Investigators at the University of California, San Diego (UCSD) School of Medicine have discovered a second pathway that the Ras proto-oncogene uses to cause cancer. The work sets the stage to develop new approaches for cancer treatment by blocking Ras' action before it can signal cells to proliferate. Ras is involved in a wide range of cancers, including stomach and lung cancer.

Normal development requires that cells respond properly to environmental cues that signal cells to grow and divide. Ras, the product of the Ras gene, plays a pivotal role in responding to such signals, and overactivation of Ras is involved in cancer.

Normally, when it is time for a cell to reproduce, growth factors bind to the cell surface and trigger the Ras protein, which starts a cascade of events that culminates in the expression of specific genes in the nucleus. These genes cause cell growth and formation of new cells. After signaling the cell to grow, Ras turns itself off. However, if a mutation occurs in the protein, ras remains active and causes uncontrolled cell growth and cancer.

Previously, scientists had identified and concentrated on a single signaling pathway between Ras and the nucleus of cells. Now, a group of scientists working with Michael Karin, PhD, UCSD Professor of Pharmacology, has discovered a second pathway.

"Ras is involved in so many actions--causing cells to grow, divide, and mature into specific types of cells. We were very puzzled about how all this could happen through just one linear pathway. Now we know that there are at least two pathways, and there could be more. We believe that there may be cross-communications between the pathways as well. This system is much more complex than we thought," said Audrey Minden, PhD, a researcher involved in the study.

The UCSD team found that Ras activates an enzyme called MEKK, which goes through a series of steps to cause the activation of another enzyme called JNK, that finally stimulates a protein called c-jun. C-jun performs many jobs, including ordering cells to grow and divide.

In the pathway originally identified by other scientists, Ras activates a protein called Raf-1, which leads to activation of an enzyme called ERK. ERK in turn helps signal cells to grow by stimulating production of a protein called c-fos. C-jun and c-fos may bind together to form another protein called AP-1.

AP-1, as shown by the Karin group several years ago, stimulates expression of genes required for cell growth and proliferation. In this way, two different branches of the Ras pathway, through different mechanisms, may be involved in regulating cell function.