Cell Cycle Flashcards
1
Q
How does Differentiation of Tumours occur, how can you distinguish between a primary and secondary tumour?
A
- Tumours are graded (how well differentiated they are) and staged(how far they’ve spread)
- Staging is MORE IMPORTANT
- High grade tumours generally have a high stage
- If you find a tumour you need to find out whether it is a primary tumour or if it is a secondary
- This can be done by inspecting the tumour histologically and looking for evidence of normal function still present e.g.:
- Keratin is made by squamous cells
- Mucin is produced by glandular epithelium (adenocarcinoma)
- Bile is made by hepatocytes
- Hormones e.g. insulin is made by the pancreas
- There are specific grading systems for some cancers:
- Breast - Nottingham scoring system
- Prostate - Gleason classification
- Tumours that show little or no differentiation are described as being ANAPLASTIC
TNM
- The grade of a tumour describes its degree of differentiation
- The stage of a tumour describes how far it has spread
- Tumours of higher grade (more poorly differentiated ) tend to be of higher stage
- Overall STAGE > grade in determining prognosis
- The TNM classification can be applied, and individualised, to tumours in all sites
2
Q
What are some reasons why Cell division is specific to each cells?
A
Different cells divide at different rates:
- This shows the Complexity of system (e.g. yeast cell divides every 1.5-3 hours)
- Embryonic vs adult cells (early from embryo cells divide every 30 mins)
- And the Necessity for renewal (intestinal epithelium - every 20 hours, hepatocytes - every 1 year)
- State of differentiation (some cells never divide i.e. neurons and cardiac myocytes)
Tumour cells have an inability to regulate the cell cycle (loose the ability to control differentiation)
3
Q
What is the Relevance of the appropriate regulation of the cell cycle
A
What can result in cell death:
- Premature, aberrant mitosis results in cell death
- In addition to mutations in oncogenes and tumour suppressor genes, most solid tumours are aneuploid (abnormal chromosome number and content).
- Various cancer cell lines show chromosome instability (loose and gain whole chromosomes during cell division) lose and gain parts oh chromosomes
- Perturbation of protein levels of cell cycle regulators is found in different tumours - abnormal mitosis
-
Contact inhibition of growth (spatial information, how do they know that they have enough members)
- cells normally grow by sensing neighbouring cells
- Tumours usually lack contact inhibition so they don’t stop growing
Attacking the machinery that regulates chromosome segregation is one of the most successful anti-cancer strategies in clinical use
4
Q
Which are the cell mechanisms that ensure Regulated progression through the cell cycle?
A
- Cell can’t divide before they have duplicated their genetic material
- The cell cycle involves duplication, division and co-ordination
- You divide both the chromosomes and organelles
- IMPORTANT: mitosis is one of the MOST VULNERABLE point in the cell cycle
- Cells are more easily killed during mitosis, which is why mitosis takes relatively little time in the whole cell cycle
- Damage. During cell division cannot be restored, metabolised in reduced
- When you damage DNA during mitosis, it can’t be repaired
5
Q
Which are the different stages in the cell cycle and what is their individual purpose?
A
- Cells are normally resting in G0 during the interphase, where the cells do their business
- The mitosis itself happens very fast (roughly 5 mins relative to the 24-hour clock model) because it is a dangerous time for the cell
- When a cell decides to enter the cell cycle, they go into Gap phase 1 (G1) (check that everything has been done)
- Following G1 is the S phase (synthesis) where duplication takes place
- Once all the duplication has taken place, it enters G2 (decision point) where the cell checks that everything is OK and ready to go into mitosis (duplicated and all ready to go)
7
Q
Define and describe the function of the Centrosome, what are they made of?
A
- Centrosome - an organelle near the nucleus of a cell which contains the centrioles, and from which the spindle fibres develop in cell division
- Always at 90 degrees between each other
- They are referred to as mother and daughter centrioles
- They regulate the microtubule network to orchestrate cell division (organize chromosomal movement)
- The centrioles themselves are made of microtubules
8
Q
Describe the process of Duplication of Centrosomes and DNA, when does it happen (what is it called when you put microtubules together?)
A
- When the cell initiates duplication and enters the cell cycle, it needs to duplicate the centrosomes
- In G1 phase there is separation of the mother and daughter centrioles (they are normally stuck together)
- When they separate they start to duplicate - the mother centriole will produce a daughter and the daughter centriole will produce a mother
- This duplication takes place in the S phase
- There is a cloud of protein complexes around them and there are points where they 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 (looks like a sea urchin)
9
Q
Describe the Condensation of Chromatin during prophase
A
- During the S phase the DNA has been duplicated and now it needs to be condensed (done in prophase)
- They need to be condensed so that you can minimise DNA damage during mitosis
- The double helices are wrapped around histones to forms ‘beads-on-a-string’ form of chromatin
- This compact the chromatin from being 2 nm wide to 11 nm wide
- The string is then further wrapped around itself to form 30 nm fibres
- The 30 nm fibres are then extended as a scaffold forming a chromosome scaffold - compacting it to a 300 nm wide fibre
- It is then further wrapped until you end up with a chromosome
10
Q
Describe the function of centromeres, kinetochores and their changes throughout Prophase
A
- This is a chromosome that has been duplicated and is being held together in this fashion
- The centromere acts like a belt - it is a constriction around the chromosomes
- 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
- Protein machine that helps condense the sisters together
- So, the condensed chromosomes are present as a pair of sister chromatids
- The centrosome has been duplicated by late prophase (shown in bright green)
- The microtubules are radiating away from the centrosome
- During late prophase, the nuclear envelope breaks down and by doing so, the chromosomes come out into the cytoplasm
- As the nuclear envelope breaks down, the centrosomes migrate to opposite sides
- They then begin to organise the spindle
- The spindle is like a highway that guides the chromosomes to where they have to go
11
Q
Describe Spindle Formation what is its purpose?
A
- Radial microtubule arrays (asters) 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 form highways telling the chromosomes which way to go
12
Q
What happens in Metaphase, how can it be further divided ?
A
- The chromosomes that have leaked into the cytoplasm, following the breakdown of the nuclear envelope, go with their pairs to the centre of the cells
13
Q
Describe what happens in Early Prometaphase
A
- 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 one side, and another microtubule array will attach on the other side
- The nucleus stars breaking down and then you have the spindle formation largerly complete and the chromosomes is the clouds of the back nucleus
14
Q
Describe what happens in Late Pro-metaphase, which proteins control it ?
A
- In late prometaphase, the sister chromatids have been captured by the microtubule arrays
- Protein will sense the stress between the chromosomes and the microtubules
- Once captured, the chromosomes slide rapidly towards the middle of the cell (even if they were captured somewhere other than the middle of the cell)
- In the kinetochores there are specialised proteins, which sense the attachment of microtubules e.g. CENP-E - this senses whether the kinetochore is attached to microtubules or not
- There are three types of half-spindle:
- Kinetochore microtubule - bound to the kinetochore
- Polar microtubule - a microtubule that has 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
16
Q
What happens in Anaphase A?
A
- Cohesin is broken down and the microtubules get shorter, and the chromatids start moving towards the centrosomes
- The daughter chromatids are pulled towards opposite spindle poles
17
Q
What happens in Anaphase B?
A
- Chromosomes at the start is the movement of the chromosomes in one direction and then segregate every part of the chromosome
- Some of the microtubules are pulled
- The daughter chromosomes can reach the opposite poles either because of the shortening of the microtubules that form the spindles or by the pulling apart of the spindle poles
18
Q
Describe what happens in Telophase
A
- Daughter chromosomes arrive at the pole
- Nuclear envelope reassembles at each pole
- The centrosomes are moved apart and the cells try to revert to their normal size
- There is a condensation of material where the cells are going to split and you get the 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
20
Q
Define Mitotic Checkpoint, what is the Spindle Assembly Checkpoint, what does it check, which proteins are used?
A
- The cell cycle has checkpoints which allow the cells to check that everything is in place so that they can move onto the next phase of the cycle
- One of the checkpoints is when the cell wants to exit metaphase and enter anaphase - this is the spindle assembly checkpoint (aka anaphase checkpoint)
- This checkpoint sense the completion of chromosome alignment and also checks for spindle assembly
- The kinetochore has proteins that emit a signal when the kinetochore is NOT attached to microtubules
- 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
- At metaphase, you’re hoping that all of the all the kinetochores will stop sending signals so that they can proceed to anaphase
- There are many proteins involved in this signalling process but two important ones are:
- CENP-E
-
BUB Protein Kinase
- BUBs dissociate from the kinetochore when chromatids are properly attached to the spindle and is part of the signelof saying that we are ll connected and we can proceed
- They then go on to signal progression to anaphase
21
Q
What happens if anaphase initiates before the spindles attach properly?
A
- This is a Mitotic Checkpoint Defect
- It results in abnormal division of the chromosomes between the daughter cells
22
Q
What are the different Mis-attachment of Microtubules to Kinetochores, what is their result?
A
- Normally, you have a chromosome made up of two sister chromatids
- There is normal attachment, where a microtubule array one centrosome is attached to the kinetochore of one sister chromatid, and the microtubule array from another centrosome is attached to the kinetochore of the other chromatid
- This type of normal attachment will allow the sister chromatids to be split apart and go to opposite poles
- Syntelic Attachment - both the kinetochores are hooked by two microtubule arrays from the SAME centrosome, they are going to give tou a duplicatipn of this chromosome
- 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 (most damage)
- Monotelic Attachment - only one of the kinetochores of one chromatid is attached to a microtubule array, the other kinetochore is unattached
- Amphelic is normal: 1 kenotochord is attached to one ☝️ from each pole
- This is how mis-attachment can lead to aneuploidy
23
Q
Describe Aberrant Mitosis, what are its causes and what are its effects?
A
- 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
