-Myc leading to different biological outcomes.
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