Myc and apoptosis
Subtitle: identifying key regulators and target genes.
Published: 2004
Language: eng
Number of pages: 182
Description: The myc oncogene is frequently deregulated in a wide-variety and large number of cancers and is a potent activator of both cellular proliferation and apoptosis. As a nuclear transcription factor, Myc is believed to drive these disparate cellular activities through direct regulation of gene expression. However, Myc target genes have been only partially defined and the rate-limiting step downstream of Myc activation along the apoptotic pathway is unclear. Our results indicate that in the presence of apoptotic agonists, Myc regulates an important aspect of Bax activation to induce cytochrome c release from mitochondria, thus potentiating the apoptotic response. However, Myc does not appear to regulate this activity through a direct interaction with Bax. Therefore, the point at which Myc acts to regulate Bax activity must lie further upstream. To identify target genes regulated by Myc during apoptosis that may play a role in Bax activation, we performed cDNA microarray analysis to profile Myc gene regulation in response to two mechanistically distinct apoptotic agonists, taxol and doxorubicin. In contrast to previous studies wherein Myc target gene analysis has been conducted primarily under growth conditions, we conducted our expression analysis under both growth and death conditions to investigate whether different cellular inputs could direct different programs of Myc gene regulation. Our analysis revealed a sustained repression of Myc-repressed target genes that were bound directly by Myc under both growth and apoptotic conditions, where these genes were expressed at high levels in the absence of Myc in response to these same stimuli. Importantly, our data supports a model wherein the repression of any single gene does not constitute the mechanism by which Myc sensitizes cells to undergo apoptosis. Instead, we suggest a more global model wherein Myc repression of a cohort of genes establishes a program of gene regulation that imposes a block to the normal response to cellular stress. The knowledge gained by these studies has contributed to our overall understanding of Myc molecular function and role during apoptosis, and further defines the molecular pathways that can be exploited to harness Myc activity in tumours.
Notes: Adviser:  Linda Penn.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2300.