For
the proteins in our body there's not much room for mercy. If old or
damaged proteins were allowed to accumulate in a cell, it would soon
become useless. Thus, a sophisticated recycling system quickly breaks
down deficient proteins.
But, as has recently been found, healthy
proteins, including proteins that inhibit cancer, often meet the same
fate.
This is due to a molecule that, together with its helpers, serves
as a "death tag." Weizmann Institute scientists have identified one of
the sinister helpers involved in the nefarious work of breaking down
cancer-preventing proteins.
Twenty
years ago, Profs. Abraham Hershko and Aharon Ciechanover of the
Technion Medical School discovered an enzyme system dedicated to
breaking down proteins in the cell.
This system contains many kinds of
enzymes, each responsible for seeking out and destroying a specific
group of proteins, according to their three-dimensional structure. The
scientists discovered the existence of a small protein called ubiquitin,
which functions as a sort of "death tag."
Ubiquitin is attached to the
damaged protein by enzymes, and it then "calls out" to the various
wrecking enzymes.
After these complete their work, the "death tag" is
released and returns to a cache in the cell.
It
has recently come to light that the same system is also responsible for
breaking down functioning proteins when their level rises above that
desired in the cell.
Prof. Moshe Oren of the Weizmann Institute's
Molecular Cell Biology Department is studying the p53 protein, product
of the p53 gene, whose proper functioning inhibits the development of
tumors.
Apparently over 50% of cancers in humans are caused by changes
in the p53 gene that lead to the protein's dysfunction.
In normal cells
the amount of p53 protein is minute; but the moment the cell is exposed
to a process that may lead to mutation and thence to the development of
cancer, the amount and activity of the p53 protein increases rapidly.
As
a result, the cell ceases to divide until the damage is repaired. In
those cases where the damage is impossible to repair, the p53 protein
instructs the cells to self-destruct so that the organism as a whole may
live. In either case the p53 protein prevents the malignancy from
evolving.
In
normal cells, where the risk of malignancy is nonexistent, the
ubiquitin system is responsible for the rapid breakdown of the p53
protein, preventing its accumulation in amounts that could disrupt the
cell's normal operation.
When the cell is "spoiled" in a way that may
cause it to become cancerous, p53 is called into action and accumulates
rapidly.
The key to its accumulation is a disguise designed to help it
evade the ubiquitin system.
"Today we know that exposing cells to DNA
damage causes the addition of phosphate molecules to the p53 molecule,"
says Oren.
"These changes prevent identification of the protein by the
ubiquitin system, and 'rescue' it."
Oren and his team have recently
begun to focus on defining the biochemical processes that oversee each
of the phosphate sites and finding the mechanism by which phosphate
affects the ability of the ubiquitin system to recognize the p53
protein.
They
have discovered that a second protein, called Mdm2, is responsible for
attaching ubiquitin, the "death tag," to the p53 protein. Thus Mdm2 is a
critical factor involved in regulating the levels of the p53 protein in
the cell.
"According to recent information, some of it acquired in our
lab, it seems that the rate at which p53 is broken down may be altered
not only by changes caused by phosphates, but also by variations in the
concentration and activity of Mdm2 in the cell," says Oren.
Red: Nucleii containing p53. Green: Nucleii genetically engineered to express Mdm2. In these cells, p53 does not accumulate because it is broken down by the ubiquitin system.
p53 fulfills a major role in the processes that affect the accretion,
or nonaccretion, of genetic mutations that may lead to the development
of cancer.
"The cells have developed complicated warning systems, each
of which can delay the breakdown of p53, thus preventing cancerous
processes," says Oren.
"If we can understand how the breakdown of p53 is
modulated, we can intervene in this process using medication and boost
mechanisms that protect from cancer."
As a result of Oren's research, drugs that cause increased p53
activity in cancerous cells by interfering with its breakdown via Mdm2
are being developed by several drug companies, in an attempt to arrest
proliferation and even induce tumor remission.
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