Okay, there can be a lot of words, we're going to start at the top and work our way
through, hang in there. So, cell cycle regulation has got a number of players. So, initially
there is some sort of growth factor stimulus and it can also be interactions with the
extracellular matrix through integrins, but there is a growth signal. That's going to start
the cell through the G1 phase. It's going to start making more proteins. It's going to be
phosphorylating proteins getting close to that G1S checkpoint. Okay, some of the genes
that get activated from the growth factors or from integrin interactions are going to be
MYC and RAS and a whole bunch of other genes and if you haven't already heard about
MYC and RAS and all the other genes, you will. They are potential targets for
chemotherapies in malignancy because they control cell cycle. The phosphorylation of MYC
and RAS and other proteins will lead to the expression, ultimately the transcription of new
message for cyclin D. Okay, so cyclin D will now be increased in amount within the tissue.
That allows it to interact with its CDK, it's cyclin-dependent kinase 4. We make a cell cycle
complex that will allow us to do the next step. We'll get us through the G1S transition.
Well, how does it do that? Well, that cyclin CDK 4 complex will now act on the
retinoblastoma protein, RB, and will hyperphosphorylate it. Don't worry, we'll come back
to this and walk you through those steps because it becomes interesting and important.
That RB phosphorylation, that's going to be a major way that we're going to regulate the
next step. We release from RB a protein called elongation factor 2 or E2F. That E2F, just
like it says, will allow us now to elongate the transcription or translation of the DNA
so we can now replicate it in the S phase. Okay? We have then also, during this period
of time where E2F is inducing the transcription of other proteins, cyclin E in particular, gets
made. And we're also going to transcribe and translate a variety of DNA polymerases
and other genes because of the effect of E2F. That cyclin E is now going to interact with
its CDK, CDK2 to make an active complex that will allow us to go finally from G1 into the
S phase. So last steps in here. Okay, that is at that particular point on our cell cycle. So,
we've gone from some sort of external stimulus, getting upregulation of cyclin D. It
interacts with CDK4 to cause ultimately the hyperphosphorylation, a lot of phosphate
groups and retinoblastoma, RB. That will release the elongation factor 2 which will allow
finally the transcription translation of cyclin E so that we can make the cyclin E CDK2
complex to drive cell cycle progression from the G1 to S checkpoint. Okay, good. There is
more regulation. Okay, so hang in there. So, there are many, many, many checks and
balances on this process. I'm only going to highlight some of them. It can become dual
ring, remember that original slide with all the ovoids on it with red and blue. Yeah, well.
Okay. So there are a number of checkpoint regulations. One of these that gets generated
during the cell cycle progression is p16INK4 that will turn off the cyclin D CDK4 complex.
Another checkpoint that can occur is the upregulation of molecule called p27. It's a
phosphorylated molecule 27 kilodaltons and it will inhibit the cyclin E CDK complex. So we
have many different ways that we can inhibit the pathways that will take us through cell
cycle. Even if everything elses go, we have ways to say "Nope, we're not going."