all right welcome back continuing without a list right here we have the second hallmark it is abating growth suppression okay so here was our first one sustained collaborative signaling the next second one evading growth suppression okay let's see so the sustained proliferative signaling okay that was a function of the proto-oncogene or oncogenic activation mutations inappropriately making the cell divide well evading growth suppression is very much the opposite as you know we have tumor suppressor genes and tumor suppressor genes have primarily one important function and that is to suppress the growth there the brakes they hold the selves back they make sure that a cell does not grow uncontrollably out of proportion and of course as we know that's exactly what cancer does so in order for this to happen cancer cells have to evade the growth suppression that these tumor suppressor genes provide okay and so these tumor suppressor genes can be deactivated by a wide variety of mutations so we can have point mutations right maybe we introduced a premature stop codon and we make a protein that is not functional we're gonna see epigenetic silencing as we going on how maybe there's no mutation in the genes but cancer cells manage to turn off the expression of very important tumor suppressor genes and thereby evade the growth suppression from these genes we're going to see deletions of entire regions of chromosomes and by the way I'm just going to put this up sometimes you see the term LOH an LOH stands for loss of heterozygosity so if you remember a heterozygote is someone who has not one normal copy and one mutated copy so if you were born with one mutated copy of retinoblastoma for instance from our previous lecture okay then you would be a heterozygote but in order to get this cancer in order to get this growth advantage you have to lose the second copy and that is referred to as LOH loss of heterozygosity losing the second copy they often that involves entire regions of the chromosome being deleted so we're gonna see this a lot where cancer cells sort of randomly take chunks out of their genome and delete it and a lot of times that results in death of that cell because a lot of times that part of the chromosome was absolutely essential for living but it doesn't really matter because if the if a thousand cells delete part of their genome and 999 cells die the one cell that doesn't die might have n growth advantage and that's gonna be the cell that is going to populate the tumor so again destruction or deletion or inactivation of tumor suppressors make up this hallmark and here's some of the tumor suppressors we're gonna encounter during this semester I'm gonna be talking a little bit about p53 we'll come back to it of course retinal blastoma is something that we'll discuss and then bracket 1 and bracket to the breast cancer susceptibility genes also something that I will discuss throughout this course alright let's look at key 53 again you'll know much more about it in available a time but here's my simple cartoon of what p53 does if t3 is always present always watching it's oh it's a whole watchdog's out be I was compared to the police force to cop the guardian of the genome so it's always present in a Cell but on normal circumstances it's held back by a protein called mdm2 issues seriously wraps itself around holding p53 in place so that without an activation event without something going on inside the cell p53 doesn't do anything something has to happen like this DNA damage that is occurring right here for mdm2 to let go of p53 and let it do its job so it's K if you will until needed but when it springs into place it does a few things first it arrests the cell cycle it doesn't really matter which checkpoint of the cell cycle whether it's the restriction checkpoint in G's in g1 or the mitotic entry checkpoint in g2 or even the spindle checkpoint during metaphase of mitosis all of these checkpoints throughout the cell cycle have the ability to stop the cell cycle that's the first thing that p53 does not talk more about checkpoints and in the context of this course okay so it means cell cannot keep on going and dividing the second thing it does it prompts the cell to repair the DNA damage the cell is a broken chromosome it says you will stop and fix your chromosome and if you do I'm gonna let you restart your cell cycle and that's what it does so the cell can fix the damage and then it's allowed to continue or the cell fails to fix the damage sometimes DNA damage is too extensive Michels unable to fix it in which case p53 said well you had your chance cow boy here we go apoptosis of this and then it initiates the programmed cell death named no named apoptosis by the way I say apoptosis I recently heard somebody say there P is silent it's called a pot OSIS I don't know that's not how I been how I've always used a term but if you ever hear that it's okay either way it's fine okay so apoptosis programmed cell death either way so this here was a cell had DNA or this cell had DNA damage it either is repaired so it's good as new or it's removed from the pool of available cell what it basically does either way this goes it ensures that the cellular and genetic stability the integrity of the genome is main that's what it does it prevents mutations from killing the cells that can't fix the mutations that are being encountered okay and so it shouldn't be surprising then that the vast majority of tumors we encounter so on the order of 60 to 70 percent in some cancer types it's like 99 percent of them have mutations in p53 it's almost impossible to grow into a successful cancer without mutating p53 because otherwise III would see that you accumulate mutations and would force you to fix it or kill you in the process either way if mutations occur in p53 that's when mutations can pile up that's when chromosomal abnormalities breaks and so on accumulate in the cell go into a malignant State okay all right 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