Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO
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extracellular domain
of receptor
binding of growth factor
triggers intracellular signaling
Figure 20–19 Mutation of the epidermal
growth factor (EGF) receptor can make
it active even in the absence of EGF, and
consequently oncogenic. Only one of the
possible types of activating mutations is
illustrated here.
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cytoplasmic domain
of receptor
truncated receptor triggers
intracellular signaling in
absence of growth factor
mutation or deletion may produce a hyperactive protein when it occurs within a
protein-coding sequence, or lead to protein overproduction when it occurs within
a regulatory region for that gene. (2) Gene amplification events, such as those that
can be caused by errors in DNA replication, may produce extra gene copies; this
can lead to overproduction of the protein. (3) A chromosomal rearrangement—
involving the breakage and rejoining of the DNA helix—may either change the
protein-coding region, resulting in a hyperactive fusion protein, or alter the control
regions for a gene so that
MBoC6
a normal
n20.150/20.19
protein is overproduced.
As one example, the receptor for the extracellular signal protein epidermal
growth factor (EGF) can be activated by a deletion that removes part of its extracellular
domain, causing it to be active even in the absence of EGF (Figure 20–19). It
thus produces an inappropriate stimulatory signal, like a faulty doorbell that rings
even when nobody is pressing the button. Mutations of this type are frequently
found in the most common type of human brain tumor, called glioblastoma.
As another example, the Myc protein, which acts in the nucleus to stimulate
cell growth and division (see Chapter 17), generally contributes to cancer by
being overproduced in its normal form. In some cases, the gene is amplified—
that is, errors of DNA replication lead to the creation of large numbers of gene
copies in a single cell. Or a point mutation can stabilize the protein, which normally
turns over very rapidly. More commonly, the overproduction appears to
be due to a change in a regulatory element that acts on the gene. For example, a
chromosomal translocation can inappropriately bring powerful gene regulatory
sequences next to the Myc protein-coding sequence, so as to produce unusually
large amounts of Myc mRNA. Thus, in Burkitt’s lymphoma, a translocation brings
the Myc gene under the control of sequences that normally drive the expression of
antibody genes in B lymphocytes. As a result, the mutant B cells tend to proliferate
excessively and form a tumor. Different specific chromosome translocations are
common in other cancers.
Studies of Rare Hereditary Cancer Syndromes First Identified
Tumor Suppressor Genes
Identifying a gene that has been inactivated in the genome of a cancer cell requires
a different strategy from finding a gene that has become hyperactive: one cannot,
for example, use a cell transformation assay to identify something that simply is
not there. The key insight that led to the discovery of the first tumor suppressor
gene came from studies of a rare type of human cancer, retinoblastoma, which
arises from cells in the retina of the eye that are converted to a cancerous state by
an unusually small number of mutations. As often happens in biology, the discovery
arose from examination of a special case, but it turned out to reveal a gene of
widespread importance.
Retinoblastoma occurs in childhood, and tumors develop from neural precursor
cells in the immature retina. About one child in 20,000 is afflicted. One
form of the disease is hereditary, and the other is not. In the hereditary form,