Let's go back to the retinoblastoma genes.
Let's talk a little bit more about that.
And remember it's going to be an important way
that we regulate the go, no, go signal at the G1S phase.
Okay, so normally retinoblastoma gene product
that the RB protein is not highly phosphorylated.
It may have a couple phosphate groups on it,
but it's not highly phosphorylated
and in that particular confirmation it binds
to elongation factor 2, E2F,
and holds it there and it's kind of like
a lock on the cell cycle.
See the motorcyclist, it's a cycle and he's got
a little lock on the wheel so that it can't go around.
That's what the hypophosphorylated RB protein is doing.
It's not allowing the cycle to progress.
And it does so because it has the E2F
and the hypophosphorylated RB protein
sit down on the E2F sites, things that
are going to be transcribed
and brings in also histone deacetylase
and histone methyltransferases
that are going to turn off transcription at that site.
So that's basically how it's a big lock on the site.
Okay. It allows E2F to bind
to its transcription site,
but it turns off active transcription
by binding so avidly. Cool.
Alright. How do we release the cell cycle?
How do we take the lock off the cycle?
Okay. This is where - now, we have
growth factors that have come in.
We have gone through the early stages of G1
and we're at the kind of G1S site on a cell cycle.
As we gone through the growth cycle,
the early growth G1 phase
we are generating cyclin D and cyclin E.
And the cyclin D is going to interact
to CDK4, also CDK6.
Cyclin D is going to interact with CDK2
and they are going to, as part of their activity,
remember when you have the cyclin bind
to a CDK, it becomes an active kinase.
Those active kinases and those complexes
now are going to hyperphosphorylate
at many, many, many more phosphate
groups to retinoblastoma.
When it does so, that protein now releases E2F.
So, you can see that hyperphosphorylated thing and now the E2F
is free to go about its business, elongation factor 2.
Now, it can sit down on its site and we no longer
have the histone methyltransferases
so the histone deacetylases and we get active
transcription of the next set of proteins. Okay?
So, we have gotten the signal that allows us to
progress through the cell cycle through the G1S checkpoint.
There are various ways that we can also stimulate
the next steps or inactivate the next steps.
And as part of the control
you can elaborate inhibitors that
block that hyperphosphorylation step.
Okay, so it can be bewildering,
but when we do have the E2F free
to do its thing away from RB,
the cell cycle lock is gone.
And now you see our motorcycle
is speeding away.
So, in words, sometimes words
are easier to understand.
Retinoblastoma is a protein that
is a break from the cell cycle.
In its hypophosphorylated state, it complexes
with E2F a transcription factor complex
as well as histone deacetylase and histone methyltransferase
to keep downstream cell cycle genes turned off.
When we get the elaboration of cyclin D
and then the complex of cyclin D plus CDK,
that will phosphorylate RB
and other proteins as well,
but that phosphorylation to the RB dissociates
it from the histone deacetylase
and removes inhibition of E2F
and now we can get elongation
of the new genetic material
will enter the S phase.
Other cyclins and other DNA
polymerases are also expressed
and this will push us ultimately
through the G1S transition,
but the key feature is the release
of E2F from the RB break.
So, now we're off and running
on that cell cycle.