Cell Cycle: Cyclin D – Carcinogenesis

by Carlo Raj, MD

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    00:02 We will pay special focus on cyclin D. First and foremost in this picture I want you to come down to the bottom and where is this RB phosphorhylation, And focus upon the RB and E2F complex.

    00:14 It is important that you memorise E2F and RB as being together. That complex, as long as it exists, will then properly regulate the cell as it moves from G1 to S phase. Your first arrest point that you will be focusing upon will be between G1 and S. You know everything about that arrest point first. And association with it's functioning, and regulators then you move on to second arrest point which will be in between S and G2. Now with this E2F/RB complex being present, then the cell is not permitted to move from G1 to S phase. Is that understood? How do you remove and how do you free up the E2F so that the cell can then move from G1 to S phase. The term is phosphorhylation.

    01:08 Whenever RB gets phosphorhylated, you remove the brakes. RB. You remove the brake. How? By phosphorhylating.

    01:19 In biochemistry, what's the name of that enzyme that is responsible for phosphoshylation? Kinase. Good. Would you take a look at our topic. Cyclin-D, CD what? 'K4'. What's the 'K' stand for? Kinase. What does it do? Phosphorhylate the RB.

    01:43 By doing so, what have you done? Remove the break. Who is set free? E2F. Who is truly set free? The cell can now move from G1 to S.

    01:56 Therefore, what this cancer want to do with RB? Does it want to phosphorhylate it? Or does it want to de-phosphorhylate it? It wants to phosphorhylate it so that you can remove the brake. So that the cell remains within the cell cycle eternally.

    02:11 What is the complex that you have to memorise between cyclin D and CDK. Which one? It's CDK4. You must memorise cyclin D, CDK4.

    02:22 I want you to take a look at the complex in the picture. You will notice cyclin D/CDK4 is the active kinase responsible for phosphorhylation of your RB so that E2F allows the cell to go from G1 to S phase. You move through exactly to how I'm instructing you, you will be in fantastic shape. Once you have understood that, then you will take a look at the other cyclin's.

    02:50 When was the last time you have heard of cyclin D? I've mentioned this a few times. You have memorized cyclin D, as part of your mantle cell lymphoma, t(11;14). At this point, it should make to you, that if you are to upregulate cyclin D, which will mean that you have increased activity of CDK4. Increase phosphoshylation of RB. Increase removal of the brakes or the tumor suppressor gene and the cell was in your cell cycle. Isn't that cancer? In this case, obviously mantle cell lymphoma.

    03:25 In addition, take a look at some of the mutation above cyclin D in the picture. We have MYC and RAS. Above that we have growth factors and the big one that you definitely want to know is PDGF. So ultimately, a Ferrari is a Ferrari. The back, the front, the side, it's all the same car. But how do you know it's a Ferrari? Because you are accustomed to the car and you know all the different angles. All I can do for you, is give you the car and the various angles. But can I guarantee that I can give you every single angle. No, but just about. So here, what I am saying is if you have excess growth factor, what kind of effect is that going to have on cyclin D? Upregulate. If you want either C-myc, N-myc, L-myc whatever it may be. Those are different types of cancer. What do you want to do with cyclin D activity? You want to then increase it.

    04:19 It is all part of your signal pathway. At any point in time if you have memorized this here, you are going to miss a question because you have'nt understood what the dynamics are of your cell cycle. I hope that's understood.

    04:33 Let's continue. In this illustration, there is one more point that I want you to focus upon and that is going to be your p53. p53 is also a tumor suppressor gene. Instead of diving into details first, first listen to what I have to say as for it's overall function. p53 is going to regulate the overall cell cycle.

    04:54 Whereas RB gene and it's tumor suppressor activity will be specific with arrest point one between G1 and S phase.

    05:04 Ultimately, what p53 is responsible for will be two major functions. If a cell has been stressed and if the DNA has been damaged but the cell can still be repaired, p53 will induce your DNA repair gene. Is that clear? And if the DNA can be cleaned up or it can be repaired, then the cell will go back into the cell cycle and it will continue on it's way. Function number 1 of p53, repair the cell. Function number 2 for p53, would be to now if the cell has been damaged beyond repair. So now you have gone beyond the point of return. The cell cannot be, it does'nt deserve to be in the cell cycle.

    05:49 Why would you want to have a mutated cell in your cell cycle when you know that it could increase the risk of cancer.

    05:54 So therefore p53 will do the right thing. It will take the cell out of the cell cycle and execute it.

    06:02 Welcome to apoptosis. So whenever you have a cell that has been beyond the point of repair, therefore p53 is going to induce apoptosis and that will be through releasing cytochrome C from the mitochondria and therefore bringing about caspase activity.

    06:17 Welcome to apoptosis. We'll talk about that soon enough. Now I told you earlier that I will take you one step further in anticipation as to what the boards will be asking. I want you to take a look at the very far end of this illustration with p53. And p53 first and foremost, yes technically those work through p21, not going to walk you through the detail, but let me ask you this though. If p53 wants to hold off a cell, from going from G1 to S phase, listen closely to what i'm saying and what I will be asking. If it monitors your cell quality and p53 finds out that the cell is not worthy of moving forward.

    06:58 Now what is that p53 going to do with cyclin D/CDK4? It wants to arrest a cell between G1 and S, does it not.

    07:06 So therefore what kind of activity would it then exert upon your cyclin D/CDK4? Did you say inhibition? Of course you did. Very good. It will inhibit cyclin D/CDK4 so that you do not phosphorhylate your RB, you do not remove the brakes off of E2F. This complex will do what? Will prevent the cell from going from G1 to S phase and in the meantime, p53 will be busy making sure that it is recruiting the enzyme to bring about apoptosis. Is that understood? It's only after you have understood that point we can start looking at the specifics here. Now p53 could and it does detail oriented with p21 inhibits your cyclin D/CDK4. Do you see that line there. That is a block. On the other side, there is something that I wish to mention here because I'm getting feedback where this also is being asked.

    08:02 At least be able to identify INK. INK means inhibition of K, kinase. What kinase are we dealing with here? Good.

    08:13 Cyclin D/CDK4. I told you earlier whenever you find the letter P, as being a prefix before a number or letters, this indicates tumor suppressor. p16 is a tumor suppressor. It is normally going to control and regulate, it will inhibit the kinase.

    08:35 What if you had a cancer that inhibits p16? You inhibit the inhibitor, who's activated? Cyclin D/CDK4.

    08:43 Thus bringing about phosphorhylation. Lot of important information that I have just delivered. Make sure that you are crystal clear with what I've given you. It is only then you move on to the next aspect of my explanation.

    08:58 Now there is something on the very end where we have MDM2 and you have your PG in there as well but I dont want to go into to much detail. Just know that p53 also through the help of MDM2 can then bring about feedback type of regulation.

    09:14 We are going to expand further and look into cell cycle so that you clearly see what I am referring to. Let's begin at the very top.

    09:24 The last time we left off our E2F was when it was bound to what? It was bound to RB. What kind of process biochemically remove the RB? Phosphorylation. Good. What is that enzyme please? Kinase. Specifically which kinase that I want you to focus upon? CDK4. So far so good. You phosphorylated, removed the break, here comes active E2F.

    09:55 And that active E2F is then going to allow for your cell to move G1 to S phase. Now, there is a little bit more detail here just let me walk you through this and guide you so that you are clear. You take a look at the cell cycle, look where you are, G1 and S phase. How do you enter G1? G0. Tell me what kind of cells are G0. Before we begin, where are you in your cell? Are you in the cytoplasm or in the nucleus? Nucleus. Next, how did you enter G1? You were in G0 perhaps.

    10:35 Give me the name of those cells. Those are quiet cells, unlike Dr. Raj. They are quiescent cells. They are silent cells.

    10:43 In other words, think of hepatocytes. Regenerative. At some point in time, the cells will come out G0 go into G1.

    10:52 And from G1 you are going to move into S. What's S mean to you? DNA synthesis. You know it better as DNA replication.

    11:01 Then you move from S to G2. And that will be your second arrest point hence the curvy line and you see a little bit of a you see that mount there, the hurdle. That is your second arrest point. I'm really not going to focus upon that at all.

    11:14 Your focus will be on the first arrest point. And then you have M. What's M mean to you? Mitosis. Obviously taking place in your nucleus Let's talk about a couple of terms here for language. Hypophosphorylated Rb. What does that mean? It has'nt been phosphorylated. Thus, Rb will be bound to E2F. Therefore can you move from G1 to S? You cannot.

    11:41 And recruits what's known as histone deacetylase. That you have to know especially from pharmacology. Histone deacetylase is being recruited. Which causes compaction of chromatin and inhibits transcription. You should know that from Genetics.

    11:59 And also pay attention, pay special attention to the enzyme deacetylase. And in pharmacology, you will hear about drugs that will utilize what's known as histone deacetylase. Trust me. That free E2F which has now come in along with cyclin D/CDK4, what's your next letter after D? E, cyclin E. What's half of 4? 2. So you add that cyclin D/CDK4, the next complex is called cyclin E/CDK2. So now the free E2F, initiates transcription of cyclin E allowing for progression into S phase. There is your, pretty much, entire picture. Between G1 and S, and then you have little details such as p27.

    12:53 Whenever you see the word p in front of a number or letter, the function of that particular element is to bring about tumor suppressor.

    13:03 And this are good things, are'nt they. It's just when we lose complete tumor suppressor activity, is when a patient is prone to different types of cancers. Apart from Rb and p53, I'll talk to you more. And another one is called VHL, von Hippel-Lindau which is of course dealing with renal cell cancer.

    About the Lecture

    The lecture Cell Cycle: Cyclin D – Carcinogenesis by Carlo Raj, MD is from the course Cellular Pathology: Basic Principles.

    Included Quiz Questions

    1. ERB-1
    2. E2F
    3. Rb
    4. CDK4
    5. Cyclin D
    1. Compaction of chromatin
    2. Increased transcription
    3. Rapid movement from G1 to S phase
    4. Upregulation of E2F/DP1/RB complex
    5. Decreased phosphorylation of E2F
    1. p21
    2. MDM2
    3. CDK4
    4. p16
    5. p14
    1. Increased phosphorylation of Rb
    2. Inhibition of Cyclin D/CDK4 complex
    3. Increased p53 activity
    4. Upregulation of E2F
    5. Decreased free E2F
    1. Decreased available CDK2
    2. Decreased transcription of Cyclin E
    3. Decreased transcription of Cyclin A
    4. Increased dephosphoylated Rb
    5. Increased E2F/DP1/Rb complex
    1. p27
    2. p53
    3. p14
    4. p16
    5. MDM2

    Author of lecture Cell Cycle: Cyclin D – Carcinogenesis

     Carlo Raj, MD

    Carlo Raj, MD

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