all right welcome back so in this video I want to talk about how cyclones and cyclin-dependent kinases control the cell cycle so we talked about mitogen-activated protein signaling right so the Cascade and I said at the very end is a kinase right it's a lot of the kinase do puts a protein it puts a phosphate on a target protein and one of the kind of target proteins that may important kind of target protein that is gonna be phosphorylated are those cdks so they're gonna get a phosphate stuck on to head by my map kinase okay so that's why they important and they are the key regulators of our cell cycle so let's see how they work okay first of all remember your cell cycle yes my g1 phase right here my S phase my g2 and then my M phase and here I have the whole thing laid out in a linear fashion and at strategic places along this along this pathway right here we have these checkpoints so what's a checkpoint checkpoints is a time for decision-making SSA right here it's where a cell has to stop and has to be prompted to go to the next phase by specific proteins in cyclin dependent kinases are those proteins CDKs or your passport if you will to go past a checkpoint if the cdk doesn't say doesn't wave you through you will stay at that checkpoint indefinitely right or die but yeah there you go so first checkpoint occurs in g1 right so we look for before we go into s phase before we make new copies of your chromosomes you first want to make sure that your DNA is undamaged if that's not true if your DNA contains damages right here p53 will hold you at the checkpoint it doesn't let you go through in the S phase in the second part right here it checks for unfavorable extracellular environment I love this I love this description because it is so big it could mean anything and the reason why it's so big is because it actually checks for a lot of different things so it checks for cell size is 2 cell big enough right because if we have a puny cell we don't want to go on with the cell cycle and make tiny tiny cells right it checks for the environment is there enough nutrients imagine a human cell has to build 3 billion base pairs of DNA that is a lot of nitrogen that is a lot of resources that you need to do this a lot of ATP being used right there right is there actually enough nutrients in the environment to do it checks for that and then lastly it checks for is there a mitogen present if there again without a mitogen in the environment without the signaling from the mitogen-activated protein the map kinase cascade you will not go past that checkpoint can't go if you do go to past that checkpoint then you'll find yourself in your S phase and once you go past that checkpoint you can't go back right that cell it goes past here will continue all the way through mitosis or die in the process you can't go back once you make the decision we have a second checkpoint right here that happens after S phase that makes sure that all the chromosomes have been faithfully duplicated right that the replication process was successful and we now have sister chromatids of every chromosome and we're gonna make sure that there's no damage because remember damage can occur during breaks Nick's all these kind of things can occur during DNA replication before we go and split up the chromosomes in mitosis we want to make sure that the integrity of the chromosome is preserved okay and then the last checkpoint right here happens in the middle in metaphase of mitosis where we want to see half the chromosomes been caught by opposite spindles and that can actually be pulled to opposite sides right here but this is the checkpoint that I want you as to all think about so the question is at what stage in a cell cycle would a cell actually be responsible responsive to a mitogenic growth factor okay so we're in this rare in this whole cell cycle if you supply the cell if a mitogen might actually do something and the answer is only in g1 once you pass the checkpoint you have committed in this green period right here right Jiwon that's where that's the period where a cell would be responsive to Milo Jennings signaling and then it gets to this our point right here this restriction point the restriction point that's this checkpoint right here that's where the cell has to decide will it go on or will it not and when I say the cell has to decide this cell is told by a mitogen and by a mitogen-activated protein signal cascade as we just explored all right so what happens here's my g1 checkpoint yes pink cell crawling along in the cell cycle I like this picture I love this picture as a matter of fact and if it gets to the checkpoint should I go on should I pause should I withdraw on g0 if there's no mitogen the cell will go into this park bench phase right here zero and it can go into this phase at any point of time in g1 in the beginning in the middle at the end too strong right here at the very end and some cells can go into this g0 phase and sort of more or less permanently withdraw or come back in so how long you stay right here depends on the cell your neurons are permanently arrested in g0 some cells are only temporarily there and can come back out the depends on what kind of cell it is okay and so again this would be sort of the formal picture right here the additional phase right here being the G of zero resting phase and which is cells perfectly happy it's just not currently in the cell cycle it's out of the cell cycle and then take note of this most of your cells are not currently cycling stuff your cells are actually in g0 and when I show you some of the pictures that I've taken in my research presentation of tissues we will see that and in most tissues cells because we have a marker if you there's a marker for being in the cell cycle versus being out of the cell cycle and we will see how most tissues cells and tissues are not actually actively cycling all right so the cells that are actively cycling how do they get from one face to the next the answer is it is the concern action of both cyclones and cyclin dependent kinases now you already know what a kinase is it's an enzyme that sticks a phosphate on target proteins in this case it's cyclin dependent so by itself that enzyme can't do anything this enzyme will only be active or activated when it is bound to its respective cyclin so if you see this right here in this complex here's my CD k and here's my cyclin and it takes the cyclin to complete the cv k so the CD k is the catalytic subunit and the cyclin is the controlling the control subunit if you will of disk of this complex and the way you get past the checkpoint the way you progress through the cell cycle is when the CDKs phosphorylate their target proteins okay so anything that happens in a specific phase is done via the cyclin dependent kinase so cell cycle events are initiated by CDKs which themselves are activated only when their cyclin is present the segments are called cyclins because their expression throughout the cell cycle is not the same the CD K is a constant they are always present it is their binding partners that go up and down an expression so let's look at this first cyclin right here the red one cycle indeed it is low at its lowest point right here the very beginning of g1 and then it jumps up and stays high all the way through S phase and so the question is this complex here this first complex of in I don't know you don't have to know by the way whether this is C D K 4 & 7 I don't really care about this but this first complex in red is our G 1 C D K complex it does literally everything that needs to be accomplished in G 1 which includes the growth of the cell differentiation and getting the cell to this checkpoint okay so that's that's an important part of the g1 C became the next thing in the cell cycle kicks on is cyclin e you can see this right here it's only present very briefly at this checkpoint so this is the cyclin that allows cells to go past the restriction SEC checkpoint okay it also initiates as you can see the early events right here in S phase okay so if you remember what's happening in you in your S phase it would be things like the helicase binding to the origin of replication to start the replication fork start the replication process those kind of things would be part controlled by cyclin e ii a kicks off right here it interacts of actually to see decades right right here and right here so it's on throughout S phase and into g2 right present all the way up here and that means that it's responsible for all the things that have to do with in S phase and in g2 phase that's its main regulator right here and then lastly we have our cycling B right here that is the mitotic cyclin-cdk now a nuclear envelope condensing your chromosomes separating the chromosomes in anaphase you name it every single thing that has had in mitosis is specifically orchestrate specifically brought about by the action of our cyclin b and the cyclin dependent kinase associated so that's how they do it they phosphorylate the target proteins in order to bring about these cell cycle events now on the pre beating there we go sorry this is the psyche g1 s complex because it gets us past is to you on its checkpoint then we have the s CD k complex because well it's present an S phase and then lastly our MCD K complex so you should know if I give you a cell cycle event like I said the chromosomes migrate to opposite spindle poles in anaphase you should say well that's my mitotic cyclins thats an event of mitosis okay so again or igus if you put your cell cycle event you can even pretty much guess which cdk is responsible for it which see the k complex okay so there's that but i told you that the psyche no look if you look at the cyclin the expression sort of goes up slowly it's a gradual increase in expression however go and pass the checkpoint that has to be a yes/no kind of decision so the question is how do you take something that is gradual and control it to have a quick response and the answer is this let me see if I can yeah see it can draw it out so here I have my CD my cyclin and here I have my CD k and so on the pre reading assignment I said name two things that turn a CD k on and off the first one is binding of the cyclin cycling right here so cyclin binding means it's on cycling severing if you will means it's off okay so that's there's that but secondly we're gonna have phosphorylation covalent modification so this is attached to then and then we have covalent modification that is happening to so we have additional enzymes that as soon as the cyclin binds to this cdk it's now ready to go but has to wait and so it's gonna put two phosphates on one phosphate and another phosphate and this is the activating phosphate and this is inhibitory phosphate so we have to kind of phosphates on there and activating an inhibitory phosphate so basically it's ready to go because it hasn't cyclin it's even more baby to go because it's activated but there is an inhibitory one and unless we're removing this it won't be active and so that's how we can wait till all the Cyclones bind to these they're primed and ready to go and then we're gonna bring Brent a phosphatase a phosphatase that's the opposite of a kinase it removes the inhibitory and phosphate and then and only then is your cyclin dependent kinase ready to roll okay and so that's how we came like wades and and then control these and so the other thing is then that a cyclin dependent kinase since since it's just such an important molecule is controlled by at least three different enzymes right a cyclin that has its binding partner a enzyme that puts on an activating in an inhibitory con phosphate and then the removal of the inhibitory phosphate by a phosphatase at least three different proteins are involved in the control independently of one another of the cyclin dependent kinases because there's such important cell cycle regular toy proteins so they have to be tightly controlled and you wouldn't be surprised that if that fails if a cdk goes rogue and can't be inhibited anymore or it goes and does its job despite the fact that it has or without the activating phosphate then its turns from a proto-oncogene to an oncogene and so these are very often mutated in cancer which is why we talked about this in the context of the cancer biology class all right be right back