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.
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.
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.
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.
So now the GTP will be acted upon by GTPase. Same concept as
ATP and ATPase. What does ATPase create? ADP.
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.
Give me the most famous RAS of them all. KRAS. You also
have HRAS and such but KRAS becomes important.
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.
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.
You need to make sure that you are asking the right question.
How do you do that? Going through what we are doing.
If you want cancer, a mutated RAS binds to GAP. What does that
mean? That means that the GAP is now been downregulated.
The GTPase is not not being augmented. You are going to
have increased GTP and further, you need to know the signalling.
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.
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.
Notice GTP. GTP is now bound to RAS. It is now active.
You also have RAF which will play a role next.
Normally speaking, once a job of RAS is completed, there is
GAP, that stands for GTPase augmenting protein.
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.
In the meantime, whenever RAS is activated, it will
communicate with the nucleus through the MAP kinase pathway.
So what then happens in cancer. That GAP gets mutated. The
GTPase activity is no longer truly present of effective.
Your RAS is further more or forever more activated. It will
therefore communicate and transduce signals to the nucleus.
So that you have increased transcription activity and
welcome to type cancer that the boards are going for.