MYC Dependent Pathways in Apoptosis and Lymphomagenesis

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DESCRIPTION (provided by applicant): The c-myc gene is among the most frequent sites of mutation for any oncogene in human cancer. Approximately 15% of all cancers exhibit amplification of the c-myc gene and about 25% of breast cancers have similar mutations. Chromosomal translocations at c-myc occur in 100% of Burkitt's lymphomas, as well as in the related mouse plasmacytomas. In addition to these gross rearrangements, missense mutations can also play a major role in the oncogenic activity of c-myc, and more than 60% of Burkitt's and AIDS associated lymphomas have mutations that alter the protein structure of the already translocated c-myc gene. The major question confronting the c-myc field (and nuclear oncogenes in general) is which cellular genes are targeted by the oncoprotein to mediate its function in oncogenic transformation, cell cycle progression or apoptosis. Of broader interest is how the c-myc gene itself is regulated in response to diverse signaling pathways. The specific goals of this project are to: 1) Dissect the functional role of individual target genes in mediating the proliferative activity of the Myc transcription factor. Research will involve functional screens to discover specific genes that contribute directly to the Myc pathway. 2) Dissect the apoptotic, proliferative and oncogenic response of the Myc transcription factor using specific mutants that are defective in each biological activity using a dedicated Myc target gene microarray. 3) Use Drosophila genetics to gain insight into the regulatory pathways that govern c-myc gene expression, with particular emphasis on understanding the unique features of c-myc gene auto-suppression.