Tuesday, March 17, 2009
- If we go back to the question he raised in the first lecture: How do cells
control their shapes, their interactions, their numbers to build tissues,
organs & organisms?
- So far we’re talked about control of cell shape, cell interactions with
themselves or with the matrix & now he’d like to turn to the control of cell
numbers, both by controlling cell division & cell death & next week we’ll
talk more about mitosis & also the link to cancer b/c one of the key things
to cancer is the control of cell number.
- Next week we’ll discuss more about cancer, but during the lecture today,
he’ll also highlight molecules, link to the cell cycle that are also implicated
in cancer as well & so we’ll cover that again next week in more detail.
! Cell duplicates and segregates its genome
- Here is the eucaryotic cell cycle illustrated in a basic way. Here we start
off with a single cell and then that cell divides. A key aspect of this is that
the material in the cell has to duplicate itself. If the cell is going to divide, a
lot of material has to be produced so the cell cycle is important to have cell
growth which is illustrated in this simple cartoon. You can see the
increased size of this cell, so that’s the increased growth of membranes,
increased growth of the cytoskeleton, for example, mitochondria, ER
membranes, Golgi membranes so there’s enough material to divide into 2
for the next round.
- The duplication and the segregation of the genome is critical because this
encodes all the instructions for everything that’s happening inside the cell
so if there is a mistake made in the duplication of this genome, during the
synthesis of the DNA, that could create mutations which would lead to
problems in the cell. If during mitosis, certain chromosomes were lost, then
of course that’s going to cause problems as well. So it’s critical for both
cells that are dividing & developing organisms that they synthesize &
segregate their DNA properly during division so that those cells maintain a
proper cell physiology & if they don’t, then that’s often associated with the
development of cancers in our bodies.
- Also for the proper passage of DNA from one generation to the another to
maintain the species, they need to maintain their DNA properly to be able
to pass on from generation to generation & this all comes down to the cell
cycle & the control of how the cell duplicates & segregates the genome
- Here is the cell cycle in more detail, broken into specific phases. So we
can start right here – this is just after division has happened so this single
cell has just been born from a division & the first phase is called G1 or gap
phase 1 and it is a period of cell growth. Here is when the cell is partially
doubling its proteins & organelles so that it builds up in size getting ready
for a future division itself. So here it’s growing.
- The next phase is called S phase which is dedicated to the synthesis of
DNA so the replication of the genome. Here we have the replication of the
- This is then followed by a second gap phase, G2, and this is another
period of cell growth where the remaining proteins and organelles will
- Then if everything is in order the cell will then enter M phase where both
the nucleus & the entire cell will divide so 1st you’ll have a nuclear
division, then you’ll have a cell division to split all the material of the cell
- So next week we’ll talk about mitosis in much more detail. Today we’re
going to talk about the transition b/w these different phases.
- You can see from the fact that it has 1 phase after the other, this needs to
be temporally regulated & coordinated & there are many processes going
- So a key thing for this is the cell must ask itself, it must check whether
things are going okay during the process. Ex: Are there enough resources
for DNA replication? Is this initial growth phase going effectively? Are
there enough resources there for me, the cell, to replicate my DNA? Then
for example, has the DNA actually replicated before mitosis starts? So
before you start trying to split the DNA into two cells, the cell has to be
sure it has actually replicated the DNA, that it has 2 copies of the DNA to
separate into the 2 cells – if it doesn’t, then one of the cells is going to be
missing huge sections of the genome. So these questions are asked at
specific phases of the cell cycle.
- So if we start again at this growth phase, before the cell goes into the S
phase, the cell will ask itself is the environment favourable? Are there
enough resources present? Here is a key checkpoint right here, the
transition into the synthesis phase of the DNA so if there aren’t enough
resources present at that time, the cell will just stay in G1 phase, it will wait
until resources are available & then it will replicate its DNA when the
conditions are better.
- The other key point where there is a checkpoint is here for the entry of
mitosis. Here it will ask is all the DNA replicated? Are there 2 copies of the
genome to divide b/w the cells & it can also check again if the environment
is still favourable. Here is a growth phase right here, the cell can monitor
whether it’s growing properly, are there enough resources there? If there
aren’t then it can halt again at this stage & wait until the environment is
more favourable & then divide.
- Then there are other checkpoints during mitosis & we’ll touch on those
again next week.
! Protein kinases
- So the core molecules here are Cdks which are protein kinases & Cdks
stand for cyclin dependent kinase. These are protein kinases & they have
targets that control the cell cycle so they phosphorylate proteins that will
control different stages of the cell cycle.
- One key step is that another protein called a cyclin has to bind to these
kinases to turn them on, so this is one way to turn on these molecules to
pass through the checkpoint.
- Diagram; We’ve got the cyclin present here, here is the Cdk – you need
both of these components, and more as we’ll see in a moment, to activate
! At different stages of the cell cycle
- So to coordinate things in time during this cycle, there are different
cyclin-Cdk checkpoints at different stages of the cell cycle.
- So if we started off here at G1 right here, the cell is growing, things are
favourable, there are lots of resources available, if that’s the case the cell
will then signal to produce this S cyclin, the cyclin that will promote the
synthesis phase. This will then bind to the S-Cdk & this complex can then
phosphorylate machinery involved with DNA replication in the cell so the
cell can dedicate all of its machinery to replicating the DNA.
- Once that job is done, the cell wants to turn off that machinery since the
genome has been replicated, they don’t need all of those enzymes present
anymore to duplicate the DNA so now this cyclin is destroyed. So we have
a very specific cyclin-Cdk complex to promote a specific phase of the cell
cycle & then it’s destroyed after its job is done.
- Now once the cell then passes through S phase, it passes the G2 phase, it
grows again & then it monitors are there is enough resources still and has
the genome been fully replicated? So if both of those things are okay, then
it will produce a different cyclin called an M-cyclin which will interact with
the Cdk, producing a different cyclin-Cdk complex & this complex
promotes the machinery controlling mitosis which we’ll talk about in detail
- Once that is done, so this would be machinery like building the mitotic
spindles out of microtubules, once that’s job is done & the DNA has been
segregated into 2 cells, you don’t need that machinery anymore, so this
cyclin is destroyed, the activity of this cyclin-Cdk complex is turned off so
then this mitosis machinery is turned off.
- So this is a molecular cycle then where the cell can control whether it’s
activating DNA replication machinery or mitosis machinery depending on
which cyclins are available & these are monitoring the availability of
resources & whether the DNA has been duplicated & so on – these are the