CHAPEL HILL, N.C. - A study at the University of North Carolina at Chapel Hill has identified a novel molecular mechanism in cell proliferation.
The study published Sept. 2 in the journal "Nature" shows that a molecular switch, transcription factor NF-kappaB, has a pivotal role in the regulation of cell growth and death. The new findings shed new light on tumor development. "Signaling pathways regulating cell growth and death are intrinsically linked to each other. Proliferating cells die unless specific growth factors are present. This provides a built-in protection against cancer. When this protection fails, cell proliferation runs out of control," says Dr. Sergei S. Makarov, research assistant professor of medicine at the UNC-CH School of Medicine and Thurston Arthritis Research Center. "Because of that, it is so important to understand the molecular mechanisms that control cell death and proliferation."
In the "Nature" report, Makarov and co-author Dr. Julia A. Romashkova detail a kind of molecular tango linking NF-kappaB with a trio of proto-oncogenes: Myc, Akt, and Ras. "Ras, Akt, and Myc are essential players in growth factor signaling," Makarov says. "They relay the signals required for proliferation. We found that NF-kappaB links the actions of these proteins."
The new findings are based on biochemical assays of cultured cells. The researchers show that after stimulation with growth factors, NF-kappaB becomes activated through an intricate sequence of molecular signals -- protein-to-protein relays -- involving Ras and Akt. The activation of NF-kappaB, in turn, leads to the expression of a protein called c-Myc -- a central regulator of cell growth, death, and differentiation.
"We know that c-Myc is essential for proliferation," Makarov says. "However, c-Myc causes cell death when it is over-expressed. In the presence of growth factors, c-Myc becomes not lethal but proliferative. How the growth factors regulate the functions of c-Myc, has not been clear," Makarov says. "When we blocked NF-kappaB activation, growth factors did not work against c-Myc-induced death.
Otherwise, activated NF-kappaB itself was able to prevent the lethal effects of c-Myc overexpression. This meant that the growth factors induce proliferation and inhibit cell death through NF-kappaB activation."
Although the study dealt with normal cells, the results have implications for understanding abnormal proliferation of tumor cells. Mutations in Ras, Akt, and Myc are found in a vast majority of human tumors. Similar to that, NF-kappaB activation is a frequent feature of tumor cells. The molecular mechanism also may apply in rheumatoid arthritis. Previous studies by Makarov's laboratory and others show that over-expression of c-Myc and activation of NF-kappaB is associated with tissue changes characteristic of the disease: inflammation and the overgrowth of synovial cells lining the joint capsule.
"Rheumatoid arthritis and tumors have lots in common," Makarov says. "You have uncontrollable growth in both. You also have over-expression of c-Myc and activation of NF-kappaB."
"These findings underscore NF-kappaB as a very attractive molecular target in the development of cancer and arthritis therapeutics," he adds.
Note to media: Contact Dr. Sergei Makarov at 919-966-9565;
email: smak@med.unc.edu
UNC-CH School of Medicine contact: Leslie H. Lang, 919-843-9687; email:
LLang@med.unc.edu;
Lynn Wooten, 919-966-6046 or email LWooten@unch.unc.edu.
Journal
Nature