RESEARCHERS FIND HOW TWO CANCER GENES INTERACT TO CAUSE
MALIGNANCY
DURHAM, N.C. -- Researchers at Duke University Medical Center
have discovered how two cancer-causing genes can interact to transform normal
cells into cancerous cells, adding further insight into the long-held theory
that cancers require mutations in multiple genes.
In a paper published in
the Feb. 26 issue of
Molecular Cell,
geneticist Joseph Nevins and his colleagues report details of the functional
interaction between the proteins produced by two cancer-related genes, called
"myc" and "ras."
Basically, the researchers
discovered that mutated ras causes the protein from myc to accumulate in the
cell, enhancing myc's growth-promoting abilities. If ras is not mutated, the myc
growth-stimulating signal dies rapidly and cellular replication is
controlled.
"The 'multi-hit' notion of cancer has been around for a
while," said Nevins, a Howard Hughes Medical Institute Investigator at
Duke. "In the mid 1980s scientists showed that if both myc and ras were
mutated, the cells became cancerous. Until now there has been little mechanistic
information as to how these two genes work together."
The
researchers' report shows that the myc protein lasts five times longer than
normal if ras is mutated. This information could eventually affect treatment and
diagnosis of many cancers, including brain, colorectal and endometrial
(uterine). Tumor cells with mutations in both myc and ras are likely to have an
even more dramatic increase in the duration of the myc growth signal, Nevins
said.
"The key to developing better therapeutics for cancer,"
said Nevins, "is using the information learned about interactions such as
that of ras with myc to design drugs that interfere with these oncogenic
processes."
Like all so-called oncogenes, myc and ras perform
important cell functions when normal, but act as accelerators to spur
uncontrolled cell proliferation when mutated. In normal cells, the amount of
protein produced by the myc gene increases to promote cell growth and then drops
to prevent cells from multiplying further. Ras is important in transmitting
signals through the cell.
In their experiments on normal cells, the
researchers found that without mutated ras, half of the myc protein initially
present was degraded within 10 minutes. However, in cells with mutated ras, it
took 50 minutes to degrade half of the myc protein. Myc protein's half-life is
longer because the mutated ras protein interferes with the cell's natural
degradation of myc protein, much like clogging a sink. As the myc protein
accumulates, the cells continue to divide after they should have
stopped.
"The myc protein is normally very short-lived, but a
mutated ras can increase its stability," Nevins explained. "This is
probably not the only way these two proteins and genes interact, but it is one
way."
The researchers still are exploring the exact mechanism by
which ras protein interferes with myc's degradation, as well as seeking other
factors in the cell that control the stability of myc. More detailed knowledge
could lead to new therapies, Nevins said.
"Understanding the precise
mechanisms that regulate these activities opens the way to developing
therapeutics that specifically target the abnormal function, leaving the normal
functions alone," he said.
Other authors of the Molecular Cell study
were Rosalie Sears and Gustavo Leone of Duke, and James DiGregori, formerly of
Duke and now at the University of Colorado at Denver
