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
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.