okay so welcome to this next video in which we're discussing the uh Vogal steam model of colorl uh carinoma so at the moment what I'm doing is I'm discussing the pathway in which K is involved so that we can understand why a gain of function mutation in K Ras is going to cause an increase in uh the uh proliferation of the cell basically okay so so far what we have seen is that AAS is activated by having a GTP bound to it rather than a GDP and uh it's activated upon uh the cell being stimulated
by growth factor uh and well growth factors and when it's activated it activates the BFF um kise and BFF then um phosphor relates the mech um protein um and when Mech is phosphorated ated it becomes an active chinise as well and it phosphates the nitrogen activated protein chinise or the map kyes which we will have not in blue we'll have it in this green color this turquoise color all right okay so here we go so this denotes the map kisee or the mitogen activated protein kisee which has a bunch of names actually so we'll go
over some of these names because they're very confusing how many names it has so it's often referred to as map kise uh map kise is what people usually call it uh some people will refer to it as mapk especially when they're writing its name down on a piece of paper in four its name is the mitogen activated protein kise the mitogen activated protein kise okay and there's another name uh that can also give the same initials basically so mitogen activated protein chinise is one reason it's called the map kise but in fact another reason that
it's called that is that it can also stand for the microt tuu associated protein kisee so this is the microtubular associated protein cyas okay so they're the same protein basically don't get it confused protein kise and then finally another name that this enzyme can all be given all the same uh all the same referring to the same protein but different names is it can also be referred to as irk which stands for the extra cellular signal regulated kise extracellular signal regulated kise Okay so so it's got a lot of names which can all be used
for this same protein and that's part of what I think makes people find this pathway confusing because if you type it in on Google and get up these pictures of these flowcharts you will see loads of different flowcharts and they're all calling these same enzymes different names and it's like what um which one's right basically are they referring to different Pathways and no they're just using different names for the same things right okay so let's have a look now at what this map kyes enzyme does once it's active well one of the first things it
does it does two important things actually so we'll refer to both of these okay uh so it's going to activate two transcription factors by phosphor them so one of the important transcription factors it's going to activate is a mick transcription Factor so it's going to phosphorate and activate mck transcription factors now mck has a very grandiose title it's often called the cell's most powerful mitogen so it's very PR growth basically okay and another transcription factor which it phosphates and activates is a transcription Factor known as elk one okay right so this is Elk one being
phosphorated and activated now I'm going to discuss elk one first first because elk one is going to actually isn't actually itself going to directly increase uh the growth of the cell instead what it's going to do is increase the transcription of another transcription factor which is then going to increase the growth of the cell so what we'll do is we'll look at that other transcription factor and then we'll Recon converge it with Mick because both um Mick and this other transcription Factor are going to increase growth so basically what elk one is going to do
is it's going to go and bind to the promoter region of a certain Gene and increase the expression of that Gene basically so increase the probability that uh the RNA polymerase enzyme is going to stick to well binds to that Gene uh bind to that promoter region and then uh transcribe the gene okay so let's say this is the gene for seos okay seos Gene here okay right let me color it in a certain color we'll have it in Orange I think so here's the seos gene in Orange and now let's have the promoter region
for the SE Force Gene just Upstream of the seos Gene and we'll have that in pink okay so basically elk one is going to go and bind to the promoter region of this caos Gene and increase the transcription of that caos Gene so you'll therefore get more mRNA for this caos Gene and therefore you will turn that mRNA into polypeptide and you'll overall get more seos out okay so seos level is going to go up now seos alone is not actually a transcription Factor but it can dimerize with another um another transcription Factor well uh
A protein that by itself actually is a transcription factor and the together the two of them can become a another transcription Factor so seos on its own is not capable of being a trans um a transcription Factor what it needs to do is it needs to dimerize with another protein called cjun and basically when it binds to C Jun and you form this fos Jun dier so let's show them together so here is uh C Jun and C together this is cjun with C basically uh this C Jun fce hetro or just Jun fce hetro
uh this is basically a very powerful transcription factor which is pro growth so it's going to help move the cell from the interphase into the um into the G1 phase of the cell cycle okay right so there's seos in this turquoise color and then we'll have SE Jun in this purple color so this is C Jun right okay so together they are a very powerful transcription factor which is pro growth and see and Mick up here is does the same basically so through these two pathways through uh Jun F hetro diers and also through Mick
what you are going to get basically is the growth of this cell so that's draw those two Pathways converging like so so it's going to cause a division of the cell it's going to take the cell from the interphase into the first growth phase um of the cell cycle so you're going to begin the cell cycle basically okay so that's the um map kyes irk pathway so what were we originally talking about in the Vogal steam model of chorl carcinoma we were talking about um getting uh gain ofun mutations in this protein Kass over here
so basically again just like all genes in the body you have two genes coding for K Ras okay so let's show them here right so um these are the two Kass genes let's say this is a k Gene and this is a k Gene now we want to increase the function of K now if the function of Kass goes up it will continue to activate b b will then activate Mech Mech will then activate the mitogen activated protein kinase or the map kinase and the map map kise will activate Mick and uh junos heterodimers which
will then cause the cell to go from the interphase to the G1 phase of the cell cycle so will cause the cell to divide so if we increase the function of uh this KZ um protein we're going to get over division of the cell basically now you need to increase the function of the K Ras uh protein so you're doing something very different from last time last time we wanted to completely remove the function of K this time you only need to increase it so do you need a mutation in both genes absolutely not you
only need a potentially a mutation in just one one of them so one Gene needs to get a gain of function mutation okay which will mean that overall you uh the activity of this kayas is increased now what sort of mutations uh can cause a gain of function in K or potentially you could get amplification of the gene so if you um somehow managed to um copy your Gene so that you had an ex ex ra one maybe let's say you put in another one next to it maybe so you then ended up with three
of these genes then uh you would make too much K and that would give you a too high function of K or you could have some sort of mutation that means that once it's uh got GTP bound to it it doesn't actually ever remove the GTP that would be another way so you could actually have some mutation that means that it's permanently activated so mutation that alters the function of the actual protein that you're making um so um another example would be one that doesn't need GTP to be bound to it in order to be
active um what other examples or you could could get a mutation in the promoter which means that you just produce far too much of it so the promoter gets too higher affinity for RNA polymerase and then you transcribe the gene too much create too much mRNA create too much protein so there are lots of different ways you can get a gain of function mutation in a protein uh whatever the mechanism kras function goes up so you get a gain of function mutation in just one of the genes of Kass and this is what's important that
for this sort of a protein to get over proliferation to for it to have an effect you only need a mutation in one of the genes and the mutation you need is a gain of function that means that K is what's known as a not a tumor pressive Gene a Proto onco Gene okay so a Proto onco Gene is any Gene within the human genome which if you get a gain of function mutation in that Gene will lead to oncogenesis will lead to the development of cancer it makes you more likely to get cancer okay
and indeed once it gets that mutation for instance let say this Gene has got to G of function mutation it then becomes known as an onco Gene so a protooncogene becomes known as an enco Gene when it has actually suffered a gain of function mutation and is now driving cancer so K once it's undergone this gain of function mutation is an enco Gene now contrast that to what we saw before with these APC genes where you needed to get losss of function of both of the genes in order to actually get um onco Genesis that
means that ABC stops you from getting cancer and you have to lose it in order to get cancer so it is what is known as a tumor suppressor Gene okay so that's an important concept so um we've seen that uh so far an example of a tumor suppressor Gene and now uh we're having a mutation in a Proto onco Gene leading to it becoming an enco Gene so we've got a gain of function of K Ras what is that going to cause it's going to cause the cell to overd divide and we'll continue this discussion
in the next video
