This is Dr. Guy-Evans' first grant as principal investigator.

Two of the four bases found in DNA and RNA are pyrimidines: cytosine and thymidine in DNA and cytosine and uridine in RNA. A Wayne State researcher hopes to learn more about how one specific protein triggers pyrimidine biosynthesis and how it is involved in the proliferation of cancer cells.

Hedeel Guy-Evans, PhD, assistant professor of biochemistry and molecular biology, is stepping up her investigation of the protein complex known as CAD, with a three-year, $600,000 grant from the National Institutes of General Medical Sciences and Cancer. Her studies were initially supported by an American Cancer Society grant from the Karmanos Cancer Institute. 

“CAD is a huge, multifunctional protein that’s composed of three major enzymes, including carbamoyl phosphate synthetase, aspartate transcarbamoylase and dihydroorotase. This complex is essential to cell growth and survival.”

Already, she and her research group have developed a hypothesis about how CAD is regulated. According to their findings, two separate signaling pathways appear to control the biological activity of the protein. The MAP kinase pathway promotes the activation of CAD, while the protein kinase A pathway serves to downregulate the activity of the complex.

“So basically you have a system in which a major protein, essential for cell growth and proliferation, is targeted by two distinctly different signaling pathways,” she explained.

Dr. Guy-Evans is focusing her work on the proliferative pathway that responds to growth factors and activates MAP kinase also called ERK, the extracellular regulated kinase. “We’re essentially looking at the role that this regulatory pathway plays in activating the target CAD complex in different kinds of cells, including cancer cells,” she said.

These studies are important to cancer research, because CAD activity is invariably elevated in tumor cells. “With this work, we think that we are close to deciphering the mechanism responsible for upregulation of pyrimidine biosynthesis. Understanding these regulatory pathways is important since CAD activation is an indispensable prerequisite for the uncontrolled growth of cancer cells.”

If all goes well, her findings might ultimately be important in the development of chemotherapeutic agents. Long before she can start thinking about potential applications, however, Dr. Guy-Evans must first understand the fundamental regulatory mechanisms. “The first step is to continue to work on our hypothesis and see if the CAD complex and the rate of pyrimidine biosynthesis is reciprocally regulated by these two signaling cascades. Then we’ll take it from there.” She added, “You never know where this will take us, but we think that we have a good lead to follow.”