So we know we have a lot of skin cells. However, what happens if a single skin cell becomes cancerous? Well, if a single cell becomes cancerous, then it starts to divide uncontrollably. And now that it's dividing uncontrollably, it can lead to a tumor which can lead to cancer.
So how exactly does this happen? How does a cell become cancerous and start to divide uncontrollably? Well, to understand this, let's focus on a single cell.
So we have our cell with our nucleus and our genome. And we know we get half of our genes from dad, and we get half of our genes from mom, and we get 23 pairs of these chromosomes. But for simplicity, let's say this represents the chromosomes we get from dad, and let's say this represents the chromosomes we get from mom.
So in our genome, there are two important types of genes. There are proto-oncogenes, and there are tumor suppressor genes. And these genes that we have in our genome are related to cancer. For example, if we get mutations in our proto-oncogenes, that can lead to cancer.
If we get mutations in these tumor suppressor genes, that can also lead to cancer. So how exactly does this happen? Well, first let's focus on the proto-oncogenes. So if we get mutations in these proto-oncogenes, what happens is these oncogenes encode proteins that promote the cell cycle.
So that's what proto-oncogenes are. They create proteins that promote the cell cycle. So let's do an example.
So again, let's say this is a chromosome we get from dad, and this is a chromosome we get from mom, and we know... every gene we get two copies of. We get one copy from dad and one copy from mom. But let's say this part of the chromosome encodes a proto-oncogene.
So again, let's say it encodes these proto-oncogenes. And let's say these particular proto-oncogenes happen to encode some kind of receptor protein. So again, it creates these receptor proteins. So let's say this proto-oncogene from the chromosome we get from mom created this particular receptor protein.
What's going to happen? How does this receptor protein work? Well, normally what happens is it binds a growth factor. And once this growth factor binds to this receptor, then this receptor goes through a conformational change, where this cytosolic tail goes through a conformational change, where now it can react with a protein. So now it activates this protein, which activates another protein, which activates another protein, which activates a transcription factor.
Now, once this transcription factor is activated, now it can turn on genes that promote the cell cycle. and now the cell starts to divide. So this makes sense. A growth factor binds.
Now it promotes growth. Now the cell starts to divide, and now it can start to divide. So that makes sense. And this is a way the cell only divides if it binds a growth factor.
If the growth factor binds, then the signal transduction cascade activates the transcription factor, which turns on these genes, and now the cell divides. However, what happens if maybe the chromosome, just let's arbitrarily, let's say the chromosome we get from dad. Let's say we happen to get a mutation in this proto-oncogene. So now we have a mutation.
Now it's going to create a faulty protein. Now it's going to create a faulty receptor. So now we have a mutation.
So we create a faulty receptor. And let's say this faulty receptor we created happens to be constantly activated. So again, the receptor we created for, so again, the chromosome we get from mom was normal. It was non-mutated.
So it created a normal receptor, which was only activated when it binded a growth factor. However, we get a mutation in the chromosome we get from dad. So now it creates this receptor that's faulty and which is constantly activated.
So maybe it's constantly activated. It might, maybe the cytosolic tail, it's constantly activated. So now what's going to happen? Well, now it's going to constantly activate this signal transduction cascade, which is going to constantly activate this transcription factor.
which is going to turn on genes that are going to promote the cell cycle. So now the cell is going to constantly divide. And now the cell cycle is constantly activated. Because again, because we had this mutation in this proto-oncogene, which created this faulty receptor, which is always activated.
So therefore, the cell is going to constantly divide, and that can lead to cancer. So again, remember, the way this normally works is normally... If the chromosome is normal, for example, let's say the chromosome we get from mom happened to be normal, then it would create a normal receptor. So normally what happens is only if the growth factor binds, then the cell divides.
So that's normally the way things work. But if we, unfortunately, for example, maybe the chromosome we get from dad happened to have a mutation in this proto-oncogene, now creates a faulty receptor that's constantly activated. So now it's constantly activated.
Now it's constantly activating the signal transduction cascade. And now the cell's constantly dividing. So even though the chromosome we got from mom was normal, all we needed was one bad copy to create these receptor proteins that are constantly activated.
Now the cell's going to constantly divide and that can lead to cancer. In just a little terminology, when the proto-oncogene is non-mutated, it's referred to as a proto-oncogene. However, if it becomes mutated, It turns into, we call it an oncogene, and now it creates this protein that's constantly activated and constantly promotes the cell cycle.
And we refer to this as the one-hit hypothesis, because we only needed one of our copies to get mutated. That's all you need. You only need one of the copies to get mutated.
So now it creates these receptors that are constantly activated. Now the cell constantly divides, and now that leads to cancer. So now let's talk about tumor suppressor genes. So again, so essentially...
tumor suppressor genes create proteins that are constantly preventing the cell from dividing. So it's blocking the cell cycle, blocking the cell from dividing. So for example, again, we know we get a chromosome from dad and chromosome from mom. And let's say this part of the chromosome happened to encode a tumor suppressor gene.
So for example, the most common and famous tumor suppressor gene is p53. So let's say this part of the genome encodes this p53 tumor suppressor gene. So what does p53 do?
Well, it's a transcription factor. So it's going to turn on genes. It's going to turn on genes.
And let's say specifically, so again, it's a transcription factor. So it's going to turn on genes. And let's say P53 specifically turns on and activates the transcription of this P21 gene.
So again, so P53, this tumor suppressor gene, essentially is a transcription factor that promotes the transcription of this P21 gene, a protein. So this P21 protein, now inhibits cyclin-dependent kinases. So when it inhibits cyclin-dependent kinases, that inhibits the cell cycle, now blocks the cell cycle. So I know this is a little complicating. There's a lot going on.
But to simplify it, again, we get chromosome from dad, chromosome from mom, and let's say this part of the chromosome encodes this tumor suppressor gene, this p53. And again, for simplicity, let's just say this p53, when it's activated, it blocks the cell cycle. It prevents, it inhibits the cell cycle.
So I like to think of this p53 as a downer. When it's activated, it's constantly stopping and blocking the cell cycle. So now this p53 is activated, it's blocking the cell cycle, now the cell isn't dividing. But what happens is when this p53 is inactivated, now it can't block the cell cycle, so now the cell cycle can go uninhibited, and now the cell divides. So again, I know it's a little complicated, but the point is when p53 is activated, it blocks the cell cycle.
When it's inhibited... it can't block the cell cycle. So now the cell can divide uninhibited.
So when it's inactivated, now the cell can divide. But so normally what happens is what happens if we have a lot of DNA damage? Well, if we have a lot of DNA damage, we should not divide it. Because if we have a lot of DNA damage and a lot of mutations, we should not divide.
We shouldn't divide and replicate these damaged genomes to create new damaged cells. So if we have a lot of DNA damage, we should not divide. We should not go through the cell cycle and we should not divide and create and replicate this genome and create new cells. So that makes sense.
So normally what happens is if we have a lot of DNA damage, essentially a protein senses that DNA damage, which essentially what happens is then it activates p53. And when it activates p53, now that stops the cell cycle. So this makes sense.
If we have a lot of DNA damage, we should activate p53 and we should stop the cell cycle. We should not divide and create new cells. Cause again, if we have a lot of DNA damage, we don't want to divide.
We don't want to divide and create new cells with DNA damage. So therefore, if we have a lot of DNA damage, we should stop the cell cycle. So we do this through p53. A lot of DNA damage, we activate p53, and when p53 is activated, it stops the cell cycle.
However... what happens is maybe now arbitrarily, let's say the chromosome we get from mom, let's say it happened to have a mutation in this p53 gene. So now it creates a mutated p53.
What's going to happen with this mutated p53? Well, maybe this mutated p53 is constantly inactivated. So again, we had a mutation from the chromosome from mom, maybe we had a mutation in this p53 gene.
So now we create a faulty p53 protein that's constantly inactivated. So if it's constantly inactivated, what's going to happen? Well now, even if we have DNA damage, even if we have DNA damage, normally what happens is DNA damage activates p53 and stops the cell from dividing. However, if we have a mutation and this p53 is constantly inactivated, now if it's inactivated, even if we have DNA damage, it's not going to be able to stop the cell cycle.
So that's bad. This mutation in this p53, now this p53 is inactivated. Now it can't stop the cell cycle when we need to stop it.
So that's dangerous. So now the cell can divide. Even if this is inactivated, now even if we have DNA damage, the cell cycle can continue to divide and the cell can continue to divide.
However, fortunately, what happens is, remember, we have a backup copy. We get the chromosome from dad. And let's say the chromosome from dad happens. create normal p53 what so now so again even if we have a mutation in the chromosome we get for mom which has inactivated p53 we have a backup copy and maybe this one we get from dad is normal it's non-mutated so this is going to create a normal p53 so if it creates a normal p53 what's going to happen now if we have dna damage it's going to activate the p53 and it's going to stop the cell cycle which is good so we need this p53 to be active well we need functioning p53 to stop the cell cycle when we have dna damage however but so fortunately because we have two copies even though the copy from mom was mutated and it created inactive p53 we had a backup copy from dad which was activated so now dna damage can stop the cell cycle now the cell won't divide and it won't lead to cancer however what if Very unfortunately, what if both copies happen to be mutated?
So the chromosome from dad and the chromosome from mom happen to have mutated genes for this p53. Now they're both gonna create inactivated p53. And now we're screwed.
Now we're out of luck. If both p53 copies are inactivated, now let's say they're both inactivated and let's say we have a lot of DNA damage. Unfortunately, the cell is going to still divide. It's going to still divide to create new cells with DNA damage and that can lead to cancer.
Because again, it's this p53 that senses the DNA damage, and when it senses the DNA damage, it stops the cell cycle, and it stops the cell from becoming cancerous. However, if both copies are mutated, now we're screwed. Now, even if we have DNA damage, we have no means to stop the cell cycle, and therefore the cell is going to divide uncontrollably and can lead to cancer.
So again, this is referred to as the two-hit hypothesis. So for these tumor suppressor genes, we need two hits. We need a mutation on both dad and mom to lead to cancer. Remember, that's different from proto-oncogenes. So these proto-oncogenes, you just needed one hit.
You just needed one of them. And again, we explained that with the receptor. So with tumor suppressor genes, we have the two-hit hypothesis where both copies from mom and dad, both have to be mutated to lead to cancer. However, with proto-oncogenes, it's the one-hit hypothesis where only one of them, only one of them, either from dad or from mom, only one of the copies need to be mutated, and that's sufficient to lead to cancer.