Voiceover: Tumor suppressor genes are those genes
whose protein products either have
a halting effect on the regulation of the cell cycle,
or they can also promote apoptosis, or sometimes both.
So in other words these proteins are like big stop signs
that act as safety checks
to help stop the mistakes in cell division
that can lead to uncontrolled cell growth and cancer.
Now there are several sort of categories
of tumor suppressor proteins.
Those that recognize DNA damage
and either repair it or initiate program cell death,
apoptosis if it can't be repaired, so DNA repair proteins.
Then there are those proteins
that act as repressors of genes
that are essential for the continuation of the cell cycle.
So if these genes are actively repressed,
and thus not expressed, the cell cycle does not continue on.
So you have cell cycle repressors.
With tumor suppressors there is this concept
called the "Two-Hit Hypothesis."
In which both alleles,
and remember that alleles are basically the copies
for a certain gene.
And you have two copies for any given gene.
One on the chromosome you got from your mom.
And one on the chromosome you got from your dad.
Now in the Two-Hit Hypothesis
both alleles must be mutated before
the effect is manifested.
Because if only one of the alleles for the gene is damaged.
Then you have this, sort of backup second copy,
that can still produce the protective protein.
So you need two hits.
One hit for each of the alleles that you have.
Another way that you can think of this is that
in mutated oncogenes
these alleles are typically dominant.
So a mutation only one of the alleles
yields the cancerous phenotype.
But with a mutated tumor suppressor allele
these mutations are recessive.
Because both alleles must be mutated
in order to lead to the cancerous phenotype.
The Two-Hit Hypothesis was first proposed
with cases of Retinoblastoma.
Rapidly developing cancer that originates
from the immature cells of the retina.
The light detecting tissue of your eye.
And I'll write this as pRb
for Retinoblastoma protein.
Now the Retinoblastoma protein
prevents the cell from replicating
when its DNA is damaged.
And it does this by preventing progression
of the cell cycle from G1
into the S phase or synthesis phase.
So the Retinoblastoma protein binds
and inhibits transcription factors.
Which normally push the cell into the S phase.
And this complex acts as a growth suppressor
and so the cell remains in the G1 phase.
This complex also attracts
a histone deacetylase protein to the chromatin.
Which reduces transcription of S phase promoting factors.
And you can remember this by recalling
that histone deacetylase
leads to chromatin condensation.
Or transcriptionally inactive chromatin.
So this also further suppresses DNA synthesis.
Another very well known
tumor suppressor protein is the p53 protein.
Homozygous loss of this protein
is found in up to 65% of colon cancers,
50% of lung cancers, and also in breast cancers.
So this is clearly a very critical tumor suppressor protein.
And so p53 activates DNA repair proteins
when DNA has sustained damage.
And it can also arrest growth
by holding the cell cycle hostage,
if you will, at the G1 to S regulation point.
And this gives DNA repair proteins
some time to fix the damage
and allow for continuation of the cell cycle.
So specifically p53 binds DNA and activates several genes
including ones that code for protein called p21,
whichs binds the cyclin-CDK
or cyclin-dependent kinase complex,
which is actually the complex responsible
for pushing the cell from the G1 to S phase
in the cell cycle.
P53 also functions in the initiation of apoptosis
if the damage to DNA is irreparable.
One significant exception to the Two-Hit rule
for tumor suppressor genes
is with certain mutations of the p53 gene product.
Which can then result
in what is called a "Dominant Negative."
Meaning that a mutated p53 protein
can prevent the protein product
of the normal allele from functioning.
So don't forget to sort of
keep that in the back of your mind
when you're thinking about tumor suppressor genes.