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RAS Protein & Signal Transduction – Carcinogenesis

by Carlo Raj, MD
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    00:02 Focus on RAS. You will find this to be quite interesting. The way that I will approach this, I'm going to quickly walk you through the verbiage. And then I will walk you through the illustration. And it is up to you to make sure that you put the two concepts together. However you wish to learn. To begin with I will tell you couple things that are important. RAS is associated with G protein. Tell me about the G protein from biochemistry. Alpha, beta, gamma, right. Alpha, beta, gamma, when associated with G protein would mean that it's inactive.

    00:36 What do you want to do to activate G protein. You get rid of the beta and gamma, you hang on to the alpha. Alpha, active.

    00:44 The specific activity of RAS and how it works is going to be through GTP. So activated GTP binding then deactivated by normally inherent GTPase activity. Stop there. That is a huge point. GTP is active. GDP is inactive.

    01:08 What do you need to then create active? Phosphorylate. And it's called guanine triphosphate. Once the job of RAS has been completed. Then you are going to inactivate the RAS. How do you inactivate the RAS? By inactivating the G protein.

    01:28 So now the GTP will be acted upon by GTPase. Same concept as ATP and ATPase. What does ATPase create? ADP.

    01:40 What does GTPase create? GDP. What's that mean to you? Inactive. This is normal. So, what happens in cancer? You never want to stop RAS activity. Which means that RAS has to be bound to whom eternally? GTP. What enzyme might you want to inhibit so that you can guarantee that GTP is bound to RAS. GTPase. So on your boards, or in general, if you're going to have cancer that GTPase activity has been completely nullified. Thus, you have increased GTP activity. Your RAS is forever more active.

    02:25 Give me the most famous RAS of them all. KRAS. You also have HRAS and such but KRAS becomes important.

    02:34 Let's take a look at another component. Once you have understood that, let's take a look at the next part and let me ask you a question. And you will get it right. GTPase augmenting protein. What does augmenting mean? To immprove, to enhance. So here is your protein that is going to enhance the GTPase activity. If cancer is to develop, what's my activity of this GAP protein. Did you say decrease? Yeah you did. Or you will. When that GAP activity is decreased, GTPase activity is decreased. Your GTP remains intact until (inaudible) activity, increased. With all that said, predict always as to what's to come so that you can answer your questions much quicker and with much more confidence.

    03:21 If you depend on the answers to give the answer, or if you depend on the answer choices so that you can figure out the answer that takes too much time and it shakes your confidence because there are going to be many answer choices that will look very much alike. So therefore, if you can predict, it's a thinking exam. You're interacting with your patient who's the question. You're asking the patient, you're asking the question, and the question is answering you.

    03:48 You need to make sure that you are asking the right question. How do you do that? Going through what we are doing.

    03:55 If you want cancer, a mutated RAS binds to GAP. What does that mean? That means that the GAP is now been downregulated.

    04:03 The GTPase is not not being augmented. You are going to have increased GTP and further, you need to know the signalling.

    04:13 We have RAS which is associated with as you move further into, now before we move on picture RAS. If you can't i'll show you a picture. RAS is going to be bound to G protein right along side the membrane in the cytoplasm. Once RAS is activated, it will follow through what's known as MAP, MYC and company. And then it will communicate with the nucleus so that you can bring about increased proliferation, bringing about neoplasia. MAP kinase will be a part of that.

    04:46 It is important that you know MAP kinase. GTPase activity is lost in mutated RAS and RAS mutated, look at this, 25% some would even say 40% of all cancers is associated with RAS. Let us now take a look at illustration, quickly and effectively of what you need to know. If by chance you were not following me on the previous discussion on the verbiage you are going to follow me now. Here is a growth factor, ECF. There is a receptor in the membrane. Where are you on the other side of the receptor. Inside my cytoplasm. Inside the cell. And from the cytoplasm, you are going down to where? The nucleus. Let's break it all up and have you take a look at RAS signal transduction. GDP located in the picture, you see it? GDP. Okay. That GDP means inactive. What is to happen to that GDP so that it can become active. Has to phosphorylate.

    05:58 Notice GTP. GTP is now bound to RAS. It is now active. You also have RAF which will play a role next.

    06:09 Normally speaking, once a job of RAS is completed, there is GAP, that stands for GTPase augmenting protein.

    06:18 What does GTPase do? It removes the phosphate. In other words it dephosphorylate so that you see the phosphate, it's been released. And you circle back around, and you form GDP which is inactive and that is perfectly normal.

    06:33 In the meantime, whenever RAS is activated, it will communicate with the nucleus through the MAP kinase pathway.

    06:44 So what then happens in cancer. That GAP gets mutated. The GTPase activity is no longer truly present of effective.

    06:53 Your RAS is further more or forever more activated. It will therefore communicate and transduce signals to the nucleus.

    07:00 So that you have increased transcription activity and welcome to type cancer that the boards are going for.


    About the Lecture

    The lecture RAS Protein & Signal Transduction – Carcinogenesis by Carlo Raj, MD is from the course Cellular Pathology: Basic Principles.


    Included Quiz Questions

    1. Low GDP, high GTP
    2. Decreased RAS activity
    3. Increased GTPase activity
    4. Low GTP, high GDP
    5. G-proteins coupled to beta and gamma particles
    1. Increased quiescence of the cell
    2. Decreased or lost GTPase activity
    3. Decreased GAP activity
    4. Increased activation of the cell
    5. Increased G-protein cascade activation
    1. Activation of transcription in the nucleus
    2. Increased GDP
    3. Upregulation of RAF-1
    4. Decreased GTP
    5. Activation of growth factor receptors
    1. RAS would not be anchored in the membrane
    2. Growth factor would fail to bind to receptor
    3. MAP kinase pathway would not be able to enter the nucleus
    4. GDP would not be transformed back to GTP
    5. Beta and gamma particles would not be able to disassociated from the G protein complex
    1. 25-40%
    2. 5-10%
    3. 15-20%
    4. 60-75%
    5. 100%

    Author of lecture RAS Protein & Signal Transduction – Carcinogenesis

     Carlo Raj, MD

    Carlo Raj, MD


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