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2: Mutations in a Number of Different Types of Genes Contribute to Cancer
(b) Tumor-suppressor genes
wild type (+/+)
factors that stimulate
2 Mutant alleles (oncogenes) tend
to be dominant: one copy of the
mutant allele is sufficient to
induce excessive cell proliferation.
wild type (+/+)
(or mutation in one
and deletion in one)
Normal growthNo inhibitory No inhibitory
produce factors that
inhibit cell division.
4 Mutant alleles are recessive
(both alleles must be
mutated to produce excessive
15.5 Both oncogenes (a) and tumor-suppressor genes (b) contribute to cancer but differ in
their modes of action and dominance.
Proto-oncogenes can be converted into oncogenes in
viruses by several different ways. The sequence of the protooncogene may be altered or truncated as it is being incorporated into the viral genome. This mutated copy of the gene
may then produce an altered protein that causes uncontrolled cell proliferation. Alternatively, through recombination, a proto-oncogene may end up next to a viral promoter
or enhancer, which then causes the gene to be overexpressed.
Finally, sometimes the function of a proto-oncogene in the
Some oncogenes and functions
of their corresponding
Part of growth-factor
Protein tyrosine kinase
GTP binding and GTPase
host cell may be altered when a virus inserts its own DNA
into the gene, disrupting its normal function.
Many oncogenes have been identified by experiments in
which selected fragments of DNA are added to cells in culture. Some of the cells take up the DNA and, if these cells
become cancerous, then the DNA fragment that was added
to the culture must contain an oncogene. The fragments can
then be sequenced, and the oncogene can be identified. A
large number of oncogenes have now been discovered
Tumor-suppressor genes Tumor-suppressor genes are
more difficult than oncogenes to identify because they
inhibit cancer and are recessive; both alleles must be mutated
before the inhibition of cell division is removed. Because it is
the failure of their function that promotes cell proliferation,
tumor-suppressor genes cannot be identified by adding
them to cells and looking for cancer. Defects in both copies
of a tumor-suppressor gene are usually required to cause
cancer; an organism can inherit one defective copy of the
tumor-suppressor gene (is heterozygous for the cancer-causing mutation) and not have cancer, because the remaining
normal allele produces the tumor-suppressing product.
However, these heterozygotes are often predisposed to cancer, because inactivation or loss of the one remaining allele
is all that is required to completely eliminate the tumor-suppressor product and is referred to as loss of heterozygosity.
A common mechanism for loss of heterozygosity is a deletion on the chromosome that carried the normal copy of the
tumor-suppressor gene (Figure 15.6).
One of the first tumor-suppressor genes to be identified
was the retinoblastoma gene. In 1985, Raymond White and
This person is heterozygous (Aa)
for a tumor-suppressor gene.
Loss of the wild-type allele, in
this case through a chromosome
deletion, causes loss of the
Conclusion: People heterozygous for a tumorsuppressor gene are predisposed to cancer.
sometimes combine with the lowered tumor-suppressor
product to cause cancer.
Haploinsufficiency is seen in some inherited predispositions to cancer. Bloom syndrome is an autosomal recessive
disease characterized by short stature, male infertility, and a
predisposition to cancers of many types. The disease results
from a defect in the BLM locus, which encodes a DNA helicase enzyme that plays a key role in the repair of doublestrand breaks. Persons homozygous for mutations at the
BLM locus have a greatly elevated risk of cancer. Persons heterozygous for mutations at the BLM locus were thought to
be unaffected. However, a recent survey of Ashkenazi Jews
(who have a high frequency of Bloom syndrome) showed
that heterozygous carriers of a BLM mutation were at
increased risk of colorectal cancer. Similarly, mice with one
mutated copy of the BLM gene are more than twice as likely
to develop intestinal tumors as are mice with no BLM
15.6 Loss of heterozygosity often leads to cancer in a
person heterozygous for a tumor-suppressor gene.
Webster Cavenne showed that large segments of chromosome 13 were missing in cells of retinoblastoma tumors, and,
later, the tumor-suppressor gene was isolated from these segments. A number of tumor-suppressor genes have now been
discovered (Table 15.4).
Sometimes the mutation or loss of a single allele of a
recessive tumor-suppressor gene is sufficient to cause cancer.
This effect—the appearance of the trait in an individual cell
or organism that is heterozygous for a normally recessive
trait—is called haploinsufficiency. This phenomenon is
thought to be due to dosage effects: the heterozygote produces only half as much of the product encoded by the
tumor-suppressing gene. Normally, this amount is sufficient
for the cellular processes that prevent tumor formation, but
it is less than the optimal amount, and other factors may
Some tumor-suppressor genes
and their functions
Source: J. Marx, Learning how to suppress cancer, Science 261:1385, 1993.
Proto-oncogenes are genes that control normal cellular functions.
When mutated, proto-oncogenes become oncogenes that stimulate cell proliferation. They tend to be dominant in their action.
Tumor-suppressor genes normally inhibit cell proliferation; when
mutated, they allow cells to proliferate. Tumor-suppressor genes
tend to be recessive in their action. Individual organisms that are
heterozygous for tumor-suppressor genes are often predisposed to
✔ Concept Check 2
Why are oncogenes usually dominant in their action, whereas
tumor-suppressor genes are recessive?
Genes That Control the Cycle
of Cell Division
The cell cycle is the normal process by which cells undergo
growth and division. Normally, progression through the cell
cycle is tightly regulated so that cells divide only when additional cells are needed, when all the components necessary
for division are present, and when the DNA has been replicated without damage. Sometimes, however, errors arise in
one or more of the components that regulate the cell cycle.
These errors often cause cells to divide at inappropriate times
or rates, leading to cancer. Indeed, many proto-oncogenes
and tumor-suppressor genes function normally by helping
to control the cell cycle. Before considering how errors in this
system contribute to cancer, we must first understand how
the cell cycle is usually regulated.
Control of the cell cycle As discussed in Chapter 2, the
cell cycle consists of the period from one cell division to the
next. Cells that are actively dividing pass through the G1, S,
and G2 phases of interphase and then move directly into the
M phase, when cell division takes place. Nondividing cells
exit from G1 into the G0 stage, in which they are functional
but not actively growing or dividing. Progression from one
stage of the cell cycle to another is influenced by a number of
internal and external signals and is regulated at key points in
the cycle called checkpoints.
For many years, the biochemical events that control the
progression of cells through the cell cycle were completely
unknown, but research findings have now revealed many of
the details of this process. Key events of the cell cycle are controlled by cyclin-dependent kinases (CDKs), which are
enzymes that add phosphate groups to other proteins.
Sometimes, phosphorylation activates the other protein and,
other times, it inactivates the protein. As their name implies,
CDKs are functional only when they associate with another
protein called a cyclin. The level of cyclin oscillates in the
course of the cell cycle; when bound to a CDK, cyclin specifies which proteins the CDK will phosphorylate. Each cyclin
appears at a specific point in the cell cycle, usually because its
synthesis and destruction are regulated by another cyclin.
Cyclins and CDKs are called by different names in different
organisms; here, we will use the terms applied to these molecules in mammals.
Let’s look at the G1-to-S transition. As stated in Chapter
2, progression through the cell cycle is regulated at several
checkpoints, which ensure that all cellular components are
present and in good working order before the cell proceeds
to the next stage. The G1/S checkpoint is in G1, just before
the cell enters into the S phase and replicates its DNA. The
cell is prevented from passing through the G1/S checkpoint
by a molecule called the retinoblastoma (RB) protein
(Figure 15.7), which binds to another molecule called E2F
and keeps it inactive. In G1, cyclin D and cyclin E continuously increase in concentration and combine with their associated CDKs. Cyclin-D–CDK and cyclin-E–CDK both
phosphorylate molecules of RB. Late in G1, phosphorylation
of RB is completed, which inactivates RB. Without the
inhibitory effects of RB, the E2F protein is released. E2F is a
transcription factor that stimulates the transcription of
genes that produce enzymes necessary for replication of the
DNA, and the cell moves into the S stage of the cell cycle.
Other checkpoints control the G2-to-M transition, the
assembly of the spindle apparatus, and the cell’s exit from
Mutations in cell-cycle control and cancer Many cancers are caused by defects in the cell cycle’s regulatory
machinery. For example, mutations in the gene that encodes
the RB protein—which normally holds the cell in G1 until
the DNA is ready to be replicated—are associated with many
cancers, including retinoblastoma (from which the RB protein gets it name). When the RB gene is mutated, cells pass
through the G1/S checkpoint without the normal controls
that prevent cell proliferation. Overexpression of the gene
RB binds E2F and
keeps it inactive.
…which activates RB,
and it releases E2F.
of cyclin-D–CDK and
E2F binds to
DNA and stimulates
of genes required
for DNA replication.
15.7 The RB protein helps control the progression through
the G1/S checkpoint by binding transcription factor E2F.
that encodes cyclin D (thus stimulating the passage of cells
through the G1/S checkpoint) takes place in about 50% of all
breast cancers, as well as some cases of esophageal and skin
cancer. Likewise, the tumor-suppressor gene p53, which is
mutated in about 75% of all colon cancers, regulates a potent
inhibitor of CDK activity.
Progression through the cell cycle is controlled at checkpoints,
which are regulated by interactions between cyclins and cyclindependent kinases. Genes that control the cell cycle are frequently
mutated in cancer cells.
Cancer arises from the accumulation of multiple mutations
in a single cell. The rate at which mutations occur is affected
not only by the rate at which they arise, but also by the efficiency with which errors are corrected by DNA-repair systems (see pp. 339–341 in Chapter 13). Defects in genes that
encode components of these repair systems have been consistently associated with a number of cancers. People with
xeroderma pigmentosum, for example, are defective in
nucleotide-excision repair, an important cellular repair system that normally corrects DNA damage caused by a
number of mutagens, including ultraviolet light. Likewise,
about 13% of colorectal, endometrial, and stomach cancers
have cells that are defective in mismatch repair, another
major repair system in the cell.
Genes That Regulate Telomerase
Another factor that may contribute to the progression of
cancer is the inappropriate activation of an enzyme called
telomerase. In germ cells, telomerase replicates the chromosome ends (see pp. 234–235 in Chapter 9), thereby maintaining the telomeres, but this enzyme is not normally expressed
in somatic cells. In many tumor cells, however, sequences
that regulate the expression of the telomerase gene are
mutated so that the enzyme is expressed, and the cell is capable of unlimited cell division. Although the expression of
telomerase appears to contribute to the development of
many cancers, its precise role in tumor progression is
unknown and is under investigation.
Genes That Promote Vascularization
and the Spread of Tumors
A final set of factors that contribute to the progression of
cancer includes genes that affect the growth and spread of
tumors. Oxygen and nutrients, which are essential to the survival and growth of tumors, are supplied by blood vessels,
and the growth of new blood vessels (angiogenesis) is important to tumor progression. Angiogenesis is stimulated by
growth factors and other proteins encoded by genes whose
expression is carefully regulated in normal cells. In tumor
cells, genes encoding these proteins are often overexpressed
compared with normal cells, and inhibitors of angiogenesispromoting factors may be inactivated or underexpressed. At
least one inherited cancer syndrome—van Hippel–Lindau
disease, in which people develop multiple types of tumors—
is caused by the mutation of a gene that affects angiogenesis.
In the development of many cancers, the primary tumor
gives rise to cells that spread to distant sites, producing secondary tumors. This process of metastasis is the cause of
death in 90% of human cancer cases; it is influenced by cellular changes induced by somatic mutation. As discussed in
the introduction to this chapter, the palladin gene, when
mutated, contributes to the metastasis of pancreatic tumors.
By using microarrays to measure levels of gene expression,
researchers have identified other genes that are transcribed at
a significantly higher rate in metastatic cells compared with
nonmetastatic cells. For example, one study detected a set of
95 genes that were overexpressed or underexpressed in a
population of metastatic breast cancer cells that were
strongly metastatic to the lung, compared with a population
of cells that were only weakly metastatic to the lung. Genes
that contribute to metastasis often encode components of
the extracellular matrix and the cytoskeleton. Others encode
adhesion proteins, which help hold cells together.
Mutations in genes that encode components of DNA-repair systems are often associated with cancer; these mutations increase
the rate at which mutations are retained and result in an increased
number of mutations in proto-oncogenes, tumor-suppressor
genes, and other genes that contribute to cell proliferation.
Mutations that allow telomerase to be expressed in somatic cells
and those that affect vascularization and metastasis also may contribute to cancer progression.
✔ Concept Check 3
Which type of mutation in telomerase could be associated with
a. Mutations that produce an inactive form of telomerase
b. Mutations that decrease the expression of telomerase
c. Mutations that increase the expression of telomerase
d. All of the above
15.3 Changes in Chromosome
Number and Structure
Are Often Associated
Most tumors contain cells with chromosome mutations. For
many years, geneticists argued about whether these chromosome mutations were the cause or the result of cancer. Some
types of tumors are consistently associated with specific chromosome mutations; for example, most cases of chronic
myelogenous leukemia are associated with a reciprocal
translocation between chromosomes 22 and 9. These types
of associations suggest that chromosome mutations contribute to the cause of the cancer. Yet many cancers are not
associated with specific types of chromosome abnormalities,
and individual gene mutations are now known to contribute
to many types of cancer. Nevertheless, chromosome instability is a general feature of cancer cells, causing them to accumulate chromosome mutations, which then affect individual
genes that may contribute to the cancer process. Thus, chromosome mutations appear to be both a cause and a result of
At least three types of chromosome rearrangements—
deletions, inversions, and translocations—are associated
with certain types of cancer. Deletions may result in the loss
of one or more tumor-suppressor genes. Inversions and
translocations contribute to cancer in several ways. First, the
chromosomal breakpoints that accompany these mutations
may lie within tumor-suppressor genes, disrupting their
function and leading to cell proliferation. Second, translocations and inversions may bring together sequences from two
different genes, generating a fused protein that stimulates
some aspect of the cancer process.
sequences that normally activate the production of
immunoglobulins, and c-MYC is expressed in B cells. The cMYC protein stimulates the division of the B cells and leads
to Burkitt lymphoma.
Many tumors contain a variety of types of chromosome mutations. Some tumors are associated with specific deletions, inversions, and translocations. Deletions can eliminate or inactivate
genes that control the cell cycle; inversions and translocations can
cause breaks in genes that suppress tumors, fuse genes to produce
cancer-causing proteins, or move genes to new locations, where
they are under the influence of different regulatory sequences.
✔ Concept Check 4
Chronic myelogenous leukemia is usually associated with which
type of chromosome rearrangement?
15.8 A reciprocal translocation between chromosomes 9
and 22 causes chronic myelogenous leukemia.
Fusion proteins are seen in most cases of chronic myelogenous leukemia, a form of leukemia affecting bone-marrow cells. As mentioned earlier, most patients with chronic
myelogenous leukemia have a reciprocal translocation
between the long arm of chromosome 22 and the tip of the
long arm of chromosome 9 (Figure 15.8). This translocation
produces a shortened chromosome 22, called the
Philadelphia chromosome, because it was first discovered in
Philadelphia. At the end of a normal chromosome 9 is a
potential cancer-causing gene called c-ABL. As a result of the
translocation, part of the c-ABL gene is fused with the BCR
gene from chromosome 22. The protein produced by this
BCR–c-ABL fusion gene is much more active than the protein produced by the normal c-ABL gene; the fusion protein
stimulates increased, unregulated cell division and eventually leads to leukemia.
A third mechanism by which chromosome rearrangements may produce cancer is by the transfer of a potential
cancer-causing gene to a new location, where it is activated
by different regulatory sequences. Burkitt lymphoma is a
cancer of the B cells, the lymphocytes that produce antibodies. Many people with Burkitt lymphoma possess a reciprocal translocation between chromosome 8 and chromosome
2, 14, or 22 (Figure 15.9). This translocation relocates a gene
called c-MYC from the tip of chromosome 8 to a position in
chromosome 2, 14, or 22 that is next to a gene that encodes
an immunoglobulin protein. At this new location, c-MYC, a
cancer-causing gene, comes under the control of regulatory
Most advanced tumors contain cells that exhibit a dramatic variety of chromosome anomalies, including extra
chromosomes, missing chromosomes, and chromosome
rearrangements (Figure 15.10). Some cancer researchers
believe that cancer is initiated when genetic changes take
15.9 A reciprocal translocation between chromosomes 8
and 14 causes Burkitt lymphoma.