The Regulation of the Cell Cycle: Understanding Key Processes and Checkpoints

iron engineer so in this video we're going to talk about the regulation of the cell cycle it's an extremely

important concept so you guys haven't already seen it go watch the video on the cell cycle we talked about all the

phases of the cell cycle in great detail we are going to talk about regulation because regulation is important we have

to know what can actually trigger at the cell to progress right throughout the cell cycle interphase and the mitosis

right but at the same time we have to know what prevents it from actually continuing throughout the cell cycle if

you remember we said that we had that the different parts of the cell cycle we had g1 then we said that what could

happen we could go into the next phase which was called the S phase and the S phase is where we replicated the DNA

then from there we could go to the next phase which was g2 then from g2 we go into the mitosis phase which was going

to be consisting of prophase then metaphase anaphase and telophase and some of the cells might go back into g1

now another thing is that some of the cells we said could go out into another area called g0 the g0 stage where they

could go into this quiescent stage right but in some situations depending upon if the cell is very active in replication

or if there's a proper enough stimulus it could go back into the cell cycle now we did mention something we said that

was really important is there's different checkpoints and where were some of those checkpoints we said there

was a checkpoint right here going from g1 transitioning into the S phase there was a checkpoint here going from g2 into

the mitosis and we said there was a checkpoint right here getting ready to go from metaphase into anaphase so we

have three different checkpoints the g1/s checkpoint and then we're going to have another one

which is the g2 and then to the M phase so g2 m checkpoint and then the last one that we'll talk about here is the M

checkpoint okay so there's different types of genes and enzymes that are going to be

regulating these parts of the cell cycle right so this was our cell cycle and again we said that it was broken up into

two parts interphase which was g1 s g2 and mitosis which was prophase metaphase anaphase telophase

and a part of that was the cytokinesis process right now what we need to understand is is how do we tell how does

the cell know when to go from this g1 into the S phase and how does it know to go from the S to the g2 phase how does

it do this well there's special types of genes so let's take a look at some of these genes we're not going to go into

super crazy detail because this could turn into us a very very long video and I don't want to do that to you guys it's

a very in-depth okay so we're gonna try to keep it moderate so there's special genes okay special genes that are

constantly telling the cell to proliferate okay they're telling the cell it's okay to proliferate so let me

make a small a tiny little crude diagram here let's pretend I take the DNA like this right here's my DNA and let's say

that there's a set of genes right here just a group of them I'm just gonna group them together let's say here's a

group of genes right here and these genes are going to be telling specific other genes that are associated with

maybe transcription or progression throughout the cell cycle maybe it might trigger the cell to go from g1 into the

S phase this gene is responsible for the transitions of the cell cycle these sets of genes there's multiple types of them

are going to be trying to stimulate this process they want to stimulate proliferation what is the name of these

genes that want to stimulate proliferation we call these group of genes the proto unko genes and there's a

bunch of them okay we're not going to talk about all of them we're gonna get the basic ones down

there's another set of genes that are like the brakes they kind of slow down this process they say like hold up we

can't continue this process there's either some type of damage the DNA or the cell is just not ready for you to go

ahead and proliferate and it's going to inhibit this gene these genes which are going to slow down the process or

inhibit this process from occurring these are called your tumor suppressor genes okay so these are called your

tumor suppressor genes and we'll talk about a couple of these all right so let's go ahead and dive into this now

the first thing I want to talk about is with these proto oncogenes there's many different types we have to think about

this very simplistically a cell how does it know when to progress there at the different parts of the cell cycle how

does it know let's just say hey I guess I'm going to do this now no it has to have some type of stimulus you know

there's different types of chemicals that are there designed to drive the proliferation we call those substances

growth factors right so what are some of these growth factors let's pretend we we write down some of these growth factors

you can have growth factors there are so many different types and these growth factors you could have like epidermal

growth factor vascular endothelial growth factor platelet derived growth factor there's so many different types

of substances that are designed to be able to trigger the growth process now how do they do that is the question well

at the same time we have receptors that respond to these growth factors what kinds of receptors you ask let's go

ahead and see so let's say let's pretend that we have a growth factor here here's our growth factor and this growth factor

is gonna come over here are they you know another name for growth factors they call them mitogens so another name

for growth factors is they're called my toe gens because they're gonna want to trigger the mitosis process so these

growth factors let's say they come over here and it stimulates this receptor if you guys have watched our videos you'll

notice by now that this is usually rep presenting a seven pass or scepter or also known as a g-protein coupled

receptor there's different types of g-protein coupled receptor let's assume that this one is what's called a G Q

protein now you know GQ not the magazine this is an actual protein GQ is actually important because what GQ does is it

comes over here it combined on you know it's normally bound to GDP gets rid of the GDP and then it binds gtp which

makes it active then from here it can come over and bind on to a special effector enzyme located within the cell

membrane and this effector enzyme can be called what there's an effector enzyme here called phospholipase C and what is

this phospholipase C do phospholipase C once it's stimulated by this GQ it converts pip2 phosphatidyl in a SCYTL

diphosphate into what's called D a G which is standing for diacyl glycerol and another molecule called ip3 now what

the heck does any of this have to do with it let me show you it's all about how these things work the downstream

effect from it this diacylglycerol can go and activate special enzymes what is these enzymes these enzymes can be

protein kinase in this case C so it's protein kinase C will put pkc for this now what can protein kinase c do protein

kinase c can go and activate different types of transcription factors isn't that cool

it can either activate transcription factors are different types of proteins that are going to go stimulate different

genes so we can put transfer transcription factors or other different types of enzymes that can activate these

genes these proto oncogenes what else this ip3 what can it do you know there's different types of calcium storage

centers let's pretend here's a calcium storage center right here it is it's going to be housing all the calcium

you can possibly imagine so here we're gonna have this calcium storage center and what this guy is going to do this

ip3 combined onto special calcium proteins and what it'll do is it'll push this calcium out into this area right so

now we're gonna have lots of calcium out here this calcium guess what it can do it can go and bind onto another protein

this protein is called calmodulin calmodulin when complexed with calcium right so you can have calmodulin and

calcium they can actually be complexed together when these two are complex together you get what's called a calcium

calmodulin complex calcium calmodulin complex or also we can say kinase what can these kinase is do they can come

over here and guess what what did we say this was doing activating transcription factors or different enzymes guess what

this sucker can do he can come over here and activate specific transcription factors or specific types of enzymes

that could stimulate these genes okay so that's one pathway what's another thing well here's another one this was a

g-protein coupled receptor but it was specifically coupled with the GQ guess what I'll see you could have you could

have another one over here look at this guy he's very similar he's a red protein this is a g-protein coupled receptor

let's say that there's the same thing here's some growth factor some mitogen that wants to tell the cell to go ahead

and start proliferating has to bind onto this receptor this receptor is actually coupled with AG stimulatory protein and

remember normally it's bound to gdp but it gets rid of it and binds gtp and it becomes active what does it do then it

comes over here and stimulates a special effector enzyme located within the cell membrane this effector enzyme here is

called adenylate cyclase and a dentally cyclase once stimulated can convert eight

TP into cyclic EMP cyclic EMP can then activate what's called protein kinase a what did the other protein kinase do

protein kinase C it phosphorylated different types of transcription factors or enzymes that can go and activate

these genes oh man there's one way there's two other ways we're just doing a couple can you imagine that let's say

there's another growth factor here's another growth factor or a mitogen and it binds on to this receptor

now this receptor let's say that it's what's called a tyrosine kinase receptor so this is called a tyrosine kinase

receptor now technically you actually need two of these so let's pretend for a second what happens is the growth factor

binds and it actually triggers the dimerization of two of these receptors these one-pass receptors and when they

dimerize it triggers this phosphorylation event you know there's different types of phosphorylation sites

there's different amino acids here there's different amino acids here called tyrosine amino acids and what

happens is once this tyrosine kinase receptors activated by some growth factor a mitogen it causes the

phosphorylation of these different tyrosine residues now once you phosphorylate that there's a protein

that sees that he's like mmhmm I need to get me some of that and what does he do he comes and binds to it what is that

protein called that comes over here there's a protein here who has a self hydro group which is just a SH group and

he's called grb-2 protein and this grb-2 protein is then connected with the Sun of seven less protein

once the grb-2 interacts with the tyrosine kinase it activates the son of cephalus protein guess who the son of

seven less protein activates he activates another protein this protein is called R as it's called rads and R as

is a GTP ace so usually he's bound to gdp but he gets rid of that sad boy and then

he binds gtp and when that happens guess what this guy this razz goes and activates another molecule which is

called wrath and then wrath can go and activate another enzyme which is called map kinase you know what map kinase can

do map kinase can then go and phosphorylate different types of enzymes different types of transcription factors

needed to trigger these response genes these genes that are going to trigger the proliferation

there's obviously one more this last one here which is pretty cool is what's called a Jonas kinase receptor so you

have what's called this is called a jack this is this pathway we're gonna talk about no it's actually just right now

this is actually gonna be Jonas kinase receptor right so again same thing here some growth factor binds on here when

this growth factor binds on to this one pass receptor it stimulates it this joint is kindness again it has specific

types of amino acids on it specific types of amino acids and these amino acids once this sucker is stimulated it

causes the phosphorylation right so now once it's phosphorylated we're gonna have special proteins that will actually

be activated so you're gonna activate the specific molecule you'll have what's called jhanas kinase we're just gonna

denote it as jak so John is kinase there's this receptor once stimulated activates an enzyme called jhanas kinase

so as Jonas kinase well guess what he can do he can go and phosphorylate specific types of transcription factors

so he can come and phosphorylate specific types of transcription factors as well so what are there's technically

a one that he does stimulate for this guy it's actually called stat okay it's called signal transducer activator of

transcription and so that's why they call this pathway the jak-stat pathway okay and that signal transducer

activator of transcription can go and bind on to some specific gene so now we know a cell is getting ready

it wants to it actually needs to know what is the drive to make it want to replicate it gets these mitogens these

growth factors these chemicals that are going to trigger these intracellular processes now once it's been activated

we've caused this interest intracellular cascade now it's up to this point these transcription factors are these enzymes

that are going to go and activate these specific genes so now it's all dependent upon these guys so what are these guys

gonna do for us how are they gonna help us let's go over here and see so you have specific genes here right here's

our DNA we just have it oriented this way for space sake but here we're gonna have our double-stranded DNA and we're

gonna have specific genes that we're going to talk about first one we're gonna talk about here is you have

different types of genes that are gonna be directly responding to these types of transcription factors look these guys

are gonna come over here and stimulate these genes what are some of these genes the example of some of these genes

there's many different types I'm definitely not gonna mention them all cause there's so many you know there's

what's called myc genes you have what's called foz genes you have Jun genes there's so many of these different genes

what are these genes do and that's the important thing to remember once you have these signals because these are

basically the signal transducers once you have these signal transducers they're gonna tell these genes to start

producing a specific product what is that product these genes will then produce a specific type of transcription

factor so let's say it produces a special type of transcription factor here's our transcription factor

transcription factor what is this transcription factor going to do well it's gonna go and tell some other gene

to do something that's how all this stuff is it's always just a cascade of events so this transcription factor it's

going to come to another set of genes I see these green green genes here these green jeans are super important

this is a jeans that are associated with producing proteins which are called cycling's there's many different types

of cyclones the ones that we'll focus on in this video is D e a and B cyclones so we'll talk about these cyclones at the

end of the video but this gene is responsible for producing cyclones so this is got to be some type of cycling

gene right now your pilot what the heck does this have to do with anything these are so important so so important and

being able to control the progression of the cell cycle and each one is specific to different

parts of the cell cycle we'll discuss that at the end there's an easy way to remember them now these cyclones they

don't like to be by themselves they don't like to work alone they like to work with a partner so there's another

gene and this gene is constantly being is producing a protein product at a constant rate

what is this protein product called these are a special type of kinase and they call these kinase since they have

to be bound with cyclin they call them cyclin dependent kinase is so let's draw this like this let's say here's our

cyclin dependent kinase alright so here is the cyclin dependent kinase right here

there's blue molecule and it has to be bound with the actual cycling's and again there's different cyclin dependent

kinases for different Cyclones and we'll talk about some of these like cyclin dependent kinase 1 cycle dependent

kinase 2 3 4 6 we'll talk about some of these now these cyclin dependent kinases have to be bound with these different

types of cyclin so let's represent the Cyclones like this so what's going to happen here the Cyclones and the cyclin

dependent kinase is will actually combine together they'll combine together so now what will we have here

let's say that we have it like this now in here we're gonna have our little green dude our little cyclin

now what is this gonna do this is the thing that you guys need to remember the halleluiah this guy is pretty much gonna

help us to drive this cell cycle how okay remember I told you this is trying to

stimulate proliferation of the cell well there's other genes that are trying to inhibit the proliferation of the cell

what is one of those there's a protein over here actually a gene product let's make him right here this this

brown one this guy right here is going to be called retinal blastoma protein so we're gonna make a protein right here

and this protein that we're making is called retinal blastoma protein will write it as RB okay retinoblastoma

protein retinoblastoma protein is really really cool and the reason why is he is bound to a special type of transcription

factor let's use red here's this transcription factor so normally retinoblastoma protein is

produced by the this specific gene the retinoblastoma gene this retinoblastoma protein is bound normally to a special

transcription factor it's normally keeps it bound and prevents this transcription factor from

binding on to specific genes that are going to want to cause the proliferation what is this transcription factor this

transcription factor is called e2f this guy is called e to F so the retinoblastoma protein is produced by

these tumor suppressor genes it is a tumor suppressor gene and it's bound to e to F preventing the e to F to bind on

to specific genes that are going to trigger the proliferation the cell the progression throughout the cell cycle

but you know what these cyclin dependent kinases are so intelligent they're like you know what I know that if I go and

phosphorylate the retinoblastoma protein he ain't got nothing so that's what I'm gonna go and do these guys come down

here and they phosphorylate the heck out of this protein they start doing what's

called hyper phosphorylation so they're gonna do what's called hyper phosphorylation on this retinoblastoma

protein now if you know anything about proteins their structure determines their function if we phosphorylate this

protein it's gonna change its three-dimensional structure in such a way that it no longer can bind on to e2f

so what's gonna happen now now that we've hyper phosphorylated it it's no longer gonna be able to be bound

so now it's gonna start disassociating away from it so once we hyper phosphorylate this bad boy now we're

going to disassociate from this guy and we're going to have our E to F protein separate so now here is going to be my e

to F protein and the e to F protein is disassociated from the retinoblastoma now what can this e to F protein do okay

the e to F protein after it's been levied and released from the RB protein it can go and bind onto specific genes

what type of genes let's say here let's say here is the ultimate goal the ultimate genes right here let's come up

a little bit here here's a special gene right here and this gene is going to be the gene that once stimulated it'll

produce different types of transcription factors that trigger the conversion throughout the cell cycle

maybe g1 to s maybe g2 to M phase whatever it's going to be stimulating the sailer progression that's the

ultimate goal so guess what e to F does once he's been alleviated and released from the retinoblastoma protein he comes

over here and he says yeah baby start producing the specific types of proteins that we need to trigger this process to

start proliferating triggering the cell to go throughout the cell cycle we wanted to progress now this is extremely

important but at the same time there's always a way you have to be very very careful you

don't want this to happen if the cell is not ready to actually undergo replication why you know we have a bunch

of different tumor suppressor genes one of the ones that is really cool let's make it this black one right here this

black gene here is called the a T mg and and the name is crazy it's it's a taxi ax telangiectasia mutated that's

probably why I like to kiss a ATM gene but this this gene it's responsible for producing different types of proteins

and these proteins these enzymes are good at being able to read the DNA what do I mean so let's say here I have the

DNA and I have some type of mismatched base pair somewhere here maybe it's right here there's a mismatch base

mismatched base pair for whatever reason there's some problem with the DNA these genes go and proofread the DNA they make

sure that there's no mistakes if there is a mistake oh boy we have to start telling another gene to stop this

process so ATM is really important for being able to read the gene so this is kind of like our proof reader this is

kind of our proof reader if you will all right so he produces different types of proteins or enzymes and they come and

they actually read the DNA and make sure that there's any mistakes it has to alert another gene a really important

gene what is that gene that it'll actually stimulate it'll stimulate this bad boy right here this guy you guys

should all be thankful for him he basically is what's helping us to prevent us from constantly having maybe

tumors this is called p53 p53 is such a powerful tumor suppressor gene such a powerful one and we'll talk about that

in a second but just remember if there is any problem maybe there is some type of

mistake here if there's a mistake guess what he's going to do he's going to go and tell this gene and then p53 will be

alerted of it and take care of it and we'll talk about how now there's another thing in the same

way if there's a mistake there's other genes other different important genes that can go and repair that there's

different types of DNA repair genes and let's just say that we have it right here here is this this red gene this red

gene can actually produce it can actually produce different types of enzymes so say there's different types

of DNA repair enzymes they can go in and do different types of you know nucleotide excision repair or Nick you

know repair whatever it might be they can come in and they can try to fix that mistake this is something that's really

important and the p53 gene can actually stimulate this process so the p53 gene can actually produce different types of

protein molecules and help to stimulate this production of DNA repair enzymes and if this is repaired properly okay

well then maybe we can go ahead and cause this cell to continue to go through the cell cycle so so far we know

we can proofread the DNA through these ATM genes and they produce proteins that read the DNA make sure there's no

mistakes if there is a mistake they alert the p53 complex and you can tell different other genes to produce

proteins that help to modulate that activity one of them is the DNA repair enzymes now here's the thing though p53

is heavily regulated there's another protein nearby let's say is this blue protein right here there's another

protein right by this gene is called mdm2 and the m2 is it produces a special type of this is the gene it produces a

protein a special type of protein and this protein loves to inhibit the p53 products so let's say that it actually

here let's do it like this here's the mdm2 any product that is produced here this guy's trying to inhibit that so

it's basically preventing the p53 complex this guy right here this mdm2 is what's called an e3

ubiquitin ligase and all he's doing is he's putting the the brakes on this p53 complex inhibited it from causing these

effects so that's important because what happens is when mdm2 whenever there is a lot of DNA damage

this mdm2 can be inhibited and if mdm2 is no longer inhibiting the p53 p53 can start telling these different types of

DNA repair enzymes different types of other tumor suppressor genes to start producing protein products so it's

important to know that p53 can't just do this on its own he has to be regulating himself what is that regulator

it's called mdm2 he produces a protein called an e3 ubiquitin ligase that basically inhibits the p53 complex

preventing it from sending signals to other different tumor suppressor genes but if the mistake is so bad we need to

tell the p53 complex to inhibit the process from continuing so what does he do he disses soat MDM to disassociate

sfrom p53 and p53 can start sharing these functions so we know that it can activate DNA repair enzymes and if it

fixes it maybe to go on but there's other ways let's say that in some situation maybe it's not enough maybe

even though the DNA repair enzymes did check it we got to do something about this we can't let this continue to

happen the cells got to go the cells got to die we can't let it progress for whatever reason we can activate special

genes these genes right here these are going to be called our pro a popped Adak genes an example of this one could be

like backs backs is you can have a gene that can produce a molecule you know like here look I say here's a

mitochondria here's a mitochondria and you're gonna have these proteins here called bcl-2 what happens is backs can

come over here and pull that bcl-2 molecule out then when it does that another molecule called cytochrome C can

leak out and bind on to specific types of enzymes what are some of these enzymes

one of them can be like cast bases and these cast bases control cause cell destruction so now we should understand

why this is important these pro apoptotic genes they could say hey we got to now cause the cell to die so

we're gonna give signals for apoptosis if there is no way of being able to fix the mistake if it's too bad there's no

going back now other ways that we can prevent this process or maybe even slow it down remember I told you that the p53

is so cool it can control so many other different types of genes it might tell the DNA repair enzymes go ahead and try

to fix it do the best you can guys it might come over here and tell the you know pro-apoptotic genes like backs

hey we got to have the cell dock there's just no way that we can prevent this cell there's no way we can allow the

cell to go any farther sometimes it says we need a little bit more time there's just not enough time we need to be able

to fix some things so let's prevent this e to F from binding here so guess what it does this

is super cool these brown genes the p53 can come over here and it can stimulate these brown genes what are these brown

genes there is so many of them are only showing it by one but there are so many of them to pretend here for a second

some of them there's what's called a p15 there's p16 there's P 18 P 19 p21 P 27 P 57 if you can imagine there are so many

of these types of genes now you're probably like what the heck are these what are they doing guess what remember

hide the cyclin dependent kinase is and they were kind of the crux of the issue they were phosphorylating the

retinoblastoma protein releasing the e2 F and triggering the transition well these guys the P 1516 27:57 18 19 21

they produce different types of proteins and these proteins oh man it's just so cool they come over here and they

inhibit these they inhibit the cyclin-dependent kinase you know the name for these things all

these proteins they actually give them a category like name they call them cyclin dependent kinase inhibitors like P 15 16

18 19 21 27 57 right they come over they inhibit the cyclin dependent kinases if the cyclin dependent kinase is are

inhibited can they phosphorylate the retinoblastoma protein no if that's the case guess what happens

e to F REE binds with the retinoblastoma can the cell can this e to F stimulate the genes to go throughout the cell

cycle no so it puts the brakes on it says hey let's wait for a little bit let's see if we can fix this up then we

can progress so that's what's really important so the p53 is only produced in low concentrations whenever mdm2

disassociates with it it can then help to regulate this process now that we've talked about that I told you that we

were going to talk about some of these cycling's and cyclin-dependent kinases throughout the cell cycle so there's an

easy way to remember this okay I remember deep okay so d e a B cyclin D is the first one okay it's gonna be in

the first part the g1 phase so in the g1 phase let's actually make another little one here so we're gonna have the g1

phase going into the S phase S phase to the g2 and then g2 into the M phase and if phase can go back here right now and

D is associated with the g1 to s transition not the transition the actual flow so it's mainly regulating the g1

phase so right here in this part throughout the g1 phase from here to here you're going to have the control of

a special type of enzyme and this is actually going to be through cyclin D remember I told you cyclones have to be

complexed are combined with CDKs but they're specific ones so if it's cyclin D it has to be combined with cdk4 and

6.now right here at this checkpoint we said this point right here there's special enzymes that regulate this part

you know there's again more CDKs more cycling's and again there's those tumor suppressor genes but for the Cyclones

here it's regulated by specific type of cycling what's the next one e cyclin e and cyclin e is combined with a special

c DK and this is cdk2 and again that's going to regulate this part now we got this next cool one from here even a

little bit so from the S phase and even going towards the s g2 transition and even even a little bit past that this is

going to be the next one so we got de a so cyclin a and cyclin a is going to be connected in our conjugated with cdk2

the last one which has a little bit of overlap here is going to control up to a specific point in metaphase and this guy

is going to be cyclin B cyclin b and cyclin b is complex with what cdk1 here's the one last thing that we have

to talk about guys and we are finally done remember I told you there was a checkpoint one last checkpoint with in

the mitosis part specifically at metaphase specifically at metaphase if you remember we talked about this before

let's pretend that we're at metaphase so we have our duplicated chromosomes if you remember we said that there should

be microtubules connected to a special protein structure around the centromere called the kinetochore there's other

proteins there there's another protein here called securin and secure in is actually bound to another protein called

separase so it's bound to a protein called separase okay now there's another protein there's

so many freakin proteins one more protein is actually going to be right here it's actually a part of the

centromere it's what's keeping these different chromatids together that protein that is kind of keeping the

chromatids together is called cohesion cohesin that's easy to remember it's cohesive it's called allowing them to

stick together well secure him is binding to separase if separase is actually bound to secure

and separation as a Proteus enzyme it likes to break down proteins what's the protein do you think it likes

to break down cohesin well we have another way of fixing this if everything is successful if these chromosomes are

aligned on the metaphase plate perfectly our body produces another protein that protein is called a P C this stands for

anaphase promoting complex guess what this does APC comes over here and inhibits securin now securing is no

longer bound to separate if separase is no longer bound to secure and guess what it's gonna go here and do it's gonna go

break this soccer down its gonna break the cohesin down if the cohesin has broke down what do you think is going to

happen the chromatids will separate and we finally finished that part where we can end the actual metaphase cause the

cells to break into two parts Oh an engineer's I'm so it's hard after that thank goodness we finished that if you

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