p73, Long Lost Cousin of p53 Tumor Suppressor Gene
By Sean Henahan, Access Excellence
BOSTON (August 22, 1997)- The discovery of a long-lost cousin
to the p53 tumor suppressor gene, called p73, could be an important new
piece in the cancer puzzle.
The p53 gene, found on chromosome 17, is mutated in 60% of human
cancers and is known to be an essential player in tumor development.
Now an international team of rsearchers report the discovery of a gene
that closely resembles p53. Called p73, the gene is deleted in at least
one type of cancer and resides in an area of the genome that researchers
have long suspected to harbor tumor suppressor genes.
The similarity of p73 to its famous relative, as well as other
findings, make it an intriguing gene, says Frank McKeon, associate professor
of cell biology at Harvard Medical School, who conducted this study with
Daniel Caput of the pharmaceutical company Sanofi Recherche in Labege Cedex,
France. Caput discovered p73 by luck, while researching growth factors
called cytokines. He then linked up with McKeon, an expert in the area
of DNA replication and cell division.
The researchers knew they were on to something because the gene resides
in the very tip of chromosome 1. This area is missing in many cancers,
including those of the skin, colon, breast and liver, as well as neuroblastoma,
a childhood cancer that while relatively rare has yielded much insight
into the molecular workings of cancer cells.
"P73 lies in one of the most interesting hot spots for putative tumor
suppressors," says McKeon. "This has been a suspicious area for cancer
for a long time." He cautions, however, that this danger zone probably
contains many genes and that only future work will clarify if and how p73
contributes
to disease.
While it has long been known that the tip of chromosome 1 is missing
in these cancers, researchers wonder why affected people cannot compensate
for the loss simply by using genes on their second chromosome 1. McKeon,
Caput, and colleagues do not fully understand this paradox, but they found
that the p73 gene gets expressed from one chromosome only, possibly that
of the mother. This finding suggests that having one faulty copy of p73
might suffice to lose all function. It also forges a connection to the
separate field of genetic imprinting, which studies why and how organisms
permanently "silence" certain genes just because they derive from a particular
parent.
The research suggests a possible approach to future treatments: trying
to awaken a silenced gene may prove easier than trying to supply a damaged
gene by gene therapy, says McKeon.
The structure of p73 is similar to p53. It contains important he core
binding region of the gene enabling the p53 protein to bind DNA, to stick
to other p53 proteins, and to activate particular genes. p73 also contains
the ten amino acids that are most frequently mutated in p53, predisposing
the carrier to cancer. Finally, p73 behaves like p53 in some of the experimental
tests routinely used to study tumor suppressor genes.
However, there are also important differences. Unlike p53, p73 does
not respond when the cell's DNA sustains damage from ultraviolet light,
the researchers report. This is important because the major function of
p53 that is currently known is to sense DNA damage and put the cell cycle
on hold while enzymes restore the DNA. If the damage is irreparable, p53
commits the cell to destroy itself. These functions have earned p53 the
sobriquet "guardian of the genome," and p73's failure to react to
DNA damage suggests that its main functions lie elsewhere, McKeon says.
McKeon's group is now laboring to produce a knock-out mouse with the
p73 gene missing. Early results suggest that p73 acts in the development
of the brain and the immune system. By contrast, mice lacking p53 show
almost no embryological defects.
Researchers also need to determine what p73 does. They want to know
what role p73 plays in the gradual process that scientists believe leads
from an initial disturbance of the cell's internal controls through a series
of exacerbating mutations to full-blown, metastatic cancer.
The research appears in the August 22, 1997 issue of Cell.
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