ras \ras\ (r[aum]s), n. [from rat sarcoma.]
The name and genetic symbol for a mutant gene that has been
identified as one of those associated with certains types of
cancer; -- it is a form of oncogene. It was first observed in
rats, but analogues have been found in humans and other
animals.
[PJC]
During the 1960s and 1970s, a great deal of research
was done on a class of viruses that affects rodents and
birds and causes tumors in those species. The
motivation for a lot of this research was the idea that
similar viruses might cause tumors in humans, but in
fact it's turned out that there are very few viruses
that cause tumors in humans. Nevertheless, the study of
these rodent viruses has been enormously fruitful in
helping us to understand human cancer, and that's the
basis of this story.
One of the viruses that was studied in those years had
two peculiarities. One was that it had lost most of the
genes that it needed to reproduce itself. It could only
reproduce if a helper virus was present in the same
cell to supply the missing functions. The second
peculiarity was that in place of the genes that were
required for reproduction of the virus was another gene
that had actually been picked up at some point in the
history of this virus when it went through rats, and it
picked up a rat gene and incorporated it into its own
genome.
At the same time that a lot of work was going on on
these viruses, other scientists were studying other
aspects of tumor formation, in particular, the action
of carcinogenic agents, chemicals and X-rays and
ultraviolet light. As you all know, human cells can
turn into tumor cells under the influence of such
agents. The tumor-like properties of those cells are
inherited by all the daughter cells through many
generations and, moreover, almost all chemicals that
turn out to be carcinogens are also able to cause
mutations.
Another observation was that in tumor cells, many of
the chromosomes seemed to have altered structures. So,
all of these observations and others certainly
suggested that changes in DNA might be involved in the
development of tumor cells. By about 1980, it became
possible to test that hypothesis directly.
If you have human tumor cells produced in laboratory
dishes or isolated from the tumor itself, then perhaps
they have a gene or genes in them which is responsible
for the fact that they're tumor cells. If you isolate
the DNA from the cells and cut it up into more or less
gene-sized pieces and then put it on top of mouse cells
growing in a dish, the mouse cells can take up pieces
of this DNA, and any mouse cell that picks up a piece
of DNA that carries on it a gene that can cause a tumor
will begin to grow like tumor cells, and its progeny
will grow rapidly and form a tight little cluster on
the cell.
Now it's possible to pick such cells off and isolate
the DNA from them and also separate the human DNA
sequence that might have caused the tumor-like property
from the bulk of the mouse sequences and to clone that
DNA. And when you do that and put that DNA, which is
now pure sequence, back in mouse cells, many of the
cells become tumor-like rather than just a rare few.
And such a gene, such a DNA sequence, bears the name of
an oncogene.
When such DNA segments are cloned, the DNA can also be
used to probe, to find out whether matching DNA
sequences occur only in tumor cells or whether there
are similar DNA sequences in normal cells. And the
answer has been for a whole group of oncogenes, that
very similar DNA sequences are present in normal cells.
To find out just how similar, the sequences of the
normal genes were compared with those from the genes
that were isolated from these tumor cells.
The first such oncogene isolated was from a human
bladder tumor, and everyone was surprised by the
results. First of all, the gene isolated from the
bladder tumor was almost identical to the normal human
gene and almost identical to the gene that was present
in the tumor virus that infected rodents that I told
you about before. This gene has become known as "ras",
because it was originally isolated from rats with
sarcoma, and it caused sarcomas and it's called that,
and it's protein is called that. And the only really
significant difference between the normal human gene,
the bladder tumor gene, and the rodent virus gene was a
change in one codon, Codon XII, and therefore a change
in amino acids.
So the normal human gene has a sequence GGC, encodes
the amino acid glycine, and does not cause tumors. But
the bladder tumor gene has GTC; it encodes valine. The
rodent virus has AGA; it encodes arginine, and both of
these cause tumors. In fact, any change that leads to a
loss of the glycine at Codon XII can change this normal
gene, ras, into a gene that would cause tumors. So
there were two different ways in which the ras gene
turned up. First, as a rat gene in a tumor virus and
second of all as the gene that could account for the
tumor-like properties of the bladder tumor.
Well by now, many of the questions that occurred to the
scientists working on this have occurred to you. What
is the ras protein normally (if anything), and what
does the altered ras protein do that differently, and
how can a change in one amino acid in a protein change
cells from normal to tumor cells?
It turns out that the ras gene and the ras protein are
important for a lot of things, but more particularly
for regulating the growth of cells. Normal cells need
to have a good ras gene in order to grow, in order to
make new DNA, to time it all right so they don't grow
out of control. Moreover, the ras gene occurs in
virtually all living things. For example, yeast cells
also have two ras genes. If either one of them is
knocked out, the yeast cells can still grow very well
and multiply. But if both ras genes are knocked out,
the yeast cells cannot multiply, and they die.
Astonishingly, if a human ras gene is applied to these
yeast cells, it completely takes the place of the
yeast's own ras genes. So we know from this that the
ras gene is very important to all living cells and that
it's probably been around for a couple billion years,
ever since the very first cells were formed on the
planet.
So ras does something important and the question is,
what does it do? David Golde told you before about
receptors that span cell membranes that bind molecules
outside the cell and provide a signal inside the cell,
and it turns out that what the ras protein does is to
help convey that signal from the receptor at the
surface down into the cell and into the gene where it
results in a change in gene expression. The ras protein
itself actually sits right under the cell membrane,
very well positioned to do this.
Well, how can it do that? To tell you about that I need
to tell you a couple of things about the ras protein
and what it does. First of all, ras combines two small
molecules called GDP and GTP, and they differ only in
the presence of one more phosphate, three in GTP and
two in GDP. This G is related; it's in fact the same
kind of molecule as the G that occurs in DNA. Moreover,
ras protein can catalyze the removal of one phosphate,
so you go from ras GTP to ras GDP and a phosphate is
lost. Furthermore, the ras GDP can lose the GDP and
pick up the GTP, and there are extra proteins in the
cell that foster either this exchange, back to GTP or
this loss of the phosphate to GDP. And the whole trick
is the ratio of the GTP to the GDP. So if you have ras
GTP, it's active and it stimulates growth, but if you
have ras GDP, then it's inactive and you don't
stimulate growth.
In fact, the change in Codon XII from a glycine results
in a change in the amount of ras GTP, so that there's
more ras GTP collecting in the cell than the ras GDP,
and therefore the cell is constantly under pressure to
make DNA and grow and divide. And this is the critical
reason for this change, this oncogenic change in those
versions of ras that cause tumors or are related to
tumor formation as opposed to the natural protein.
How can that happen, a small change like that? You've
heard a little bit about the importance of shapes of
proteins. If one looks closely at the atoms in the
proteins then you see that the whole shape of the
protein changes as you go from GTP to GDP.
Now one ras gene and protein all by itself would be
interesting, but it turns out that there's a whole
family of ras genes and ras proteins. Two of them are
specially similar to the type that I've been
describing, and mutations in those genes are associated
with a whole variety of human tumors including some
that are believed to be the result of the reaction to
environmental agents.
A mutant in one of those two related genes, which was
also first discovered in a tumor virus, is very
frequently associated with human tumors of the colon
and rectum. And again, it's Codon XII in that similar
gene that is altered in the oncogenic form of this kind
of ras. Tumors of the colon and rectum are the third
most common human malignancy worldwide, and surgical
removal of the tumors can actually cure the disease in
many cases, but only if the tumor is detected very,
very early. Recent work has shown that you can, in
fact, detect the change in the gene even by looking at
the DNA in the stool of people who are suspected of
having the colon tumor.
Even though the mutant DNA only occurs in a very small
percentage of the cells in the stool, namely the cells
that come from the tumor, not from all the normal cells
or all the bacterial cells that are there, it is
possible to amplify the amount of a possible abnormal
ras gene and test directly for it. So, for example in
this test, DNA from the stool of patient #1 matched a
probe for the normal ras gene, but DNA isolated from
the stool of patient #2 matched a probe not only from a
normal ras gene but also from a ras gene with a
mutation at Codon XII, thereby permitting a very early
diagnosis of a colon tumor and thereby providing real
hope that such tumors can be detected early, when the
tumor is small enough to be removed surgically with a
successful cure. --Maxine
Singer
(http://www.accessexcellence.org/AB/BA/Ras_Gene_and_Cancer.html)
[PJC]
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