all right welcome back so the second video lecture right here says compare and contrast how uncle gene activation in tumor suppressor deactivation can lead to cancer okay so inherent in this is there's two classes of genes that are associated with cancer so if you remember from the last video of course you wrote everything down right last video I told you that about five to ten percent of genes in the human genome could contribute to cancer if they were mutated so five to ten percent of genes in the human genome fall into these two classes they either proto oncogenes or they are tumor suppressor genes so two classes of genes that exist that are normal physiologically normal genes in the human genome called proto oncogenes and tumor suppressor genes okay and a proto-oncogene is a gene that advances the cell cycle that makes the cell divide and that if and so because it can do that because it makes cells to bite or it makes cells move around whatever it might be because of that their expression has to be highly controlled we can't just let them go Wow and it is when the loss of this control is when we lose control of these kind of genes that a proto-oncogene is activated to an oncogene so the proto-oncogene is the normal unmutated version and uncle gene activation means that a mutation turns this into a gain of function mutation so mutation changes this from highly controlled to gone rogue okay so that's the idea of uncle gene activation tumor suppressor loss is the opposite of tumor suppressor deactivation is the opposite a tumor suppressor gene is supposed to halt descent cell cycle is supposed to provide checks and balances in the cellular physiology it's supposed to not make a cell move to make a cell stationary it's supposed to make a cell die if necessary it's supposed to make a cell fix its DNA if there are breaks if there's any kind of DNA damage so any kind of DNA repair enzymes and there's a lot of them a lot of enzymes involved in the repair of breaks or nicks or mutations all of these would be considered tumor suppressor genes why because if you lose them if you lose the ability to repair your DNA guess what you might accumulate mutations and guess what that could do lead to cancer so because that counteracts this any kind of DNA repair mechanism would be considered a tumor suppressor gene and so again these have to be activated loss of function mutations occur in tumor suppressor genes so here's sort of the cartoon and here's a single cell that's part of a normal epithelium so by the way a cancer aceptas again I said it's yesterday but I'll be reiterated a cancer of the epithelial layer which is most cancers occur in the epithelial layer it would be considered a carcinoma if this was if this layer of cells right here was part of the duct of a breast it would be a ductal carcinoma that we see right here alright and so so this cell might accumulate a mutation and this mutation gives it a slight growth advantage right so now it can divide ever so slightly faster than the neighboring cells so there's more copies that are made of this red cell right here that we have in this tissue in this sheet of cells now then we might have to get a second mutation the cell might even get a bigger growth advantage and so now more and more of these cells accumulate maybe a third mutation more and more and so again these mutations right here can be either oncogene activation events or can be tumor our losses but the more of them accumulate the more likely we're gonna get into a tumor which as you can see right here has become invasive and is again invading neighboring tissues on its way to metastasize into other parts of the body breaking through this layer right here called the basal lamina the membrane onto which to feel yourself are attached okay so uncle genes and tumor suppressors if I always use this example for teaching if you think about a car you accelerator of the car would be a good analogy for a proto-oncogene it's important to drive to call forward so without it it wouldn't work cells needed abide so but it has to be highly controlled as long as you normally control your accelerator your car's a okay it's when you lose control of it if your accelerator got stuck inappropriately now you're in trouble that's a gain-of-function activation activating mutation then your tumor cell in the same analogy tumor suppressor genes would be your brakes all right and so if you lose your brakes right as long as you have normal brakes even if the car goes forward you can bring the car to a halt that's its job that's their job the brakes right but if you lose your brakes somebody cut the cables now you're lost you'll run out of control and the important part of this analogy is in order to be in real trouble it takes both it takes the stuck accelerator the car indiscriminantly lurching forward and you don't have the ability to stop it by a brakes that's when we're in trouble so by the time you get to this state right here we have multiple tumor suppressor genes that are lost and multiple proto oncogenes that have been turned into oncogenes via mutations alright so hopefully there's a lot less work for you and then and only then do we get this malignant invasive phenotype all right so classification oncogenes I actually copied and pasted this from a book I quite like this the way this is broken down so to classified in society type of genes oncogenes proto-oncogenes are the normal versions they promote cell survival or proliferation and here's examples of them so anything that is anti-apoptotic so survival factors that help the cell survive any kind of factors that drive the cell cycle forward transcription factors that let you express genes you name it we'll talk about a lot of these as we go forward and those will be examples of normal proto-oncogenes they need to be there right any kind of growth factor growth factor receptors that help cells grow and divide they need to be there but when they're mutated and they have gone rogue then we are in trouble okay and so this requires only a single mutation so these mutations tend to be genetically speaking dominant meaning a single mutation it doesn't really matter if this is an accelerator which still responds to your gas pedal if your second accelerator is stuck in the gas engine the engine it's full gas when you go forward you're still going to be in trouble so the attending mutations tend to be dominant because it only takes a single hit a single mutation to turn a proto-oncogene into an oncogene that gives the cell a survival or growth advantage so at the end of the day we get excessive cell survival and proliferation by a single mutation and that's a proto-oncogene go into an oncogene becoming an oncogene and here's some of the here's the mutations that could be point mutations chromosomal rearrangements where but chromosomes are broken and stitched together and this example of amplification and I want to say a little bit more about that because it's a little bit less intuitive again amplification means that even though the gene is not mute the DNA copy is a-okay you have additional copies when there shouldn't be any and if one or two copies give you a normal growth if you have 17 copies you now gain this survival and growth advantage this excessive survival and growth advantage that shouldn't be there and because I told I told you about her to yesterday and breast cancer I'll bring it back to that again I try to tie things in as we go to be this video lecture so her2 is a growth factor receptor that is overexpressed now that is inappropriately over expressed that's not normal right it's a proto-oncogene that has been mutated into an overactive Honka gene by a amplification in about 15% of breast cancer this happens to the gene amplification all right so here's a normal cell a normal cell has two copies of the her2 gene which is also called herb b2 you're gonna read about that a little bit later in the course so I'm gonna talk about growth factor receptors so they sit on the cell surface right here and two copies give you enough to have in this case five different with five receptors sort of sprinkled on the cell surface now in a cancer cell in a her to positive or her two overexpressing cancer cells one of these these breast cancer cells then you have multiple copies so in this case how many are in the cartoon you see multiple copies of the gene which means you have a lot more cell surface receptors so the cell surface here is completely covered with these receptors so if I had a random let's see just about everything in in in cell biology happens in a dose-dependent manner so if I have just a few signals right here so these are a few growth factors that hit the cell they're gonna miss the receptor so at low concentration of growth factors they're not gonna bind to the receptors so at low concentration this cells not going to divide by at the same low concentration this my mic hit this one might miss and this one might hit too so now we have because we have so many more receptors some of these growth factors are going to bind to these receptors and this cell is gonna start dividing so it has a growth advantage because it has much more ability to react to low levels of growth factors in the cellular environment and so here's the how this looks like on the clinical level we're looking for but looking at right here is the invading edge of a tumor these are normal cells these are tumor cells okay and so we're looking at two colors we're looking at a probe for the centromere of chromosome 17 which is where the her2 gene is located okay so it's a small fluorescent probe that shows us where in the cell is the chromosome and by the way this blue thing right here is the nucleus okay in a normal cell should have two copies of chromosome 17 so I would expect two centromeres or two green dots and then this is a probe a red probe against the her2 gene where exactly on the chromosome it occurs and so here for instance we have a normal cell that has one two green dots right here so two copies of chromosome 17 and two red dots two copies of the her2 proto-oncogene just normal okay so that's a normal cell while this cell right here we still count one two copies of chromosome 17 but check it out there is fourteen copies of the her2 milkers fourteen copies of this proto-oncogene and that is considered an oncogenic activation by amplification so again these these gene copies are not mutated and these receptors are perfectly normal they're doing what they're supposed to do there's just a whole lot the same by the way the same effect you might have if you don't have an amplification but you have a mutation right here which makes this was set to have a higher affinity for the growth factor so whether and so again then this might be sort of sucked into there just because of the high affinity that it might have so it doesn't really matter whether you have a mutated proto-oncogene that is overactive or you have many more copies and you should have of a normally active proto-oncogene either way it's considered an oncogenic event and you can provide a growth advantage that can lead to cancer alright so lastly tumor suppressor genes I told you were the opposite and with tumor suppressor genes their normal job is to inhibit cell survival and inhibit proliferation okay so that makes sense they're polar opposites and the way these lead to cancer is vietname have loss of function mutation where the ability to stop the cell cycle the ability to kill the cells so apoptosis promoting proteins proteins that say I'm sorry it is time to die you you have reached the midpoint of the monthly cycle and pregnancy has not occurred now kill yourself that would be the function of a proto-oncogene in the next cycle the genes that kick on and say now grow grow grow those would be the function of a proto-oncogene okay so and in this case the mutations are recessive what does that mean it means that we need two copies that need to be lost in the same cell okay so we first have a mutation right here in which we lose the copy of a of a tumor suppressor gene and that itself is not problematic because that cell still has one normal copy left so as long as you have one break that can bring the car to a halt you are not in trouble it's when you lose the second copy of that the second break that the car can no longer be stopped and so this happens right here we have the second mutation that also mutates the second copy right here now we have two mutated copies and that can lead to an excessive growth and survival advantage right here again these mutations happen by deletion you lose the copy that can be point mutations or that can even be silencing events so promoter methylation we'll talk about some of the epigenetic changes where the gene is perfectly fine but if you don't make a protein you can't actually stop the cell cycle you have still lost the breaks okay so tumor suppressors and proto oncogenes those are the two kinds of classes of genes I want you to know what they do and I want you to know how we tations and these genes can lead to cancer by providing an excessive survival and proliferation advantage