CHAPEL HILL - A study led by a University of North Carolina scientist sheds new light on the process of cell growth regulation. The study, which focuses on the complex network of biochemical signals between proteins and enzymes within cells, helps clarify how those signals initiate or limit cell growth.
Although still too basic for clinical use, the findings suggest the possibility of new drugs that would target specific growth-inducing molecules within cancer cells.
A report of the study appears in the January 20 issue of the science journal Nature.
According to Lee Graves, Ph.D., assistant professor of pharmacology at UNC School of Medicine in Chapel Hill and the study's principal investigator, the enzyme MAP kinase (MAPK) is a key component of a signaling pathway initiated by growth factors.
"This is just one of many signaling pathways but we know it's essential for growth," he said. "So the key question has been, what are the specific targets of MAP kinase; that is, what are the important things it does, and how does it regulate cell growth?"
In their search for the answer, Graves and his study collaborators at UNC Lineberger Cancer Center and Wayne State University in Detroit, focused on an enzyme called carbamoyl phosphate synthetase, or CPS II. Deep within the cell's molecular machinery, this enzyme determines the rate of pyrimidine nucleotide biosynthesis, without which cell growth is impossible. Nucleotides are the building blocks of RNA and DNA synthesis. Consequently, blocking the synthesis of these molecules has been the strategy of numerous anti-cancer therapies. Normally, as cellular levels of pyrimidine nucleotides build up, CPS II is turned of by a process of 'feedback' inhibition, Graves explains. "What we think happens is that in response to a growth signal, MAP kinase attaches a phosphorous molecule to CPS II, thus preventing feedback inhibition and allowing cells to make more nucleotides."
The UNC pharmacologist points to studies of tumor cells showing that abnormal increases in MAPK and pyrimidine nucleotide synthesis are observed.
"It's been shown by a number of investigators that MAP kinase is elevated in tumor cells. What we find is that the properties of carbamoyl phosphate synthetase from tumor cells are consistent with increased phosphorolation by MAP kinase," Graves said. "We've also been able to correlate increases in levels of pyrimidine nucleotide biosynthesis in normal cells with increases in MAP kinase activity. We are now studying if this effect occurs in tumor cells." Graves finds the possibility intriguing that breakdowns in the cellular signaling pathways may be associated with the unbridled cell growth associated with tumors.
"What we're most intrigued by is looking at tumor cells, or in particular human leukemia cells, where there may be a dysregulation of the normal nucleotide biosynthetic pathways and determining whether or not phosphorolation mediated by MAP kinase is adding to that problem," Graves said. "If so, this may help us to design new therapies that specifically affect these pathways."
A pioneer in CPS II research was Dr. Mary Ellen Jones, a former chair of biochemistry at UNC. "Her work made it possible for us to complete our studies," Graves said.
Note to media: Contact Dr. Graves at 919-966-0915; email: lmg@med.unc.edu UNC MEDICAL SCHOOL CONTACT: Leslie H. Lang, 919-843-9687; llang@med.unc.edu
Journal
Nature