dc.creator | Boone, David Nelson | |
dc.date.accessioned | 2020-08-22T00:10:01Z | |
dc.date.available | 2012-04-08 | |
dc.date.issued | 2011-04-08 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-03282011-011755 | |
dc.identifier.uri | http://hdl.handle.net/1803/11585 | |
dc.description.abstract | 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. | |
dc.format.mimetype | application/pdf | |
dc.subject | transcription | |
dc.subject | Egr1 | |
dc.subject | ARF | |
dc.subject | Myc | |
dc.subject | apoptosis | |
dc.title | Transcriptional regulation of Myc by the tumor suppressor ARF | |
dc.type | dissertation | |
dc.contributor.committeeMember | Ethan Lee | |
dc.contributor.committeeMember | Scott Hiebert | |
dc.contributor.committeeMember | Antonis Hatzopoulos | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Cell and Developmental Biology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2012-04-08 | |
local.embargo.lift | 2012-04-08 | |
dc.contributor.committeeChair | Stephen R. Hann | |
dc.contributor.committeeChair | Steven R. Hanks | |