Document Type


Degree Name



Dept. of Molecular and Medical Genetics


Oregon Health & Science University


c-Myc is a powerful oncoprotein whose expression is misregulated in a wide variety of human tumors. Studies of conditional c-Myc transgenic mouse models have demonstrated that loss of c-Myc from tumors may induce tumor regression. Therefore expanding our understanding of the regulation of c-Myc function and its degradation is critical to developing new targeted cancer therapies. In this study I use Saccharomyces cerevisiae, the budding yeast, as a model system to examine c-Myc degradation, as well as to identify novel c-Myc binding partners. Specifically, I found that c-Myc is phosphorylated at Threonine 58 (T58) and Serine 62 (S62) in an interdependent and sequential manner in yeast cells, as has been reported to occur in mammalian cells. Additionally, phosphorylation at these sites regulates c-Myc stability in yeast as in mammalian cells. Furthermore, yeast orthologs of mammalian proteins that regulate phosphorylation and dephosphorylation events on S62 and T58 in mammalian cells, appear to largely play a role in regulating the phosphorylation events on these sites in yeast. This is an important finding because it supports the discoveries made in mammalian cells. Additionally, it has been demonstrated that alterations in phosphorylation of T58 and S62 change the affinity c-Myc has for binding proteins that regulate its stability. It has also been reported that phosphorylation at these sites alter c-Myc activity. Therefore, this study also validates the use of S. cerevisiae to screen for novel c-Myc interacting proteins that regulate c-Myc stability and/or function. In my yeast two-hybrid screen I identified ten potential new c-Myc interacting proteins that appear to bind within the transactivational domain (TAD) of c-Myc, three of which have been validated to interact in mammalian cells. One of these proteins, HMG Box Protein1 (HBP1), has been described as a tumor suppresser protein. Therefore, I characterized the interaction between HBP1 and c-Myc. Specifically, I found that HBP1 can bind to both the TAD and C-terminus of c-Myc in mammalian cells. This interaction appears to prevent c-Myc from binding the promoters of its target genes, thereby inhibiting c-Myc transactivational activity. This is a significant finding because it further solidifies the role of HBP1 as a tumor suppressor protein and it increases our understanding of the regulation of activity of the c-Myc oncoprotein.




School of Medicine



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