August 07, 1998
Molecular Circuit Breaker Can Prevent Runaway Cell Growth
A long-standing mystery about how cells resist the powerful effects
of cancer-causing genes has been solved by researchers studying a
genetic check-and-balance system that prevents cells in the body from
multiplying chaotically.
Drugs that activate this system, says Charles J. Sherr, an HHMI
investigator at St. Jude Children's Research Hospital in Memphis,
Tennessee, could increase the effectiveness of conventional anti-cancer
therapy.
Cells are equipped with several systems for controlling their
multiplication, but when these cease to work properly, uncontrolled
cell growth can lead to tumor formation. Sherr and St. Jude colleague
Martine F. Roussel have been studying how some of these systems work at
the molecular level.
In 1995, the HHMI team discovered an unusual example of such a
"checkpoint" whose key component is a protein they named ARF. Now they
have learned that this protein "monitors the system carefully and works
like a fuse or circuit breaker," Sherr says. "The gene for ARF is not
activated until signals that stimulate cell growth exceed a critical
threshold. It's as if too much current runs through the circuit and the
breaker trips."
Although it is generally thought that one gene encodes one protein,
the gene encoding the ARF protein initially escaped attention because
it lies embedded within another gene called INK4a. Sherr's group
realized that, like the protein specified by the INK4a gene, ARF
also inhibits cell growth. The intimate physical relationship between
two overlapping genes that ordinarily restrain cell multiplication
explains why the INK4a-ARF gene pair is missing in many human
cancers. Without the growth inhibitory effects of this gene pair, cells
are more likely to grow uncontrollably.
Now, the investigators are refining their understanding of how ARF
works. ARF's major role is to monitor various kinds of signals that
stimulate cells to proliferate. When the strength of these signals
rises to dangerous levels, ARF relays this information to another
growth inhibitory protein, p53, that in turn prevents the
over-stimulated cells from growing and can even induce them to commit
suicide. One protein whose levels are carefully monitored by this
ARF-p53 "fail-safe" mechanism is Myc, a protein that is required for
normal cell growth but whose unregulated overexpression can lead to
cancer.
"The ARF protein controls a p53-dependent process that helps to
safeguard cells against runaway growth promoting signals," Sherr says.
"ARF and p53 act together to limit Myc's stimulatory potential, but in
cases where ARF is damaged and can no longer function, unchecked Myc
activity can cause havoc."
Sherr and Roussel collaborated with Scott W. Lowe and his colleagues
at Cold Spring Harbor Laboratory, and Carol Prives at Columbia
University in an attempt to further generalize these findings. The Cold
Spring Harbor researchers have been studying another tumor-inducing
viral gene, called E1A. They had previously found that p53 suppresses
the tumor-generating activity of E1A. The new findings reveal that this
ability of cells to resist E1A also depends strongly upon ARF.
Understanding how ARF works has helped to interpret the actions of
what Robert Weinberg [of the Whitehead Institute for Biomedical
Research at MIT] calls 'collaborating oncogenes.' This theory posits
that truly normal cells resist certain oncogenes and refuse to be
transformed into cancer cells.
"We have known for 15 years that genes like Myc and
E1A help to overcome this resistance. Myc and E1A kill normal
cells by activating the ARF-p53 checkpoint," says Sherr, "but they also
select for the emergence of rare tumor cells that have lost the ARF-p53
checkpoint and no longer die." The studies on ARF's ability to
counteract the effects of Myc and E1A were published in two articles in
the August 7, 1998, issue of Genes & Development.
While it has been known for several years that damage to a cell's
DNA can signal a p53 response that induces cell suicide, these
researchers have concluded that ARF sends an alternative signal that
does not rely upon DNA damage. However, the ARF pathway can also act
hand in hand with the DNA damage pathway in triggering p53-induced cell
suicide. According to both Sherr and Lowe, drugs designed to emulate
ARF or stimulate ARF production might make cells more sensitive to the
many conventional forms of anti-cancer therapy that act by damaging the
DNA of tumor cells.
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