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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(A) overactivity mutation (gain of function)
normal cell
normal cell
mutation
event
inactivates
tumor
suppressor
gene
single mutation event
creates oncogene
(B) underactivity mutation (loss of function)
no effect of
mutation in one
gene copy
second
mutation
event
inactivates
second gene
copy
activating mutation
enables oncogene to
promote cell transformation
two inactivating mutations
functionally eliminate the
tumor suppressor gene,
promoting cell transformation
cells
en route to
cancer
Figure 20–17 Cancer-critical mutations
fall into two readily distinguishable
categories, dominant and recessive.
In this diagram, activating mutations
are represented by solid red boxes,
inactivating mutations by hollow red
boxes. (A) Oncogenes act in a dominant
manner: a gain-of-function mutation in a
single copy of the cancer-critical gene can
drive a cell toward cancer. (B) Mutations
in tumor suppressor genes, on the other
hand, generally act in a recessive manner:
the function of both alleles of the cancercritical
gene must be lost to drive a cell
toward cancer. Although in this diagram
the second allele of the tumor suppressor
gene is inactivated by mutation, it is often
inactivated instead by loss of the second
chromosome. Not shown is the fact that
mutation of some tumor suppressor genes
can have an effect even when only one of
the two gene copies is damaged.
We begin by discussing some examples of each class of cancer-critical genes
to illustrate basic principles. These examples are chosen also for their historical
importance: the experiments that led to their discovery—at different times and by
MBoC6 m20.27/20.17
different methods—marked turning points in the understanding of cancer.
Retroviruses Can Act as Vectors for Oncogenes That Alter Cell
Behavior
The search for the genetic causes of human cancer took a devious route, beginning
with clues that came from the study of tumor viruses. Although viruses are
involved only in a minority of human cancers, a set of viruses that infect animals
provided critical early tools for studying cancer.
One of the first animal viruses to be implicated in cancer was discovered over
100 years ago in chickens, when an infectious agent that causes connective-tissue
tumors, or sarcomas, was characterized as a virus—the Rous sarcoma virus. Like
all the other RNA tumor viruses discovered since, it is a retrovirus. When it infects
a cell, its RNA genome is copied into DNA by reverse transcription, and the DNA
is inserted into the host genome, where it can persist and be inherited by subsequent
generations of cells. Something in the DNA inserted by the Rous sarcoma
virus made the host cells cancerous, but what was it? The answer was a surprise.
It turned out to be a piece of DNA that was unnecessary for the virus’s own survival
or reproduction; instead, it was a passenger, a gene called v-Src, that the virus
had picked up on its travels. v-Src was unmistakably similar, but not identical, to a
gene—c-Src—that was discovered in the normal vertebrate genome. c-Src had evidently
been caught up accidentally by the retrovirus from the genome of a previously
infected host cell, and it had undergone mutation in the process to become
an oncogene (v-Src).
This Nobel Prize-winning finding was followed by a flood of discoveries of
other viral oncogenes carried by retroviruses that cause cancer in nonhuman animals.
Each such oncogene turned out to have a counterpart proto-oncogene in
the normal vertebrate genome. As was the case for Src, these other oncogenes
generally differed from their normal counterparts, either in structure or in level of
expression. But how did this relate to typical human cancers, most of which are
not infectious and in which retroviruses play no part?