Cancer 2 Flashcards
what are reasons for cells dividing at different rates?
- Embryonic vs adult cells
- Complexity of system (e.g. yeast cell divides every 1.5-3 hours)
- The necessity for renewal (intestinal epithelium - every 20 hours, hepatocytes - every 1 year)
- State of differentiation (some cells never divide)
- Tumor cells are unable to regulate their cell cycle
what happens in the regulation of cell division in cancer?
- in normal cells, premature mitosis results in cell death
- normal cells grow by sensing their neighboring cells grow
(this is called contact inhibition of growth)
- cancer cells lack contact inhibition so they don’t stop growing
- cancer cells also show chromosome instability which results in aneuploidy
what must happen before cells duplicate?
- cells cannot divide before having duplicated their genetic material
- the cell cycle involves duplication, division, and coordination
what is the most vulnerable part of the cell cycle?
- mitosis
- cells are most easily killed during mitosis which is why mitosis is so short
- when you damage DNA during mitosis it cannot be repaired
what are the sections of the cell cycle?
- M phase (mitosis) very short maybe 5 mins
- interphase
- G0 (resting)
- G1 (decision point)
- S ( synthesis of DNA)
- G2 ( decision point)
what occurs during S phase?
- DNA replication
- protein synthesis takes place
- replication of the organelles takes place (centrosomes, mitochondria, Golgi)
- replication of mitochondrial DNA takes place
what is the centrosome?
- very important for cell division
- consists of 2 centrioles made from microtubules
- the functions =
- forms the microtubule-organizing center to organize chromosome movement
- mitotic spindle
what is the life cycle of centrosomes during mitosis?
- In G1 phase there is separation of the mother and daughter centrioles
(they are normally stuck together)
- When they separate they start to duplicate
(mother produces a daughter and daughter produces a mother)
- duplication happens in S phase
- surrounding protein complexes make nucleating sites for the microtubules
- When you put microtubules together it is called nucleation
- As the cell encounters a need for mitosis, the microtubules start to grow from these points and form an array of microtubules
what are the 6 phases of the cell cycle?
insert the pic
what occurs during prophase?
- During the S phase the DNA has been duplicated and in prophase, it is condensed
- the DNA needs to be condensed to minimize DNA damage
- The double helices are wrapped around histones to forms ‘beads-on-a-string’ form of chromatin
- it is further wrapped till a chromosome is made
- the centromere acts as a belt
- At the centromere, there are a load of protein complexes that forms the kinetochore
- The kinetochore is a complex of proteins and it is a key regulator of the processes around chromosomes in the cell cycle
how is the chromatin compacted?
- 2nm to 11 nm wide
- the string is further wrapped to form 30nm fibers
- the 30 nm are extended to make a 300 nm wide fibre
what has occurred at late prophase?
- The centrosome has been duplicated by late prophase
- The microtubules are radiating away from the centrosome
- the nuclear envelope breaks down and the chromosomes come out into the cytoplasm
- the centrosomes migrate to opposite sides
- They then begin to organize the spindle
how does spindle formation happen?
- radial microtubule arrays form around each centrosome
- The radial arrays from the two centrosomes meet in the middle and when they meet each other they are then called polar microtubules
- these tell the chromosomes which way to go
what happens at metaphase?
- the leaked chromosomes go with their pairs to the centre of the cells
what happens at pro metaphase?
- Each of the microtubules meeting in the middle needs to find a chromosome
- the chromosomes attach to the spindles via the kinetochores
- one microtubule array will attach to the kinetochore on each side
what occurs in late pro-metaphase?
- Once captured, the chromosomes slide rapidly towards the middle of the cell
- CENP-E (a protein in the kinetochores) senses whether the kinetochore is attached to microtubules or not
- a half spindle is formed
what are the three types of half spindle?
- Kinetochore microtubule - microtubule bound to the kinetochore
- Polar microtubule - a microtubule that have met and connected with a microtubule from the other centrosome
- Astral microtubule - a microtubule that is originating from the centrosome that does not connect to a kinetochore
what happens at anaphase?
Paired chromatids separate to form two daughter chromatids
what is the action of cohesin?
Cohesin is a protein complex that holds the sister chromatids tightly bound together
what are the parts of anaphase?
anaphase a and b
what happens at anaphase A?
- cohesin is broken down and microtubules get shorter
- chromatids start moving towards the centrosomes
- The daughter chromatids are pulled towards opposite spindle poles
what happens during anaphase B?
- the shortening of the microtubules and the pulling apart of the spindle poles allows the daughter cells to reach the opposite poles
what happens at telophase?
- Daughter chromosomes arrive at the pole
- Nuclear envelope reassembles at each pole
- the centrosomes revert to normal size
- there is a condensation of material where the cells are going to split - this results in an assembly of a contractile ring of actin and myosin filaments
- The contractile ring then squeezes the cell so that it divides into two daughter cells
- The cleavage furrow is where the cells are going to be cleaved
what happens at cytokinesis?
- this is the last phase of mitosis
- there is the insertion of a new membrane at the cleavage furrow
- Midbody = where the actin-myosin ring is formed
what do the cell cycle checkpoints do?
- the cell cycle has checkpoints that check that everything is in place before moving forwards
what is the spindle assembly checkpoint?
when the cell wants to exit metaphase and enter anaphase
what does the spindle assembly checkpoint check for?
- checks for the completion of the chromosome alignment
- checks for spindle assembly
how does the cell know then the kinetochore is NOT attached to microtubules?
- The kinetochore has proteins that emit a signal
- Once the kinetochore attaches to microtubules, it stops emitting the signal
analogy : when a formula 1 car comes in for a pit stop, several technicians change the tyres. When one of the tyres is changed successfully, the technician will signal to say that they’re finished. In effect, each chromosome has a flag and when hooked to a microtubule, it stops sending the signals thus saying that they are good to go
what are the main signalling proteins involved in the signalling process?
- CENP-E
- BUB Protein Kinase
how do BUBS work?
- BUBs dissociate from the kinetochore when chromatids are properly attached to the spindle
- they then go onto signal progression to anaphase
what is the mitotic checkpoint defect?
This happens if anaphase initiates before the spindles attach properly - this results in abnormal division of the chromosomes between the daughter cells
what is mis-attachment of Microtubules to Kinetochores?
- normally the chromosome is made up of two sister chromatids
- one centrosome is attached to the kinetochore of the other chromatid
- this normal attachment allows the sister chromosomes to be split apart and go to different poles
- there is sometimes monotonic, syntelic and merotelic Attachment
what is Syntelic Attachment?
both the kinetochores are hooked by two microtubule arrays from the SAME centrosome
what is Merotelic Attachment?
there is more than one microtubule array attached to the same kinetochore
- this means that one of the chromatids is being pulled in two different directions
what is Monotelic Attachment?
only one of the kinetochores of one chromatid is attached to a microtubule array, the other kinetochore is unattached
what is Aberrant Mitosis?
- If the centrosomes are not duplicated properly you could end up with 4 centrosomes in one cell
- This can lead to very abnormal attachment of the microtubule arrays to the kinetochores leading to abnormal cytokinesis
how does anti-cancer therapy work?
- one can slow down cancer by inhibiting the proliferation of the tumor cells
- One mechanism of cancer therapy is exploiting checkpoint control
- the kinetochore signaling tells the cell when metaphase is complete
- by inhibiting this checkpoint the nucleus can think it is correctly hooked onto microtubules
- this allows cells to proceed to anaphase
- By altering the microtubule dynamics you can cause long-term mitotic arrest
- this means they are killed easily
what happens if a check point realises that a cell is damaged?
- if the damage is temporary then it is called cell cycle arrest
- if the damage is irreversible it causes apoptosis
where do the normal checkpoints take place ?
- G1 - just before synthesis
- metaphase-anaphase checkpoint
- G2 - just before mitosis
how does the cell cycle become de regulated during tumorigenesis?
- normally once cells come out of G1 they enter G0 (active phase)
- tumors block the ability of cells to enter G0 instead they enter a new cell cycle and replicate rapidly
what are the signaling cascades through the cell?
- response to extracellular factors
- signal amplification
- signal integration
- modulation by other pathways
- regulation of divergent responses
how do peptide growth factors signal?
- in the presence of the ligand
- the receptors form dimers and are activated by phosphorylation
how does protein phosphorylation work?
- transfer of phosphate from ATP to hydroxyl groups
- The added phosphate group (negatively charged) can alter protein function by causing a change in shape leading to change in activity
what does receptor activation result in?
kinase cascades
binding of adapter proteins
how do protein kinase cascades work?
- the protein kinase cascade results in signal amplification, diversification and opportunity for regulation
