Full transcript
0:05hello in this video we're going to talk
0:07about uncle genetics a mechanism of
0:11cancer from a gene point of view in
0:14order to understand this we have to
0:15learn again about the cell cycle so a
0:19normal cell can just be at rest this is
0:23at a quiescent phase the g0 phase the
0:26cell can then enter the cell cycle the
0:31first phase of the cell cycle is known
0:33as the g1 phase the growth phase this is
0:37where the cell's organelle duplicates so
0:39here you can see the mitochondria of the
0:42cell is duplicated after the growth one
0:45phase is the S phase also known as a
0:47synthesis phase this is when the DNA
0:50duplicates after the S phase there is a
0:54g2 phase where the cell essentially
0:57grows again the growth phase and
1:00prepares itself for the M phase the M
1:04phase is also known as mitosis where a
1:07cell which is now already essentially
1:11divides into two identical daughter
1:14cells these new cells can then re-enter
1:17the cell cycle or go back to the g0
1:20phase now the cell cycle is as it as it
1:26looks a continuous cycle however things
1:29can go wrong throughout the cell cycle
1:31and so it's important to have
1:33checkpoints to make sure that there are
1:34no problems along the way the first
1:37checkpoint is actually at the end of the
1:39g1 phase called the g1 checkpoint this
1:42is to make sure that there's no problems
1:44in the DNA and in the cell itself the
1:48second checkpoint is at the g2
1:50checkpoint this is to make sure that the
1:52cell has no problems before it enters
1:55mitosis and then there's another
1:56checkpoint at the M phase as well the
1:59cell cycle is a continuous progression
2:01from g1 s g2 and M but what actually
2:04drives the cell through the cell cycle
2:07well when a cell enters the cell cycle
2:10you will start making proteins
2:13allowing it to go and progress through
2:15the cell cycle these proteins are your
2:18cycling's and your cdks which are the
2:21drivers of the cell cycle so for example
2:24a cell wants to enter the cell cycle the
2:27cell will start producing proteins the
2:29CD carryin cycling's in the early g1
2:32phase cdk4 and six are produced and when
2:37cyclin D binds on to this it will cause
2:40a reaction to occur inside that cell it
2:43will cause e to F to detach from the
2:45retinoblastoma protein when e to F is
2:48released it acts like a transcription
2:50factor allowing that particular cell to
2:53progress through to the S phase however
2:56at the end of the g1 phase before the S
3:00phase there's also another CD k and
3:01cyclin CDK 2 and cyclin e once at the S
3:06phase the cell will produce another city
3:08kin cyclin CDK one and two and even
3:10cyclin Ain and then the g2 phase again
3:14cdk1 and cyclin b and these cdk and
3:18cycling's again will allow the cell to
3:20progress through the cell cycle so cdk
3:23and cycling's are the drivers of the
3:24cell cycle if you have two low amounts
3:28of cdk in cycling the cell doesn't
3:30really progress through the cell cycle
3:32but if you have too much cyclin CDK then
3:36you get these cells that continuously
3:38enter the cell cycle and thus you get
3:40this uncontrolled growth of cells and
3:42this is one of the mechanisms of cancer
3:45so what can potentially cause an
3:48increase in cdk in cycling within the
3:51cell
3:51so this is where genetic mutations come
3:54in so the mechanism of cancer genetic
3:57mutations so let's just look at this
4:00normal cell and pull out its genetic
4:03material which is DNA DNA is a double
4:06stranded helix made up of four types of
4:08nucleotides now mutations can occur
4:12within the DNA which will cause changes
4:15to that cell some types of mutations
4:18include point mutations a single change
4:21in the nucleotide another is what's
4:23called DNA amplification when a certain
4:26gene
4:26get amplified so many times it could be
4:28a badging for example then there's
4:31another one called chromosomal
4:32rearrangement where the chromosome
4:35basically attached to one another where
4:38where it shouldn't and another one is
4:40called epigenetic modifications such as
4:42methylation and acetylation of genes and
4:47this can is essentially silent certain
4:49genes and even cause genes to become
4:51more more active and so you can imagine
4:55with these mutations a normal cell can
4:57become a cancerous cell and so when they
5:00cell enter the cell cycle you get an
5:03uncontrolled cell growth it bypasses all
5:06the checkpoints you get uncontrolled
5:08cell growth and these uncontrolled cell
5:11growth is essentially caused by two main
5:14changes that occurs in cancer cell these
5:17are one activation of oncogenes such as
5:21the rash gene and your myc gene the
5:26other change is the inactivation of
5:29tumor suppressor genes such as
5:32inactivation of p53 APC and braca one
5:36and two so the mechanism of uncontrolled
5:41cell growth as we discussed the point
5:43mutations the gene amplification the
5:45chromosomal rearrangements the
5:47epigenetic modifications these
5:49mechanisms of uncontrolled cell growth
5:52essentially causes two main things in
5:56the cancer cell these are activation of
5:59oncogenes and inactivation of tumor
6:01suppressor genes so now let's look at
6:05each of these in a bit more detail
6:07beginning by looking at oncogenes first
6:11so let's begin by looking at uncle gene
6:14activation looking at the wrasse and myc
6:17gene as an example so let's look at this
6:20cell here that's about to enter the cell
6:23cycle at a g1 phase now normally
6:27normally our cell contains DNA and
6:30normally our cells contain a gene called
6:32the rass gene now the Rast gene makes
6:35the wrasse protein which basically is an
6:38intracellular protein that sits below
6:39the plasma membrane next to it is a
6:43receptor the growth factor receptor now
6:46obviously normally when a cell enter the
6:49cell cycle there needs there is a growth
6:52factor which stimulates the growth
6:54factor receptor when the growth factor
6:57is stimulated it will actually activate
6:59the Rast protein once the rest protein
7:02is activated it will cause a cascade of
7:04intracellular phosphorylation of other
7:07proteins which will essentially at the
7:10end activate a transcription factor once
7:13this transcription factor is activated
7:15it will essentially go to the DNA and
7:19read the genes to make proteins to make
7:23proteins for cell growth particularly to
7:26make proteins to allow this cell to go
7:29from the g1 phase to the S phase and
7:32these proteins are the cdk and cycling's
7:34we talked about so you can imagine what
7:37would happen if you have a mutation in
7:39the Rasch gene when you have a mutation
7:42the rest gene you are making actually
7:44Rast proteins which are already
7:45activated and so you get always this
7:48cascade of phosphorylation events and
7:50you always get the activation of these
7:52transcription factors and so you are
7:54overproducing
7:56at the end these proteins for cell
7:59growth such as the cyclins and cdks
8:02now the myc gene is another one the myc
8:06gene normally makes proteins in our body
8:10these proteins are important for cell
8:12growth cell survival and also cell
8:15activity and so when you have a mutation
8:18of the myc gene the cell becomes morte
8:21answers you get more cell growth more
8:23cell activity and
8:24or cell survival and so activation of
8:27these oncogenes activation of the regime
8:30and the myc gene for example will allow
8:33a cell to bypass the checkpoints of the
8:37cell cycle and will allow the cell to
8:40have an uncontrolled cell growth
8:44now normally the cell has a mechanism to
8:46stop any abnormal cells from progressing
8:49to the cell cycle this is where tumor
8:51suppressor genes come in so for example
8:54let's just say this cell gets held up at
8:56the g2 phase because it has an abnormal
9:00DNA it has a damaged DNA this cell that
9:04was stopped with the damaged DNA will
9:06not progress the cell cycle because it
9:07had it is abnormal it has a damaged DNA
9:10so now let's talk about how this
9:12happened let's talk about tumor
9:13suppressor genes normally focusing on
9:17p53 so let's zoom into this cell the
9:20cell contains damaged DNA when there's
9:23damaged DNA the cell produces p53
9:26proteins which can act like a
9:28transcription factor
9:32it will read the DNA and will actually
9:34make proteins it will make proteins for
9:37cell arrests such as p21
9:42what does p21 do well p21 is a protein
9:46that causes cell arrest it actually
9:49inhibits the cdk and cycling's and thus
9:53inhibits the drivers of the cell cycle
9:56so the cell cycle will not progressed
9:59p53 will also make proteins important
10:02for cell repair and so hopefully when
10:06the cell is arrested and the cell can
10:08repair itself it can repair the DNA the
10:13p53 protein will also make proteins
10:15important for apoptosis if the cell
10:17cannot repair itself it has to die
10:19because we don't want any abnormal cells
10:23so you can imagine now if you have
10:25inactivation of tumor suppressor genes
10:28such as inactivation of p53
10:33when you have inactivation of p53 you
10:36are not making proteins for sole arrest
10:38you're not making proteins for a cell
10:41repair you're not making proteins for
10:43apoptosis and so you have this cell that
10:45enters the cell cycle and can bypass the
10:48checkpoint and continuously grow and
10:50proliferate and so in summary the
10:52genetic changes that occur in cancer are
10:56the inactivation of the tumor suppressor
10:59genes and the activation of the
11:02oncogenes and so you have this cell that
11:05enters a cell cycle and came bypass the
11:07checkpoints and continuously grow and
11:09proliferate I hope this video was
11:11helpful thanks for watching
11:20you