J. Anthony Graves attended Bucknell University from 1987 to 1991 and graduated with a B.A. in Biology and a minor in Black Studies. He started graduate school in his hometown of Pittsburgh, PA at Carnegie Mellon University. He studied yeast genetics in the lab of Dr. Susan Henry and graduated in 1996 with his doctor dissertation entitled, Analysis of the Role of the OPI1 Gene Product in the Negative Regulation of the Phospholipid Biosynthetic Pathway of Saccharomyces cerevisiae. Next, he matriculated at The Johns Hopkins University School of Medicine. He completed his first year of training and then did a two year research fellowship at Johns Hopkins in the laboratory of Dr. Chi Van Dang where he studied various aspects of Myc biology, including its impact on apoptosis. He returned to the medical program in 1999 and graduated with his M.D. in 2002. He started his residency in 2002 in Pediatrics at the Children’s Hospital of Pittsburgh, and continued at the same hospital for his fellowship in Pediatric Hematology/Oncology. Following the completion of his fellowship, Dr. Graves joined the faculty at the Children’s Hospital of Pittsburgh of UPMC. Under the mentorship of Dr. Edward Prochownik, he again has focused his studies on the Myc oncoprotein as well as the role of the regulation of reactive oxygen species in tumorigenesis. Currently he is a Hyundai Hope on Wheels Scholar and a Harold Amos Medical Faculty Development Scholar sponsored by the Robert Wood Johnson Foundation. He is married to his wife Becky and has two children: Isaac (age 7) and James (age 7 months).

c-Myc protein is one of the most important proteins in human biology. It serves as a major regulator of the transcription of over 25% of the entire human genome. The genes that are expressed are involved in many normal cellular functions including cellular growth, differentiation and control of metabolism. If the amount or activity of c-Myc becomes inappropriately increased, many of its target genes can be expressed abnormally; furthermore, new genes can become regulated by the overexpressed c-Myc. Of the many cellular changes that occur in this setting, the most significant is the development of many types of human malignancies, including: cancers of the breast, prostate, colon, and brain, as well as some leukemias and lymphomas. Given the importance of this protein, a great deal of research has attempted to determine the steps required for the development of a c-Myc-driven tumor, for which no clear pathway as been determined to date.

I have helped to develop a set of c-Myc proteins that have been engineered to harbor subtle changes in their sequence. I have been characterizing how these changes affect the ability of the protein to perform many of its functions, including the ability to turn a normal cell into a tumor cell. This type of analysis will allow me to identify which of the numerous characteristics of a cell overexpressing c-Myc are necessary for tumor formation. To date, I have shown that no single aspect of the function of c-Myc is absolutely necessary for tumor formation; rather, it appears that multiple characteristics can make non-essential contributions to the development of cancer. Most interestingly, one of the altered forms of c-Myc that has been engineered has been shown to be incapable of expressing virtually all known characteristics of the c-Myc protein, with the notable exception that it can turn cells cancerous at a high rate. I have identified a number of genes whose expression is altered in cells that overexpress both the normal and mutant forms of the c-Myc protein. I am undertaking a detailed analysis of these target genes which to better understand some novel pathways that I hope to prove are essential to the formation of a tumor.

Deregulation of c-Myc (Myc) occurs in many cancers. In addition to transforming various cell types, Myc also influences various transformation-associated cellular phenotypes including proliferation, survival, genomic stability, reactive oxygen species production, and metabolism. Although most cancers express wild-type Myc (wtMyc), certain lymphomas contain point mutations. Some of these confer a survival advantage relative to wtMyc despite partially attenuating proliferation and transformation. Here, we have evaluated four naturally occurring or synthetic point mutations of Myc for their ability to affect these phenotypes, as well as to promote genomic instability, to generate reactive oxygen species and to up-regulate aerobic glycolysis and oxidative phosphorylation. Our findings indicate that many of these phenotypes are genetically and functionally independent of one another and that transformation can be achieved, albeit at reduced efficiency, in their absence. The higher glucose metabolism imparted by wtMyc was completely lost by the mutants despite the fact that they remained transformation-competent. Indeed, one mutation (Q131R) was unable to confer any Myc phenotypes except transformation. These findings indicate that, while all of the Myc phenotypes examined here make additive contributions, no single one is crucial for achieving a baseline level of transformation. Microarray analysis was performed on cells overexpressing either wtMyc or Q131R, and several genes that are regulated by both cell lines have been identified. These genes are being assayed for their ability to transform cells when overexpressed irrespective of Myc levels.