PROFESSOR: OK so
on Monday we talked about how cell division is
regulated at this single cell level. On Wednesday we talked
about how regeneration is mediated at the level
of an entire tissue. And today we're going to
talk about how all of that can go wrong, OK? And when all of
this goes wrong, it results in a disease, actually
many different diseases, but are commonly
known as cancer. And as illustrated in
this cartoon, what you see is that cancer can
often be defined as having distinct steps in
its progressive, essentially, deregulation of normal
cell and tissue behavior. So when we're
thinking about cancer, we're thinking about a
stepwise degeneration. And cancer is a disease
that affects an individual's own cells, but those cells get
progressively and progressively dysregulate d in their
behavior and the coordination of their behavior with
the rest of the tissue. So it's a stepwise degeneration
of normal cell behavior. And it results from mutations
that are occurring in the cell. And we'll talk about what
types of mutations right now. And then I'll take you
through some examples of different signaling
pathways and we'll try to classify what
different types of genes should be labeled as. So first, I want to talk
about classes of genes and their involvement in cancer. And the first example
that I'll take you through is known as an oncogene. And it's referred
to as an oncogene after the mutation
has already happened. And so an oncogenic
mutation is a mutation that's going to promote
growth and survival of a cell. So this promotes growth. Before the gene is
mutated, it's referred to as a proto-oncogene. So before mutated, the gene
is labeled a proto-oncogene. And the normal function
of these proto-oncogenes is also to promote
growth and survival, but they do so in
a regulated manner. So a gene becomes
an oncogene when there's a mutation
that causes it to be unregulated by the
environment of the cell or even the surroundings
of the cell. And so you can think of this
as a constitutive activation. Often oncogenes are
constitutively active forms of normal genes. And one way to
think about this is you have a gene whose normal
function is to promote growth and it's kind of stuck in
the state of the gene that always promotes growth, which
is not normally how it works. Normally there are signals
that tell a cell to grow, and those signals come
and go, and that's how the body regulates
when cells divide. But you can have a situation
where it's essentially the equivalent of what you might
consider a stuck accelerator, if you're thinking
about an automobile. So if you have a
stuck accelerator, and you can only speed up,
and you can't slow down, this is analogous to
an oncogenic mutation. Now a different class
of gene, actually kind of the opposite
of an oncogene, is called a tumor suppressor. And tumor suppressors are
genes whose normal function is to inhibit growth
or even promote death. So tumor suppressors inhibit
growth or promote death. You could see how these
two different things would have the same effect
in that it's not allowing one cell to
become a lot of cells because the tumor suppressor
will either prevent it from dividing or will
cause the cells to die. And so the cancer
phenotype is associated with a loss of function
of the tumor suppressor. So these result from loss of
function mutations in the tumor suppressors. So if you remove the thing
that's inhibiting growth, then that allows
the cells to divide in a more unregulated way. And so sticking with the
analogy of an automobile, you could think of the
tumor suppressor mutation as a cell having
defective brakes. So you can think of this
as defective brakes. So it's the loss of function
of these that lead to cancer. Now I want to tell you about
one last class of genes that are implicated in cancer. And these are what, in
the diagram up there, are referred to as
caretaker genes. And what that refers
to is the fact that these genes are
involved in maintaining the genomic integrity of a cell. And they can do that
by mediating DNA repair when it needs to happen. So these are involved
in the repair of DNA. Or actually, I
know what I'll say. We'll say genome. It's involved in genome repair. But not only repair, but
also genome stability. So making sure that
chromosomes are equally segregated to daughter cells
so that you don't end up with cells with
extra chromosomes or lacking entire
chromosomes, which is known as being aneuploid. So genome repair
and also integrity. And again, because these
promote genome integrity, it's a loss of the
function of these genes that is what promotes cancer. So a loss of function
mutations in caretaker genes are what can drive
a cancer phenotype. And that's because if you
lose a caretaker gene that's involved in DNA repair, actually
one example of a caretaker gene is the BRCA1 gene, which is
involved in breast cancer. And so if you lack
this BRCA1 gene, it makes it so that
the cells are not as good at repairing their DNA. And then the cell can
accumulate additional mutations, and the cell might get
an oncogenic mutation or it might lose
tumor suppressors. And that's what drives
that cancer phenotype. Now I just want to point out
something that just happened this week, which is that one
of our very own colleagues here at MIT, Angelika
Amon, whose lab has done a lot of research that has
provided fundamental insights into how a lack of
genome integrity influences both normal
and cancer cells. She just won what's known
as the breakthrough prize. And so this is a prize that was
initiated by Chan Zuckerberg initiative, so it's
out of Silicon Valley. And the point of the prize is
to basically celebrate science, like we would movies
at the Oscars. And so this is Angelika here
receiving this breakthrough award, and this just
happened this past weekend. And this is for her
fundamental work on how aneuploidy influences
the biology not only of normal cells, but also
cancer cells because it plays an important role
in the biology of cancer. All right, so now
that we've defined some of these key
genes, I want to talk about one example of a pathway
that influences cell division. And we'll go through all of
the genes in this pathway and decide whether
or not they should be considered oncogenes, tumor
suppressors, or caretakers. And the pathway we're
going to look at involves the G1 to S transition. And you'll recall
that this G1 to S transition in the cell cycle
is referred to as START and is the point at which
an individual cell commits to going through the
entire cell cycle. So this G1 S
transition, or START, what kicks off the whole process
is the expression of a cyclin. And that is specifically
the G1 cyclin. And this G1 cyclin is regulated
by many different things. And we've talked
about a lot of them. First of all, there
are growth signals. These are secreted
proteins that allow cells to communicate with each other. And many growth signals promote
growth and cell division by up regulating this G1 cyclin. So you're actually regulating
the gene expression of this particular cyclin gene. We also talked about Wnt. And Wnt is another type
of signaling system. And one of its targets
is also the G1 cyclin. So both of these
signals promote growth. There are also other
types of signals, like cytokines, which also
promote G1 cyclin expression. So this is a really
pivotal control point for the cell to
decide whether or not to enter into the cell cycle. I'll point out
that there are also other types of signals
that inhibit growth, and I'll call those
growth inhibitors. And so these growth inhibitors
inhibit G1 cyclin expression. So if you have a
cell in your body, and it's trying to decide
whether or not to divide, it's basically reading out how
many growth positive signals it's seeing versus
growth negative signals, and it's able to integrate
that information based on how much G1
cyclin it produces, and that determines
whether or not it goes into the cell cycle. So G1 cyclin. And G1 cyclin functions with
cyclin-dependent kinase. So this depends on
cyclin-dependent kinase. This eventually leads to
the expression of the G1 to S cyclin. And it's the G1
to S cyclin which is responsible for activating
the transition from G1 to S, which is known as START in
yeast and the restriction point in mammalian cells. But it all starts really
with this G1 cyclin. So I want to talk about
this step in the cell cycle. And I'll show you the nitty
gritty of the mechanisms that are involved. And we'll talk about what types
of genes all of these genes are. And it's going to involve
a very important gene that I'm going to tell you
a lot more about in just a few minutes. All right, so the critical
determinant of START is this G1 S cyclin. So I'm drawing a
piece of DNA here. Here's the G1 S cyclin gene. So this is DNA. I just drew a piece of DNA. Part of the genome. This is the G1 S cyclin gene. And this gene is activated,
its transcription is activated, by a transcription
factor known as E2F. So we'll keep track
of what these are. E2F is a transcription factor. So E2F is a
transcription factor that will activate the expression
of this G1 S cyclin. But in early G1, there's a
protein that binds to E2F. And this protein is called Rb. I'll tell you what Rb
stands for in just a minute. But what Rb does
is it binds to E2F and it inhibits its
transcriptional activity. So in early G1, E2F is
inhibited and the expression of this G1 cyclin is off. So this is off or repressed. So before the cell passes
START, this expression is off. So this is early
G1 before START. Now what happens is this state
is changed by the G1 cyclin. So if there's adequate
levels of G1 cyclin, and this is in complex with
cyclin-dependent kinase. Because cyclins, their
functions are always mediated through
cyclin-dependent kinase. So the cyclins are never, as
far as I know, functioning on there by themselves. They're always
functioning through one of the cyclin-dependent kinases. So G1 cyclin CDK
phosphorylates Rb. And so you then get an Rb
that has a bunch of phosphates attached to it. And this inhibits Rb's function
such that it can't bind to E2F. So when G1 cyclin CDK
phosphorylates Rb, that causes Rb to go away
from the promoter of the G1 S cyclin. And now you have this
transcription factor, E2F, free to transcribe
the G1 S cyclin gene. So this now gets turned on. And it's this activation
of G1 S gene expression which is the signal to undergo. You get G1 S cyclin CDK
because you express this gene. And that activates the
transition into S phase. All right, now take
a look at everything I just drew on the board. Who can tell me where
the tumor suppressors are in this pathway? Miles. MILES: Rb. PROFESSOR: Rb is a
tumor suppressor. That's exactly right. Let me get some
colored chalk here. All right, I'm going to circle
tumor suppressors in pink. Are there any other
tumor suppressors? So Rb is a tumor suppressor. Yeah, Amanda. Did you have one, Amanda? Georgia. Georgia, sorry. GEORGIA: The growth inhibitors. PROFESSOR: The growth inhibitors
are also tumor suppressors, exactly. OK, how about oncogenes? What would be considered a
proto-oncogene in this system? Jeremy? JEREMY: CDK. PROFESSOR: CDK
would be one, yup. So oncogenes. CDK can be considered
a proto-oncogene. Anything else? Well, what defines an
oncogene or a proto-oncogene? What's its normal
function in the cell? Carmen? CARMEN: Its function is to move
the cell along the cell cycle. PROFESSOR: Yes. So it promotes growth. And moving a cell along the
cell cycle will promote growth. So yes, exactly. So anything here promoting
growth besides CDK? CARMEN: E2F. PROFESSOR: E2F would be
a proto-oncogene, sure. Jeremy, did you have an idea? JEREMY: G1 cyclin. PROFESSOR: G1 cyclin. Basically everything else
here would be considered a proto-oncogene, right? Wnts are proto-oncogenes. They're promoting
growth by promoting the expression of G1 cyclin. The growth signaling
pathway, all of those genes would be considered
proto-oncogenes. And so anything that
is promoting growth will be a proto-oncogene here. Great. All right, so now we're going to
move on and talk about this Rb gene, which I just showed you
mechanistically what it does. But what Rb stands
for is retinoblastoma. So Rb stands for retinoblastoma. And this Rb gene,
as you suggested, is a tumor suppressor. It was actually the first tumor
suppressor that was cloned. And so retinoblastoma,
as the name implies, is involved in a human disease. And it's involved in a
rare childhood eye tumor. So I'm going to show you
one last weird eye picture. If you don't want to look, look
down or look the other way. I'm going to show you a
child that has retinoblastoma and what it looks like. So it's going to
appear right now. So this is an individual
with retinoblastoma. You can see that there's
something inside the eye, growing in the back of it. And to give you a better
picture of what is happening, this is now a cross section
through a normal eye. This is a cartoon
of the normal eye. And individuals
with retinoblastoma have a growth in
the back of the eye. From the retinal
tissue you can see this huge tumor that's present
in the back of this eye. So this disease
involves the formation of these tumors in
the eye that originate from the retinal tissue. All right. So this disease results -
this is a tumor suppressor. It's a loss of function
in the retinoblastoma. So there's a defect in
the retinoblastoma gene. But this disease
of retinoblastoma manifests itself
in different ways. So there are different
forms of the disease and I'll tell you how
they're different right now. So there are two
forms of the disease. The first, it's called sporadic. And it's called
sporadic because this is a form of the disease
that arises in families that have no history of the disease. So the sporadic form, the family
has no history of the disease. And this disease presents
in a certain way. The first is it is what is known
as unilateral, meaning usually only one eye is affected. So it usually
involves only one eye. And this disease can
be treated in children. And if the sporadic
form of the disease is treated in the child,
then later on in life that individual does not
have an increased risk of getting further tumors. So there's no increased risk
of cancer later in life. For example, in a
different organ. So this is one form
of the disease. The other form of the
disease is called familial. And as the name
implies, familial means that the disease
runs in the family. So what familial means is
there's some inheritance. There's an inherited
form of the disease. And the familial
form of the disease can be distinguished
from the sporadic form because it presents differently. The way the familial
form presents is it's often bilateral, meaning
that both eyes become affected. So it affects both eyes. And also in individuals
with the familial form, even when they're cured
from the eye tumors, they have a higher risk
of getting other tumors in other organs of their
body later on in life. So in this case, there is
later an increased risk of cancer in other organs. So this is an example
of a familial form of retinoblastoma, where
affected individuals here are colored in green. So what would you say the
inheritance pattern is for this particular phenotype? Carmen? CARMEN: Autosomal recessive. PROFESSOR: Why do you
say autosomal recessive? Can you explain your logic? CARMEN: Yeah. It looks [INAUDIBLE] are
affected regardless of-- with colorblindness it was
always the sons that got it. [INAUDIBLE] getting it as well. But you can see some
generations where neither parent had retinoblastoma. PROFESSOR: So Carmen's
exactly right. And she's saying that both males
and females are getting it, so it looks like that
would argue that it's not sex linked, but autosomal. So it looks autosomal. And why do you say recessive? Can you explain
your logic there? CARMEN: The third from the left. The one that has an arrow on it. Both parents are
affected [INAUDIBLE].. The only way that's
possible for their children to get the recessive gene. PROFESSOR: So Carmen
is exactly right. She's looking at
this individual here. And in this case,
this individual was not affected
with the disease, but passed on the disease
to their daughters. Now I think one thing. This is an exception
to the rule. What you see in pretty
much all the other cases is that individuals in this
generation in the middle here do have the disease,
and they pass on the disease to the next generation. So because I'm seeing the
disease in all generations, I would say that this is likely
to be autosomal dominant. And Carmen picked
up on something that I want to come to. It so happens that
this individual was not affected by the disease,
but still clearly carried a disease allele. And I'm going to talk about
why this is an exception and why this is still an
autosomal dominant inheritance pattern. But if we take it that this is
an autosomal dominant disease, it's kind of counter intuitive,
at least to me, and maybe to you, because I just told you
that tumor suppressors result from a loss of
function of the gene. And we're used to seeing
loss of function mutations being recessive. And actually, at the
cellular level, it's true. The cancer is recessive. But in this case,
what you see is that, at the organismal
level, the inheritance pattern actually acts as a
dominant phenotype. So there's kind of a difference
between the inheritance pattern at the cell level
and at the organismal level. And I want to tell
you why that is because I think it's
important for understanding the risk to cancer. And so what's inherited is
not the full blown disease. What's inherited in the
case of retinoblastoma and many other cancers is a
predisposition to the disease. So what is inherited is the
predisposition to the disease. And that's because
if we look at, let's consider the top male up here. If that male is heterozygous
for the Rb gene, then he can have a
gamete, which is Rb-, so lacking a functional
copy of the Rb gene. And he married an individual
without a disease a label, so she's going to
just make Rb+ gametes. And if they have children
and one of the children gets a gamete that is
derived from Rb- allele, then you get an individual
in the zygote here which has one functional
copy of the Rb gene and one mutant copy
of the Rb gene. So that's the egg,
and then that egg is going to develop
and give rise to all of the cells of the body. And so in this case,
all of the somatic cells from this individual
are going to be heterozygous for the Rb gene. So all somatic cells
are heterozygous for Rb. So they're Rb+ over Rb-. And the effect of
that is, is it means that each of the cells
in this individual are only one step away
or one mutation away from lacking both copies of Rb. So by being
heterozygous, it means that all cells in the individual
are just one mutation or step from losing Rb. And so the inheritance
pattern, what you're looking at is the predisposition
to the disease. And the predisposition
doesn't mean that a person is guaranteed
to get the disease. And that's illustrated in
this family tree, right? There was an individual here,
this male here with the arrow, who clearly was a
carrier for the disease because he passed on the
disease to his children, but who himself never actually
was affected by the disease. So because it's
a predisposition, it doesn't mean
there's a guarantee. That if you are
heterozygous for Rb, there's not a
guarantee that you're going to have the
disease, but you are going to be predisposed to it. And in the case of Rb,
more often than not, if you lack one
functional copy of Rb and are heterozygous
for all of your cells, then you're going to be
affected by the disease. Does that make sense, Carmen? CARMEN: Yeah. PROFESSOR: OK. Yeah, Jeremy? JEREMY: [INAUDIBLE]
people who are heterozygous and homozygous for
the disease are affected by it. PROFESSOR: Well, actually, if
you are homozygous from Rb, the individual would
probably not be born. Yeah. So I think it would be
impossible to be heterozygous for Rb. Yeah. So really what you're inheriting
here is that predisposition. And because the predisposition
just requires heterozygosity, it manifests itself like
a dominant phenotype. Because you only need
to inherit one allele that's mutant in order to be
predisposed to get the disease. So that that's why it appears
at the organismal level to be a dominantly
inherited phenotype. But then to get the
disease, you need to lose a second
copy of the gene. And so for the sporadic
form of the disease, so we just talked about
hereditary or familial retinoblastoma, all of the
cells of the individual will start out
being heterozygous and then some of
them will lose, what is known as lose heterozygosity,
and become homozygous mutant in a particular tissue. And that would be
the tumor tissue. So what are some
ways that there could be this loss of heterozygosity? Can you guys come up with
some possible ways to do that? Heterozygosity. How might a cell lose
that second copy of Rb? What are some
potential mechanisms that you could lose it? Rachel? RACHEL: Point mutation. PROFESSOR: It could be a
point mutation, exactly right. So one way would be
point mutation in Rb. Other ideas? Yeah, Patricia? PATRICIA: There isn't proper
separation during mitosis and you only get one copy. PROFESSOR: So if you
lose a chromosome, right? So if you guys
remember back, remember way back when we are all young
men and women in early October. We did the whole
demonstration with mitosis and we had a case where
we had two good friends across the metaphase plate. And that brought both sister
chromatids off to one side. That would result in
loss of a chromosome. And in this case, if
you have a division and you lose the
wild type copy of Rb, if you lose that
entire chromosome, then you're going
to be left with only the mutant copy of the Rb. So another mechanism
would be chromosome loss. Where the chromosome that's lost
is the chromosome with the wild type Rb+ allele. Any other ideas as
to how you might lose the second
functional copy of Rb? Yeah, Miles. MILES: I'm not sure
if it completely falls under point mutation,
but overall DNA damage? PROFESSOR: Yeah,
can have DNA damage. You can have a
deletion that deletes the entire region of the
chromosome that contains Rb. There could be even
chromosomal abnormalities, like translocation,
that somehow delete Rb. So I'll just say
deletion for now. Any others? Can anyone think
of something that wouldn't be necessarily a
genetic change, but more of an epigenetic
change, so to speak? Yeah, Natalie. NATALIE: [INAUDIBLE]
mutagenized? PROFESSOR: Being mutagenized? NATALIE: Exposed to
rays of something. PROFESSOR: But then
that would cause a mutation, which might fall
into one of these three classes here. What about without being
mutagenized, non mutagenic. Yeah, Maxwell. MAXWELL: Are there any
other environmental factors that control expression of Rb? PROFESSOR: Yeah. So Maxwell's saying,
what else would control the expression of the Rb gene? What if you had an effect
that would basically cause that functional copy
of Rb to be not expressed? And so this is another way that
you can lose heterozygosity, as you have repression
of transcription. And I'm not going to go
through the nitty gritty of the details, but one way
in which genes are regulated is by modification of DNA
by chemical modifications, like methylation. And so promoter
methylation is a mechanism that causes repression
of gene expression. And in many cases in
cancer, the functional copy of a tumor suppressor
will basically be lost by promoter methylation,
so that you no longer express that gene in that cancer cell. And therefore, the cancer
cell has a cancer phenotype. Any questions on Rb
before I move on? Everyone understands
why retinoblastoma is dominant at the
organismal level, yet recessive at the cell level? That's an important point. The concept behind that
is also the same for BRCA1 and other tumor suppressors
like p53 and APC, which you'll see
in just a minute. All right. So now I want to move
up kind of from thinking about the mechanism of
cancer at the level of a cell and let's think about it
at the level of a tissue. And as an example, I
want to use colon cancer. And you'll recall
from Wednesday, I talked about the
intestine as a system. And the way it works
is pretty much the same for both the small and
the large intestine. It just happens in the large
intestine or the colon, you don't have villi, but you
do still have these crypts. So that would be
what a colon would look like, more or less, or
at least one crypt of a colon. And remember, at the
base of the crypt, there was this
specialized compartment, which was the stem cell niche. And this is where
renewal was happening. And renewal and cell division
down at the base of the crypt then results in this conveyor
belt-like movement up to the region of the tissue
near the lumen, where cells are shut off into the lumen. So what might be one
barrier to cancer that has to be overcome
in order for a tumor to form in this organ? Yeah, Miles. MILES: You know the
diagram [INAUDIBLE] cells. So the one part that [INAUDIBLE]
would be [INAUDIBLE].. It's when the cells get
[INAUDIBLE] into the lumen. [INAUDIBLE] system anymore. So if cancer cells, [INAUDIBLE]
just never shed off [INAUDIBLE] keep [INAUDIBLE] and it would be
just moved along the intestine and never die. [INAUDIBLE] undying cells
that won't ever shed. PROFESSOR: Yeah, so
what Miles is saying is that these cells are going
to move up and get shed off. And so if you have a mutation,
either an oncogenic mutation or loss of tumor suppressors,
if it goes up, and sheds, and is removed from the
organ, it doesn't matter. That cell is not going to
be able to form a tumor. So one thing that has
to happen for a cell to form a tumor in this
system is this treadmill has to be blocked, such that
cells are no longer exiting the organ, so that
you have a cell actually stay in
the organ that would be able to accumulate
additional mutations and undergo tumorigenesis. And this is what
happens because, as we know in colon cancer, one of
the first steps in colon cancer is disregulation of the
signaling that really regulates this movement of cells and
the homeostasis of the tissue. So step one here. Step one is to dysregulate the
main signaling pathway that's involved in this,
which is Wnt signaling. And so another famous
tumor suppressor is called the APC gene. This is a tumor suppressor. And this APC gene is associated
with another familial form of cancer. In this case, it's familial
adenomatous polyposis. And so this is a normal colon. Normally your colon
has a smooth surface. It's basically smooth here. I mean, there are some
folds, but I'm not sure that that's not an effect
of having this dissected out of the organism. But in individuals with
familial adenomatous polyposis, what happens
is that the colon forms many of
these polyps, which are benign cancer outgrowths. But you see all
these polyps here and you see how very different
the morphology of the colon is from a normal individual
and an individual that has familial adenomatous polyposis. So the formation of a polyp is
kind of equivalent to something like this. It's not invasive yet. It would be known as benign. But you can see that
there is clearly a dysregulation in
how this tissue is behaving because you get
all of these polyps forming. And it's thought that
frank carcinoma then results from cells in
one of these polyps accumulating additional
mutations that then cause the
cancer to progress to a more malignant stage. So I told you that APC
a tumor suppressor. And in this case,
this tumor suppressor is associated with this
disease right here. And I showed you the
Wnt pathway last week. And I went through
it quickly, but you notice this central
protein right here in this destruction
complex, that's APC. APC stands for adenomatous
polyposis coli. I will write that down. So adenomatous polyposis coli. And what APC does, as
represented in that slide above, is it's part of this
destruction complex that destroys beta-catenin, which
is the downstream step of Wnt signaling. So the wild type function of
APC is to basically inhibit beta-catenin, which
then is mediating the effects of Wnt signaling. So you can think of APC
as one of the genes that's the brake on Wnt signaling. And normally, it's
regulated by Wnt. So Wnt would
normally inhibit APC. But if you just
delete APC in a cell, then it's like the cell is
seeing Wnt all the time. So by deleting APC, you get
a constitutive activation of beta-catenin and you
get constitutive activation of Wnt signaling. So if the organism starts out
being heterozygous for APC, then there is a high probability
that another mutation will take out the wild
type function of APC or the wild type allele of it. And when you take
out that allele, now you all of the sudden
start having these cells that it's like they
are always in Wnt, even though they're not. And so if you constitutively
activate Wnt signaling, what that does is it
prevents the cells from leaving the organ. So they're stuck. So normally in a
normal colon, cells that are renewed at the bottom
of the crypt, they move up, and then they're
shed into the lumen. But in an APC mutant,
the cells are constantly feeling like they're
getting Wnt signal, and so they stay in the colon. And that allows them to
accumulate further mutations. So step one in colon cancer is
to dysregulate Wnt signaling, and that really disrupts
the whole tissue homeostatic mechanism of the intestine. Then there would be further
steps, at least three usually in colon cancer. And that would involve
mutations, oncogenic mutations, loss of tumor suppressors. And that would just
cause the cells to get more and more oncogenic
and more and more transformed. And eventually, they
can become invasive, and we'll talk about
what happens when cells become invasive next week. So I wanted to end
today's lecture by talking about targeted
treatments for cancer just to see how they
interface with the mechanisms that we've discussed. And of course, some of the
primary ways to treat cancer are through surgery
and also chemotherapy. But there are also more
directed ways to target cancer. And because time's up,
well, I have one minute. I'll tell you about
the first one. And then if I have
more to go, I'll start with that in
next week's lecture. So the first one I
wanted to tell you about is this disease, chronic
myelogenous leukemia, which involves activation
of the ABL gene. And it's activated,
in this case, by a translocation between
two different chromosomes. So this is chromosome 22. This is chromosome 9. And in many patients with
chronic myelogenous leukemia, a large part of chromosome 22 is
translocated onto chromosome 9, and a little bit of chromosome
9 is attached to chromosome 2. And this translocation generates
a gene fusion between the BCR gene and the ABL gene. And so ABL is a non
receptor tyrosine kinase. So it's a tyrosine
kinase that is present in the cytoplasm of
the cell and promotes growth. So this is a proto-oncogene. And when ABL becomes
hooked up to BDR, then this results in the constitutive
activation of BCR ABL. So this is now a
constitutively active kinase. Now when this was
realized, then researchers started looking for small
molecules that would inhibit the kinase activity of ABL. And the famous
example is Gleevec. And this is a picture
of Gleevec here. You can see it's
a small molecule. And what Gleevec
does is now this is a crystal structure of the
ABL tyrosine kinase in green. And it has two lobes, an N
terminal lobe, a C terminal lobe, like a lot of kinases. And what Gleevec does is
to bind in the interface between these two lobes. And it locks this kinase in
an inactive conformation, such that if cells see
this Gleevec, then their ABL tyrosine
kinase is inhibited. And this is the driver of
chronic myelogenous leukemia. So Gleevec has been very
effective in treating this type of leukemia
and it results in a pretty good
prognosis for patients. All right, so we'll talk about
more therapies next Wednesday, but have a good holiday weekend.
