Download Essay 9.1 The Cell Cycle Runs Amok: Cancer

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CHAPTER 9 Genetics, Mitosis, and Cytokinesis
Essay 9.1 The Cell Cycle Runs Amok: Cancer
T
he cell cycle reviewed in this chapter is, in one sense, a
common natural process: Cells grow; they duplicate
their chromosomes; these chromosomes separate;
one cell divides into two. This goes on like clockwork,
millions of times a second in each one of us. But then one day
we learn that an aunt or a grandfather or a friend is experiencing an unrestrained division of cells. Things aren’t explained to
us in this way, of course. We are simply told that someone we
know has cancer.
At root, all cancers are failures of the cell cycle. Put another
way, all cancers represent a failure of cells to limit their multiplication in the cell cycle. What is liver cancer, for example? It is a
damaging multiplication of liver cells. First one, then two, then
four, then eight liver cells move repeatedly through the cell
cycle, and as their numbers increase, they destroy the liver’s
working tissues. Given that cancer manifests in this way, it’s not
surprising that a large portion of modern cancer research is cellcycle research. The logic here is simple: To the extent that uncontrolled cell division can be stopped, cancer can be stopped.
A number of ideas are being tested for how cancers get
going in the first place, but a common thread that runs through
these ideas is that, for cells to be brought to a cancerous state,
two things are required: Their accelerators must get stuck and
their brakes must fail. The control mechanisms that induce cell
division must become hyperactive, and the mechanisms that
suppress cell division must fail to perform.You may have heard
a couple of terms used to describe the genetic components of
this process. There are normal genes that induce cell division,
but that when mutated can cause cancer; these are the stuckaccelerator genes, called oncogenes. Then there are genes that
normally suppress cell division, but that can cause cancer by
acting like failed brakes. These are tumor suppressor genes.
Note that both kinds of genes must malfunction for cancer to
get going; indeed, it usually takes a long succession of genetic
failures to induce cancer. This is why cancer is most often a disease of the middle-aged and elderly: It can take decades for the
required series of mutations to fall into line in a single cell,
such that it becomes cancerous.
For cells to be brought to a cancerous
state, two things are required: Their
accelerators must get stuck and their
brakes must fail.
How do oncogenes interact with tumor suppressor genes?
In the normal case, cells will not begin division until prompted
to do so by a signal from outside themselves. A protein (called
a growth factor) will bind to a cell, setting off a cascade of
chemical reactions inside it that triggers division. One of the
links in this chemical cascade is a protein called Ras that could
be thought of as an old-time railway switch. When Ras is
chemically pointed one way (toward “on”), the cell moves
through the cell cycle. When it is pointed the other (toward
“off”), the cell stays in G1. The gene that codes for Ras can become mutated, however, and when this happens, the Ras protein changes shape and points in the “on” direction all the
time—no matter what signals it is getting from the outside.
Thus, ras is an example of an oncogene. It normally prompts
the cell to divide intermittently; when mutated, it prompts the
cell to divide continuously.
A cell with a mutated ras gene is not doomed to become
cancerous, however. What can save it is a good set of brakes,
in the form of tumor suppressor genes. The most important of
called the metaphase plate. As the centrosomes move apart, they begin sprouting microtubules in all directions. One variety of them forms a football-shaped cage
around the nuclear material, while a second variety attaches to the chromosomes
themselves. Taken together, the microtubules active in cell division are known as the
mitotic spindle.
Metaphase By the time metaphase begins, the nuclear envelope has disappeared completely, and the microtubules that were growing toward the chromosomes now attach to them. Through a lively back-and-forth movement, the
microtubules align the chromosomes at the equator. With this, each chromatid
now faces the pole opposite that of its sister chromatid, and each chromatid is attached to its respective pole by perhaps 30 microtubules.
Anaphase
At last the genetic material divides. As you may have guessed, this
is a parting of sisters. The sister chromatids are pulled apart, each now becoming
a full-fledged chromosome. All 46 chromatid pairs divide at the same time, and
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Mitosis and Cytokinesis
these genes—one known as p53—is so vital to human health
that it is sometimes referred to as the “guardian of the
genome.” In the presence of certain kinds of mutations, p53
protein levels rise in the cell, and these levels start turning selected genes on and off. The result is the cell’s first line of defense against cancer—the cell cycle is shut down until the
mutation has been repaired. This shutdown doesn’t happen
at just any point in the cycle, however. As cancer researchers
Leland Hartwell and Ted Weinert discovered in the 1980s,
cells have specific checkpoints in their cycle. Just as NASA
mission control will stop at a defined point in a countdown to
see if “all systems are go” for a launch, so a cell has specific
points at which it makes sure that all its systems are healthy
enough for cell division to continue. The first of its checkpoints comes in G1, as it is about to enter S phase (during
which it doubles its DNA). The second point comes in G2, as
it is about to enter into mitosis and cytokinesis. Thus, if a dividing skin cell, for example, has acquired some mutations in
G1, it will not enter S phase until its DNA repair enzymes
have fixed the problem.
But what happens if the DNA damage spotted in G1 can’t
be fixed? Then, prompted by p53, the cell goes to level-two of
its emergency responses: It commits suicide. Through an orderly process called apoptosis, the cell shuts down its activities,
breaks up, and dies. If you have ever been sunburned, you have
probably seen the effects of apoptosis up close. The ultraviolet
light in the sun damages the DNA in skin cells. When this
damage cannot be fixed with repair enzymes, these cells undergo apoptosis; their remains are the peeling skin that comes
with a bad sunburn.
In sum, when genes such as ras become mutated, they can
lead to an out-of-control cell cycle, but this process can be
halted in several ways by tumor suppressor genes such as p53.
With this, you can probably see what comes next. What will
stave off cancer if a cell has both a mutated ras gene and a mutated p53 gene? Perhaps nothing, because now the accelerator
is stuck and the brakes have failed. As noted, there is generally
more to cancer than two mutated genes, but when both ras
and p53 malfunction, a cell is well on its way to cancer.
As it turns out, ras is probably the most important human
oncogene among the hundred or so that have been identified.
And p53 certainly is the most important tumor suppressor
gene among the two dozen that have been identified. A mutated ras gene is found in about 30 percent of all human cancers,
while a mutated p53 is found in half of all human cancers. As
you can imagine, there is intense research interest in both
these genes. From 1989 to 2000, more than 17,000 scientific
publications were written on p53 alone. The war on cancer may
not have been won, but it certainly is being waged.
FIGURE E9.1.1
Harmful Division Pictured are two prostate can-
cer cells in the final stages of cell division.
each member of a chromatid pair moves toward its respective pole, pulled by a
shortening of the microtubules to which it is attached.
Telophase
Telophase represents a return to things as they were before mitosis
started. The newly independent chromosomes, having arrived at their respective
poles, now unwind and lose their clearly defined shape. New nuclear membranes
are forming. When this work is complete, there are two finished daughter nuclei
lying in one elongating cell. Even as this is going on, though, something else is
taking place that will result in this one cell becoming two.
Cytokinesis
Cytokinesis actually began back in anaphase and is well under way by the time of
telophase. It works through the tightening of a cellular waistband that is composed of two sets of protein filaments working together. These filaments—the
same type that allow your muscles to contract—form a ring that narrows along
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