grantor:
University of TorontoThe c-'myc' proto-oncogene encodes a nuclear phosphoprotein, whose expression has been tightly linked to cellular transformation ' in vivo' and 'in vitro'. The strong tumorigenic potential of Myc is reflected in its biological activities. Myc can promote cell cycle progression, inhibit growth arrest in the form of quiescence and senescence, and abrogate cellular differentiation in a diverse array of cell types. In essence, the net effect of Myc is to enhance cell growth by promoting cell proliferation and inhibiting growth arrest. Myc is believed to mediate these diverse biological activities by acting as a transcription factor, inducing or repressing the expression of specific subsets of genes. Analysis of the function of the Myc-induced genes that have been identified, reveals that some of these genes are required for progression through the cell cycle, particularly the transition from G1 to S phase. This observation suggests that Myc may enhance cell growth through the induction of genes which are essential to cell cycle progression. In comparison, less is known about the importance or mechanism of Myc repression activities, due to the small number of genes that have been reported to be repressed by Myc. Identification of the subset of genes which are repressed by Myc will help us to understand the mechanism of Myc-mediated gene repression, and how the repression of genes by Myc can promote cell proliferation. The crux of my research has been to identify and characterize novel gene targets for Myc repression, with the intention of revealing novel Myc-dependent pathways to drive cells out of growth arrest and promote cell proliferation. We have focused primarily on three genes: the 'cyclin D1' gene; the Platelet-derived growth factor ß receptor ('pdgf-ßr') gene; and the growth arrest gene, ' gadd45'; analyzing their expression in response to Myc-activation. In contrast to previous results obtained in selected immortalized cell lines, we clearly demonstrate that in primary mouse embryonic fibroblasts, cyclin D1 expression is not repressed by Myc. Indeed, loss of cyclin D1 expression is only evident in cells which exhibit Myc-activation and lack retinoblastoma tumour suppressor protein expression. Our data further suggest that the decrease in cyclin D1 expression is an indirect effect of cellular transformation rather than a direct effect of Myc. In addition, we have identified and characterized the repression of 'gadd'45 and the 'pdgf-ßr' genes by Myc. Analysis of these Myc-mediated repression mechanisms revealed that unlike Myc-mediated transactivation, Myc-mediated repression is comparatively more complicated and can be mediated by multiple pathways. The precise nature of these repression mechanisms is currently under study. The identification of these genes as targets for Myc repression has revealed that Myc repression pathways serve an important role in the ability of Myc to regulate the cellular response to changes in the extracellular environment, to drive cells out of growth arrest, and aid in tumour progression. Thus, it would appear that we are at the dawn of a new era of Myc research. Deciphering the significance of Myc repression will help us to understand how both Myc transactivation and Myc repression cooperate together to regulate normal cell proliferation, through the induction of cell cycle progression and the inhibition of growth arrest.Ph.D
