the cell cycle and its control Flashcards
what determines thje rate at which cells divide
embryonic v adult - embryonic divide faster
complexity of system
necessity for renewal - intestines faster than hepatacites because intestine cells shed a lot becasue of poo passing through them, however liver really slow unless have an injury then it can speed up
state of differentiation - if dividing you’re not differentiating (some cells never divide ie neurons and cariac myocytes, however hair adn intestine divide rapidly - highly proliferative = affected in chemo)
tumour cells - lost proliferative control, so proliferate a lot
why is it important that the cell cycle is regulated *
premature, aberrant mitosis = cell death
solid tumours usually have mutation in oncogene and tumour suppressor gene and are aneuploid (abnormal number and content of chromosomes) because steps in mitosis are deregulated
cancer lines show chromosome instability - lose and gain whole chromosomes during cell division = deregulation of everything that was part of the chromosome that was lost
change in protein levels of cell cycle regulators is found in tumours = deregulation of cell cycle
contact inhibition of growth - normal cells grow until they have spatial recognition that they need to stop - in tumors this control is lost so they invade
what is an important anti-cancer strategy *
attacking the machinery that controls chromosome deregulation
what is the cell cycle *
an orderly sequence of events in which a cell duplicates its contents and divides in 2
involves dupilcation then division
what are the 2 phases of the cell cycle *
M phase - mitosis
- division phase
- nuclear division
- cellular division
interphase
- dupilcation
- dna
- organelles
- protein synthesis - increased because all materials are split into 2
why is mitosis a vulnerable phase for the cell *
cells are more easily killed - irradiation, heat shock, chemicals
DNA damage cannot be repaired - mutation will be in daughter cells
gene transcription silenced
metabolism reduced - focus energy on division
relatively how long is the M phase *
quick becasue cell is vulnerable here
what are the phases of interphase *
G0
G1
S
G2
describe G0 *
cell machinery is dismantled
where most cells are - doing their function
describe G1 *
gap phase
decision point - check that everything has been done so the cell can move onto the next step
ie check mitochondria etc
describe s phase *
synthesis of DNA/protein - DNA replication
increased protein synth - initiation of translation and elongation increased, capacity increased (ribosomes increased to produce proteins quickly)
replication of organelles - centrosomes, golgi, mt - mt dna replication is coordinated with whole cell dna replication
describe G2 phase *
gap
decision point - check DNA has replicated and sorts any mutations
what is the centrosome organisation *
made of 2 centrioles - double barrels of 9 triplet microtubules, barrels at 90degrees - held together by dense protein material
illustrate the cell cycle *
function of the centrosome *
coordinates chromosomal movement
they form the microtubule organising centre - form highways of microtubles that control chromosome movement
describe the life cycle of centrosomes during the cell cycle *
have daughter and mother - they split and are duplicated - become functional to go into mitosis
then they polymerise microtubules from nucelating sites in the electron dense cloud that maintains the position of the barrels
what are the 6 phases of mitosis *
prophase
pro-metaphase
metaphase
anaphase
telophase
cutokinesis
describe prophase *
chromosomes are condensed to avoid breakage
each condensed chromosome consists of 2 sister chromatids - has a centromere which is a constriction of the chromosome
kinetochore is the protein that attaches to the centromere that allows movement of the chromosome
have heterogenous nucleus - see the chromosomes and centrosomes where microtubules are being proliferated
describe chromosome condenstion *
dna is 2nm diameter
first phase form beads on a string form of chromatin (histones are the proteins) - 11nm
beads on string fold into itself - 30nm - 3 fold
chromatin fibre of packed nucleosomes loops around scaffold in nucleus - 300nm - 10 fold
the extended scaffold associated form wraps in on itself = condensed scaffold associated form - 700nm
then becomes visual chromosome - 1400nm
makes it easy for chromosomes to travel in cell
describe late prophase*
the chromosomes are condensed
centrosomes migrate to opposite sides of the nucleus and organise assembly of spindle fibres
mitotic spindle fibres form outside the nucleus between 2 centrosomes
describe spindle formation *
radial microtubule arrays (ASTERS) form around each centrosome
then the radial arrays meet from the other centrosome and this changes their properties
they become polar microtubles which are stabalised in these positions
the microtubles are dynamic - constantly depol and pol changing shape and length
describe metaphase *
chromosomes are aligned at the centre of the spindle
nucleus is broken down and chromosomes are loose in the cell
metaphase is broken down into early prometaphase and late prometaphase
describe early prometaphase *
nuclear membrane is broken down
spindle formation is complete
attachement of chromosomes to spindle via kinetechore - spindle catches the chromosome when it is released as nucleus breaks down
describe late prometaphase *
microtubule from laterl pole is captured by sister kinetechore
chromosomes move to middle
they slide rapidly towards centre along microtubules
CENP-E - centromere protein E (kinetochore tension sensing - sense tension of microtubules
describe anaphase *
paired chromatide separate to form 2 daughter chromosomes
multi-protein complex including cohesin holds the sister chromatides together
anaphase is made of anaphase a and b
describe anaphase a *
breakdown cohesin
microtubules get shorter
daughter chromosomes are pulled to opposite spindle poles
describe anaphase b *
daughter chromosomes migrate to poles
spindle poles (centrosomes) migrate apart
this is important so that when the cell constricts the dna is out of teh way
some microtubules remain
describe telophase *
daughter chromosomes arrive at the spindle
nuclear env reassembles at each pole - form the daughter cells
assembly of contractile ring made of actin and myosin filaments - split the cytoplasm contents
still some radial microtubules from teh centrosome
describe cytokinesis *
actin-myosin ring contracts
midbody begins to form, new membrane is inserted
when cells are separated, midbody is still between them
describe the spindle assembly checkpoint *
senses completion of chromosome alignment and spindle assembly - monitors kinetochore activity
kinetochore unattached to spindles sends out a signal - stop cell going to anaphase
checkpoint kinase (CHKE1 and CHEK2) - serine threonine kinase activation holds cell in G2 phase until ready
requies CENP-E - senses tension, and BUB protein kinases (they come off the kinetochore when it is linked to spindles)
when all BUB is dissociated - the kinetochores are in an amphelic attachment (normal attachment) anaphase proceeds
describe how mis-attachment of microtubules to kinetochores can lead to aneuploidy *
both kinetochores attached to microtubles from same centrosome - they send signal to say bound but both get taken into 1 cell = aneuploidy - this is a syntelic attachment
more than 1 microtubule can attach to sister chromatid - chromosome is broken during cytokinesis because being pulled to both sides at the same time - merotelic attachment
monotelic attachment - only one kinetochore is attached so signal stops anaphase taking place
descrieb how aberrent centrosomes/DNA duplication leads to aneuploidy *
aberrent centrosomes - have 4 centrosomes
mess up spindle and chromosomes wouldnt know where to go - divide into 3/4 cells
inviable because dont contain the right amount of chromosomes
explain anti-cancer therapy by introducing gross chromosome mis-segregations
aim to kill tumor cells
checkpoint kinase inhibitor inhibits attachment error correction mechanism - induce cells to thgink ready for anaphase but they’re not = division before chromosomes are aligned = inviable because have incorrect number of chromosomes = apoptosis
cancer cells proliferate so much, they are effected more than normal cells
mechanism of taxanes and vinca alkaloids for breats and ovarian cancers*
alters microtubule dynamics, produces unattached kinetochores = long term mitotic arrest
cells are vulnerable in this position so die
what happens when something goes wring in cell cycle eg cell not big enough/DNA damage *
1
cell cycle arrest - at checkpoints (G1/spindle check point), can be temporary - following DNA repair
2
programmed cell death - apoptosis, when dna damage is too great and cannot be repaired or there are chromosomal abnormalities or toxic agents
describe the cell cycle checkpoints *
start checkpoint in G1 - growth factors initiate the checkpoint and tell cell ready to go
G2 checkpoint before entry into mitosis - check DNA damage
exit from metaphase - metaphase checkpoint check sister chromatid alignment
how do tumours affect the cell cycle checkpoints *
for G1 checkpoint - upregulation of receptor and signal of growth factors = increase speed and freq of cycle
G2 checkpoint - tumours block entry to mitosis, cell enter mitosis with DNA not ready
tumours block alignment checkpoint - cells lose or gain chromosomes
other than effecting checkpoints, how else can tumors affect the cell cycle *
they block cells entering Go so they keep dividing in the cycle
what signals a cell to enter the cell cycle and divide *
most cells are in G0 - not dormant, they are performing their function but are non-dividing
exit from G0 is regulated - needs growth factors and intracellular signalling cascades
- GF binds to receptors
- this triggers elements = signal amplification
- signals integration
- modulation by other pathways
- regulation of divergant responses - regulate metabolic pathway, gene expression, changes in cytoskeleton
describe signalling through peptide GF *
epidermal GF (for differentiation and proliferation) and platelet derived GF
receptors are found in monomeric, inactive state
receptors are receptor protein tyrosine domains - have site for GF to bind, and site for kinase in cell
in presence of ligand - receptors form dimers, are activated by phosphorylation - the kinase domain is pulled into close proximetry and cross-phosphorylate each other
receptor is activated and there are phosphorylated amino acids pulled into close domain
phosphorylation occurs in serine, threonine and tyrosine
the aa have side chain with hydroxyl group outside - kinase will catalyse removal of hydroxyl group with ADP and add phosphate group (not only kinase domain that is phosphorylated, other sites are too) - provide -ve charge - change properties and conformation of residue = start process of activation - creates docking site for another protein
the activation triggers kinase cascades and binding of adaptor proteins - this causes divergance in signalling by hooking to another network
describe kinase cascades *
frequently the protein regulated by a kinase is another kinase and so on
leads to signal amplification, diversification and opportunity for regulation - different substrates and networks
everything is transient - only blip of activation - reversed by phosphtases
when do cells enter Go *
when there is no stimulus
