Essential Cell Biology 5th edition

731
It turns out that APC regulates the activity of this pathway
by facilitating degradation of β-catenin and thereby
preventing it from activating TCF in cells where no Wnt
signal has been received (see Figure 20−54A). Loss of
APC allows the concentration of β-catenin to rise, so
that TCF is activated and Wnt-responsive genes are
turned on even in the absence of a Wnt signal. But how
does this promote the development of colorectal cancer?
To find out, researchers turned to mice that lack
TCF4, a member of the TCF gene family that is specifically
expressed in the gut epithelial lining.
Tales from the crypt
Although it may seem counterintuitive, one of the most
direct ways of finding out what a gene normally does is
to see what happens to the organism when that gene is
missing. If one can pinpoint the processes that are disrupted
or compromised, one can begin to decipher the
gene’s function.
With this in mind, researchers generated “knockout”
mice in which the gene encoding TCF4 was disrupted.
The mutation is lethal: mice lacking TCF4 die shortly
after birth. But the dying animals showed an interesting
abnormality in their intestines. The intestinal crypts,
which contain the stem cells responsible for the renewal
of the gut lining (see Figure 20–35), had completely
failed to develop. The researchers concluded that TCF4
is normally required for maintaining the pool of proliferating
gut stem cells.
When APC is missing, we see the other side of the coin:
without APC to promote its degradation, β-catenin
accumulates in excessive quantities, binds to the TCF4
transcription regulator, and thereby overactivates the
TCF4-responsive genes. This drives the formation of
polyps by promoting the inappropriate proliferation of
gut stem cells and precursor cells. Differentiated progeny
cells continue to be produced and discarded into the
gut lumen, but the crypt cell population grows too fast
for this disposal mechanism to keep pace. The result is
crypt enlargement and a steady increase in the number
of crypts. The growing mass of tissue bulges out into the
gut lumen as a polyp (see Figure 20–50 and Movie 20.9).
A number of additional mutations are needed, however,
to convert this benign tumor into an invasive cancer
(see Figure 20–51).
More than 60% of human colorectal tumors harbor
mutations in the APC gene. Interestingly, among the
minority class of tumors that retain functional APC,
about a quarter have activating mutations in β-catenin
instead. These mutations tend to make the β-catenin
protein more resistant to degradation and thus produce
the same effect as loss of APC. In fact, mutations that
enhance the activity of β-catenin have been found in a
wide variety of other tumor types, including melanomas,
stomach cancers, and liver cancers. Thus, the genes that
encode proteins that act in the Wnt signaling pathway
provide multiple targets for mutations that can spur the
development of cancer.
(A) WITHOUT Wnt SIGNAL
(B) WITH Wnt SIGNAL
Wnt protein
inactive
Wnt receptor
β-catenin
DEGRADATION
OF β-CATENIN
inactive TCF complex
Wnt-RESPONSIVE
GENES OFF
inactive signaling
protein
active APCcontaining
complex
DNA
active
Wnt receptor
active signaling
protein
inactive APCcontaining
complex
released stable β-catenin
active TCF complex
DNA
TRANSCRIPTION OF Wnt-
RESPONSIVE GENES, LEADING
TO PROLIFERATION OF GUT STEM
CELLS AND PRECURSOR CELLS
Figure 20–54 The APC protein keeps the
Wnt signaling pathway inactive when
the cell is not exposed to a secreted
Wnt signal protein. (A) It does this by
promoting degradation of the signaling
molecule β-catenin. (B) In the presence of
Wnt (or in the absence of active APC), free
β-catenin becomes plentiful and combines
with the transcription regulator TCF to
drive transcription of Wnt-responsive
genes and, ultimately, the proliferation
of stem cells and precursor cells in the
intestinal crypt (see Figure 20–39). In the
colon, mutations that inactivate APC
initiate tumors by causing excessive
activation of the Wnt signaling pathway.