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Summary SSA9 p53 and apoptosis
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Summary and WG answers of SSA9 p53 and apoptosis of the course MBO (molecular biology and oncology) at University of Leiden
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SSA9 p53 and apoptosisChapter 9 Weinberg
9.1 Papovaviruses lead to the discovery of p53
Large T is a multifunctional protein of the SV40 virus and it disturbs regulatory circuits of the
host cell. It can bind and thereby inactivate pRb but it can also do this with p53.
9.2 p53 is discovered to be a tumor suppressor gene
Co-transfection of functioning p53 cDNA clone with an oncogene can actually suppress the
transformation of cells. This indicates that p53 is a tumor suppressor gene. p53 is mutated in
30-50% of human cancers. However, p53 is not a typical tumor suppressor gene as p53-/-
embryos do not seem to have any problems with cell proliferation. It is thus not simply an
negative regulator of proliferation.
9.3 Mutant versions of p53 interfere with normal p53
function
The p53 gene did not seem to obey Knudson's scheme
for the two-hit elimination of tumor suppressor genes. A
mutant version can alter the behavior of the wild type
version. The mutations in the p53 allele dus have some
type of dominant function. Many of the mutations seen in
human cancer are actually point mutations in the reading
frame that lead to missense instead of nonsense codons
and therefore the mutated protein is still produced. It
creates a dominant-negative/interfering allele instead of a
null allele.
p53 is a nucleus protein that normally exists as a
homotetramer. This configuration also explains the dominant-negative effect of the mutated
allele. 15 out of the 16 combinations would actually carry one or more mutant type of p53.
Consequently only 1 in 16 has full normal function. Experiments in which they played with the
promotors of wild type and mutant alleles confirmed this hypothesis. Mutations that lead to
such a dominant-negative allele are much more useful for a tumor than mutations that result
in null alleles. Often the second mutation is a LOH which leaves a cell with only the altered
version of p53.
9.4 p53 protein molecules usually have short lifetimes
There are three mechanisms known to regulate activity of transcription factors:
1. Concentration in the nucleus
2. Concentration is constant, but their intrinsic activity is boosted by a covalent
modification
3. Levels of collaborating TFs can be modulated
In the case of p53, the changes in level in the nucleus is the most important. It is a
metabolically unstable protein. This was investigated with experiments using cycloheximide
which is a drug that blocks protein synthesis. The p53 half-life time is only 20 minutes. This
pattern of synthesis followed by rapid degradation is a futile cycle which is actually quite
wasteful for a cell. However, there is a logical reason behind this as the cell needs to be able
to very rapidly modulate the levels of p53. If then first transcription would need to be
, activated, it would take too long. Normal healthy cells have a steady state of p53 levels in
which as much is produced as is being degraded.
9.5 A variety of signals can cause p53 induction
Signals can lead to stabilization of the normally labile
p53 protein which causes its levels to rise as the rate of
degradation stays more or less the same. Signals that
can have such effects have mainly to do with mutations
or problems with replication, hypoxia and abnormal
oncogene signaling. The same genotoxic agents that
cause the increase in p53 levels were also already
known to work cytostatic; arresting the cell
cycle/growth. It was later shown that increase in p53
was causing this. This was demonstrated in an
experiment in which they radiated cells and looked at
the viability of cells. The viability seemed to increase if
there was one mutant p53 allele and was almost 100% when both alleles were defective. p53
thus has cytostatic and pro-apoptotic powers.
p53 is induced by multiple stresses like hypoxia, genomic damage and imbalances in
signaling pathways. All of these stresses occur in tumor cells so this explains why many
tumor cells have to shut down p53 in order to survive.
9.6 DNA damage and deregulated growth signals cause p53
stabilization
A dsDNA break anywhere in the genome is sufficient to induce significant increase in p53
levels. Sensors of dsDNA breaks transfer signals to ATM kinase which then transfers a
signal to Chk2 kinase which is able to phosphorylate p53. This phosphorylation causes p53
to be protected from degradation by a protein called Mdm2.
Another pathway is activated by ssDNA breaks
which stall replication forks. ssDNA sensors
activate ATR kinase which acts via Chk1 to
phosphorylate p53.
A third pathway is when there are aberrant growth
signals which result in deregulation of the pRb-E2F
cell cycle control pathway. This does not depend
on an intermediate kinase.
The fact that p53 is central in three major
pathways indicates its vulnerability. By inactivating
only one gene, a cell now is blind to many defects
and can now proliferate under circumstances that
normally cause halt of proliferation or even
apoptosis. Loss of the DNA repair and genome
stabilizing functions that are promoted by p53, a
cell also becomes more likely to acquire more and
more mutations that are in favor of malignant
transformation.
Hyperactive p53 can actually cause premature ageing as it leads to too many cell death. UV
light can cause cross-links in the DNA which lead to increase in p53 levels. However, the UV
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