Four Classes of Normal Regulatory Genes & Signal Transduction – Carcinogenesis

by Carlo Raj, MD

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    00:01 So what's the next step. There are four classes of normal regulatory genes that are often damaged.

    00:07 Growth promoting oncogenes. A mutation in this, gives rise to cancer. If the tumor suppressor genes have become inhibited, gives rise to cancer. Example, RB, p53. I am going through this quickly. Because we have done this already.

    00:20 And we are going to keep doing this moving forward. Evading apoptosis and then finally the DNA repair genes in which we have completed it's discussion already. Signal transduction, let me set this up for you. And this picture overall gives you an idea as to what's happening within your cell and giving rise to perhaps different cancers.

    00:45 I wish to point out to you. There is no cell that looks like this that has all of your growth factors, and receptors on one membrane. But there is enough interaction here in which you can cleary tell what kind of cancer you might then develop. Let's begin. The way to set this up is the fact you begin at the top with growth factors. And there might be times in which growth factors may then become mutated.

    01:11 Excessive growth factor activity, is going to do what? From your growth factor, it will bind to the receptor, increase receptor activity, it will then signal transduce to the cytoplasm, to the nucleus so that you do what? Why am I doing this? I'm revving up my cycle. And the cell will continue eternally through the cell cycle. Welcome to neoplasia. Welcome to cancer. So here we have PDGF and in a little bit I will give you tables, in which i'll talk to you a little bit more about associated cancers. Well platelet derived growth factor, it's association at least know one. It's known as astrocytoma. Astrocytoma. On the other side we have transforming growth factor beta. Definitely note transforming growth factor beta. Lots of research TGF-beta. And as far as you are concerned at this point, transforming growth factor beta also involved in repair. In other words, responsible for fibrosis and collagen. And that becomes important. Growth inhibiting factor.

    02:15 Finally we have something called your adhesion molecule. And for this we will call these cadherin.

    02:25 You pay attention to adhere. What if there is a mutation? In a particular cadherin called E cadherin, If E cadherin, has been lost in a cancer what does that cancer want to do? It wants to move. And it wants to move quickly.

    02:49 Breast cancer, what is the number 1 prognostic indicator? Axillary lymph nodes. So what is your cadherin activity? Depressed. You have heard of lobular invasive breast cancer. Number 2, cadherin, in the GI, in the stomach.

    03:09 Maybe it spreads out to the left supraclavicular lymph node. You get the point. Cadherin. Receptor activity.

    03:19 receptor activity example for that would be something like your epidermal growth factor receptor.

    03:24 Now at the bottom portion the receptor are then bound to certain signal transducers. We will be spending a lot of time with RAS.

    03:32 If that becomes mutated and becomes active you can only imagine there is going to be increase signalling down to the nucleus which is down to the right end to the bottom. We'll talk later about NF-1, that is important.

    03:44 It's called Neurofibromatosis type I. This then gives rise to a particular cancer called neurofibroma.

    03:52 Not to worry I'm just giving you an idea of all the different things to come and how important molecular pathology has now become in terms of cancer. Here is that APC and beta catenin I told you that I would talk to you about.

    04:04 APC normally controls beta catenin activity. Beta catenin is a transcription factor or it controls transcription factor activity. So therefore, if APC gets mutated, take a look, it can no longer control beta catenin. How much transcription activity are you going to have? Upregulation. What does that mean to you? Familial adenomatous polyposis.

    04:36 At some point later on, we will dive into the nucleus. In the nucleus I will talk to you about great detail about cyclin D, CDK 4. Focus on that, big time. You have heard of mantle cell lymphoma, you have heard of t(11;14).

    04:50 It is associated with cyclin D. You will see why. MYC, look where you are. In the nucleus. At some point, I will have you recall where these genes are located. Either growth factors, either receptors, signal transducers in the cytoplasm or in the nucleus. At any point, if you have increased activity, you have increase nuclear activity, welcome to cancer. So I've done a flow chart. The most important point will be this one. In which we talk about in great detail, the molecular mechanism. It's imperative that you understand this. There is BRCA-1, BRCA-2, deep down inside your nucleus.

    05:35 Then we have the RB. We will talk about the RB in great detail. Then you have your what's known and your CDKi's. Now that also becomes important. For example, if you know that you want increase CDK activity to bring about cancer, if you have a CDK inhibitor, it normally inhibits CDK. As the name implies. So, if you want cancer, what do you want to do with CDKi? If you inhibit the inhibitor, you have stimulation. Thus, we will talk about melanoma there. Apoptosis, with this we will talk about with BCL2 more so. Here is MSH2, MLH1. What does that mean to you? You have memorised, HNPCC I hope. Spend little bit of time with this. Give yourself an overall picture, as what's happening or occuring with molecular pathology and all the different points at this juncture, that you at least need to know.

    06:36 This is the least that you need to know. There is a lot more in terms of the overall picture, I have just at least based on the feedback that I have gotten, giving you a simplistic version as to what is going on with increased carcinogenesis on a molecular level. If I had to all over again, I would do haem onco without a doubt.

    About the Lecture

    The lecture Four Classes of Normal Regulatory Genes & Signal Transduction – Carcinogenesis by Carlo Raj, MD is from the course Cellular Pathology: Basic Principles with Carlo Raj.

    Included Quiz Questions

    1. PDGF
    2. TGFβ
    3. Ras
    4. Cadherins
    5. NF-1
    1. Cadherins
    2. PDGF
    3. TGFβ
    4. NF-1
    5. Ras
    1. Quiescent β-catenin with increased transcription
    2. Up-regulation of transcription
    3. Dysregulation of β-catenin
    4. Proliferation and cell growth
    5. Lack of inhibitory regulation of β-catenin
    1. BCL-2
    2. Cyclin D
    3. p53
    4. MYC
    5. BRCA-1

    Author of lecture Four Classes of Normal Regulatory Genes & Signal Transduction – Carcinogenesis

     Carlo Raj, MD

    Carlo Raj, MD

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