Scientists unravel mechanism
of key cancer gene
CHAPEL HILL -- June
8, 2001 (Cancer Digest) -- Scientists have discovered how an
important gene keeps cell division in check, offering more insight
into a key breakdown that results in cancer.
The new research published
today in the journal Science explains for the first time
how the tumor suppressor gene, p53, is activated in response
to DNA damage to keep tumors from forming.
About half of all human
cancers possess defective copies of the p53 gene. The new findings
may have implications for the development of drugs aimed at boosting
p53 activity in cancer patients.
Led by Dr. Yue Xiong,
scientists at the University of North Carolina's Lineberger Comprehensive
Cancer Center found an amino acid sequence within p53 that is
responsible for transporting the protein from the cell nucleus
to the cytoplasm, where it is degraded or broken down. In addition,
they discovered how this transport is blocked when DNA damage
occurs.
"P53 is not needed
in normal cell growth under conditions of no DNA damage,"
Xiong said in a press release. "Otherwise, the cell won't
be able to grow. So the cell handles that by exporting p53 from
the nucleus to the cytoplasm for degradation."
According to Xiong,
who is also an associate professor of biochemistry and biophysics
at the University of North Carolina, Chapel Hill School of Medicine,
the gene normally monitors biochemical signals indicating the
occurrence of DNA damage or mutations associated with tumor development.
Previous research has
shown that this phosphorylation process is somehow associated
with p53 activation. The new study shows the mechanism underlying
P53 activation induced by DNA damage.
When such signals occur,
the transport pathways are blocked by adding a phosphate to the
p53 protein and the protein accumulates in the cell nucleus where
it either stops further cell division or triggers the cell to
self-destruct.
"We found that
the addition of the phosphate inhibits the export of p53 to the
cytoplasm. We found a small sequence or small peptide in p53
that's required for p53 to be exported out," Xiong says.
"And we also determined
that phosphorylation occurs in that area. We discovered this
in normal cells, but we can also take tumor cells in which p53
is not working and insert functioning p53 into the nucleus and
it will remain there," he says.
In addition to further
understanding one of the cellular control mechanisms of p53,
Xiong's findings have other implications.
In half of all tumor
cells, p53 is not working sometimes because a kinase gene responsible
for p53 phosphorylation is mutated. When that gene is broken,
DNA damage cannot be repaired because P53 is continually exported
to the cytoplasm and getting degraded there.
"One could imagine,
if we were to develop a compound to block p53 export, we might
be able to restore p53 function in tumor cells with mutated kinase
genes. We could give the compound to patients to wake up the
p53 or prevent its degradation," he says.
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