Genetic Changes that Affect Cell Cycle Control

hi everyone its mr. cinti and today I’d like to discuss with you today one of the more serious and important topics in molecular biology and that is how the cell cycle is regulated and when that regulation normally occurs things are great but when there are some abnormal events that occur during cell cycle regulation it can result in something pretty serious which is the formation of cancer now I know that this is a serious topic and it requires serious attention therefore and hopefully this video it’s a brief look actually it’s not going to go too far into it but I hope it stimulates you more importantly than just understanding the content I hope it stimulates in you a desire to want to research it even further that goes for all the things that we’re really talking about but this in particular it’s a real cancer as a killer and it must be stopped and I think it begins with the awareness and the motivation to do so so one of the things that I want to talk about is that gene regulation systems can go wrong and when that happens it can result in abnormal cell growth which is cancer and so as you can see a cancer here is an outgrowth of cells in the back of the retina of an eye this is an example of a cancer the cancer of the retina called retinoblastoma so it just could be an example of that so there’s genes associated with cancer and so just to establish that the mutations which are changes to nucleotide sequences of DNA can affect whether or not the cell properly regulates growth and division and some of the things that can affect this is mutations in genes having to do with growth factors you may be familiar with the fact that growth factors initiate cells to know when to grow or when not the mutations could occur in proteins that are found in the membrane of cells that receive those signals from the outside or it could be mutations in the signal transduction pathway leading to cell division or could be in a number of of genes that are responsible for tumor suppressor suppression and so that’s what this video is all about and so I also wanted to point out something that you may or may not be familiar with it that viruses which are small proteins surrounding DNA or RNA that are not living so these biological particles some viruses are tumor viruses and they are known to cause cancer you might be familiar with this like things like hepatitis B virus can lead to liver cancer and the papilloma virus can lead to cervical cancer and epstein-barr virus can lead lead to mononucleosis usually though viruses can cause it but sometimes we we think about the things that cause mutations are caused damage to DNA as being ultraviolet light or carcinogens which are chemicals that are you know unfortunately present in our environment and sadly some of them are man-made and so just to establish some basic terminology so we can talk about this more profoundly unka genes it’s an important term oncogenes are cancer-causing genes in the study of cancers oncology so oncogenes so pro proto meaning coming before proto-oncogenes are the normal cellular genes that are responsible for cell growth and division that’s what we’re talking about here cell growth and division in particular it’s the conversion of the proto-oncogene to an oncogene that leads to the the abnormal stimulation of the cell cycle and thus responsible for initiating cancer you might be familiar with the cell cycle there’s inter phase and then there’s the mitotic which mitosis proceeds cell division which is cytokinesis okay and there’s a few checkpoints along in the cell cycle you might be familiar with with this I actually produce a video on the cell cycle regulation you’re welcome to check that out but there is an important checkpoint right here at the beginning of DNA replication the cell sort of it assesses how things are going in terms of its growth whether or not it’s ready to to replicate its DNA or not and so there’s a there’s a couple of proteins that I won’t go into the details of this

that regulate the the process of DNA synthesis and regulates whether or not a cell undergoes mitosis or not and these are called cyclin-dependent kinases or CDKs you may recall these proteins somewhere in your paths cyclic depending kindnesses and what they do very briefly is that they they’ll add a phosphate to to various proteins and what that’ll do is either activate or inactivate proteins and so these CD cases as you want imagine work together with cyclones okay so they’re cyclin-dependent kinases and they work in concert and bind with cyclin and that’s how they do their work so the first checkpoint as I was mentioning is right over here right in front of DNA replication so there’s certain cyclones and thus they cycle certain certain cyclones are made at different times in the cell cycle and the main point here is that only when the CDKs are bounded the cyclin that they become active and so as you can see in this diagram down below here that cyclin d are produced early on a g1 and cyclin e as well and then the initiation of cyclin a starts to happen here and so you’ll see that these cyclin DS and E’s are getting produced early in g1 and then they bind to kinase a–‘s and cyclic cyclin dependent for in particular will phosphorylate a protein called RB which is going to be important in a moment I’ll discuss that and so what RV does is that normally RB this protein inhibits DNA replication that’s what it does normally however when RB has a phosphate stuck on it it becomes inactive and thus replication can proceed you’re following that let me repeat that so it normally inhibits replication but when it has a phosphate step stuck on it it becomes inactive it changes shape and so therefore replication can proceed okay so as we move through the S phase you can see that cyclin a is being made and it’s going to complex and it binds to cyclin-dependent too and it activates DNA replication then as you move along cyclin be that’s produced during GFE the GM g2 phase bind suits cyclin-dependent one and activates cell division so just to review all of that you may want to pause and take notes if necessary but so just to review the process through these checkpoints you need to have cycling proteins present in order to move through the cell cycle normally so the control here’s here’s a main point the control the cell cycle occurs on a higher level though so one of the key molecules in regulation of the cell cycle is a is a protein called p53 and that might be kind of a random but it’s actually named after the fact that the protein in question p53 is 53,000 Dalton’s molecular weight it’s a pretty significant protein as it turns out and it’s actually referred to somewhat appropriately as the guardian angel of the genome meaning that it’s really crucial and sort of watches over things as it turns out it’s a transcription factor you might be familiar with those those are necessary for RNA polymerase to effectively bind to DNA so when it binds DNA directly it then allows the DNA to produce a protein that blocks the progression of the cell cycle okay and one of those proteins that that does this is p21 and again there’s a gene p21 but it’s the protein that i’m talking about its function is to inhibit cyclin dependent kinase and so it will not be able to activate DNA replication or activate mitosis so in other words RB which is another protein that can inhibit DNA replication so these these proteins if you will these molecules are then considered to be tumor suppressant and the genes that produce them are considered to be tumor suppressant genes because their activity prevents DNA replication and mitosis from occurring so the thing is if these tumor suppressant genes have a mutation they can’t function properly and it results in the cells having abnormal cell cycle or cancer okay and so how important you might ask is this well about fifty percent of tumors have defective p53 genes that’s significant likewise RB which gets its name from retinoblastoma

as i was referring to us at the top of the video as well so some tumor suppressant genes code for proteins that repair DNA if you from if you’re familiar with the fact that sometimes ultraviolet light damage can cause thymine dimers in the DNA and then through an excision repair process that portion of the DNA is is cut with endonucleases and then it’s repaired by an RNA polymerase some tumor suppressant genes that repair DNA the function is not working and so therefore mutations accumulate because the those proteins are not available and so this is an age-dependent phenomenon in other words as a person gets older they’re more likely to occur more mutations over the course of a lifetime and that will result in cancer so the idea is that these genes are pretty important and they make sure that the cells divide and don’t divide and in particular you know control the cell cycle so they’re pretty important and so what’s going on like how can these Pro proto-oncogenes be converted to oncogenes well here’s just three ways in which this can happen you can have movement of DNA DNA is capable of pieces of DNA can actually excise from one place on a chromosome and actually relocates basically like moving from one place in a city to another place you can you can move around and when when DNA moves around like that that’s kind of haphazard it could end up near if it’s a crucial gene it can end up near an active promoter and that increases transcription which may influence cell cycle regulation or there could be simply repeats there can be amplification of particular genes in there they’re copied more than other genes or there could be simply a point mutation a single nucleotide substitution base substitution in a particular control element which causes an increase or D or decrease depending on what activator protein attaches to it and transcription factors now I know that’s kind of a lot to take in but here’s here’s a diagram of this so translocation in other words a pro proto-oncogene actually moves into a new location and there’s a new promoter and that’s what that stimulates abnormal production of our excess of a protein and as I mentioned before you can have gene amplifications or many copies of the genes or repeats and of course that’s going to influence the overproduction of a protein which would affect the cell cycle and that’s possibly result in an oncogene which then results in cancer or you could have a point mutation like for example here’s the gene and then you know this line suggested this is pretty distal from the location of the gene but there could be a point mutation within a control element in other words were proteins bind to this and so you can have over stimulation and so hyper activity or degradation or resistant protein you can have problems with the result of mutation gene amplification or translocation and so so tumor suppressant genes are really important because simply and I mean let me emphasize this whoops we go back over here to didn’t mean to push that sorry about that here we go oops tumor suppressant genes are really important because they help prevent does the name suppress it they help to prevent uncontrolled cell growth so that’s rather important and so mutations that decrease protein production of tumor suppressant genes results in cancer on set so these are highly studied areas in molecular biology and oncology and so what some of these tumor suppressant proteins do as I alluded to them a little bit earlier is that they repair DNA that’s one of their functions they also regulate the cell cycle I’ve been talking about that but they also in fact affect whether or not a cell is adhering to a particular substrate or other cells it won’t get too far into this but cell adhesion is a way in which cells recognize that there’s crowding going on in tissue and therefore stop growing and so when cells are not able to recognize that there they become cancerous and without going into a lot of detail here and this is the heart and soul I think

of cancer research currently is that there’s different stages within signal transduction pathways that occur so it’s not just abnormal receptor proteins but it’s the it’s the proteins or the secondary molecules involved in signal transduction that leads to regulation problems in cancer and so let’s talk about a few examples of this so a mutation in the in a rass proto-oncogene okay so rouse is a rat sarcoma proto-oncogene and p53 tumor suppressant genes are common in human cancer so that these areas are highly studied so a mutation in the rats gene can lead to hyper production of rass proteins and increased cell division and so the rass protein if you’re not familiar with this is is a classic g protein which is involved as i was mentioning before in signal transduction pathway so again you could have abnormal receptors that will receive more signals to divide growth factors and then you can have this rass protein what’s interesting is that it’ll actually initiate a signal transduction pathway when it doesn’t even receive a message from the outside and as a result it produces and stimulates the cell cycle to to be hyperactive and therefore the cells divide uncontrolled ok and so if you can also have a problem with the p53 as well and so that protein normally inhibits the cell cycle and so if there’s a mutation in in that it can’t activate transcription and therefore it doesn’t prevent the cell cycle from from happening and so therefore you have uncontrolled so mutation in the p53 prevents the suppression of the cell cycle thus cancer ok if that makes sense so mutation to that gene and the rass gene is as significant and again the effects of mutation are in general affecting proteins that regulate the cell cycle so if there’s proteins present that that should be or if there’s proteins not present that should be it’s ultimately going to affect the cell cycle and so this process sometimes fortunately is when cancer actually develops it’s usually a multiple-step model generally there needs to be multiple mutations for full fledged cancer too to occur and so this again accumulates usually over the course of a person’s lifetime as they get older and as DNA level the cancerous cell usually is characterized by more than one active oncogene and so they start to accumulate mutations and several tumor suppressant genes and then ultimately the individual sir comes to cancer one of the one of the more troublesome cancers is colon cancer you might be familiar with the colon which is the large intestine its function is to reabsorb water mainly the lining of the or the epithelium layer of the colon can become tumorous here as a malignant tumor carcinoma Stage four meaning that it’s going to metastasize and spread into the lymph nodes surrounding it which is potentially lethal you can inherit these mutations that are passed from your parents and so individuals that have mutations in the gene in particular that I’m talking about in with regard to colon cancer is a PC and so you could do a genetic screen and determine whether or not you’re a carrier for this or homozygous for this heterozygous or homozygous for this and so that’s fairly hopeful as you might be able to then go in for more colonoscopies or you could take precaution if possible and then finally I wanted to talk about breast cancer which is a real devastating disorder one in eight I us women about twelve percent of the population will eventually develop this invasive breast cancer over the course of a lifetime and so for women the u.s. breast cancer rates are higher he believed this than any other cancer besides lung cancer and so it’s a problem that affects you probably are familiar with someone who has breast cancer which is unfortunate and so it’s again I said this at the top of the video video and sorry for coming in so strong

and with this statement but it’s you know the awareness the fact is it’s got its gotta motivate us this is a social awareness which needs to impels us to action because the fact that tent five to ten percent of the cancer is linked to abnormal mutations in the genes and the fact that it’s inherited makes us want to rally and love look and find these genes and so we we have located some of these genes so this mutation in the brca1 and 2 genes are some of the genes that are most common in inheritable breast cancer so on average women with this brca1 mutation have approximately a sixty percent chance in the lifetime of developing breast cancer now that’s important information to have so if you had your gene screened and you and you had that mutation you might want to take a preventative measure in other words it you might want to go in for for a mammogram more calm more often or you might even want to take the action I’m not a physician on this but you may want to take a the action of a of removing the breast tissue in order to prevent that from occurring okay so a mutation here is a forty five percent chance of developing breast cancer and so these mutations are found in at least half the inherited breast cancers and the way you can do that is simply to as sample your cells you can amplify your these particular genes using primers using PCR and then you would run a sequence on that to determine whether or not you had a mutation in those jeans and so it’s something at the you know the first step is is knowing that you have the gene in the first place so i hope this particular video shined a little bit of a light on how genetic changes can affect the cell cycle control thanks for watching