the cell cycle and its control

Question 1

what determines thje rate at which cells divide

Answer 1

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

Question 2

why is it important that the cell cycle is regulated *

Answer 2

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

Question 3

what is an important anti-cancer strategy *

Answer 3

attacking the machinery that controls chromosome deregulation

Question 4

what is the cell cycle *

Answer 4

an orderly sequence of events in which a cell duplicates its contents and divides in 2

involves dupilcation then division

Question 5

what are the 2 phases of the cell cycle *

Answer 5

M phase - mitosis

• division phase
  
  • nuclear division
  • cellular division

interphase

• dupilcation
  
  • dna
  • organelles
  • protein synthesis - increased because all materials are split into 2

Question 6

why is mitosis a vulnerable phase for the cell *

Answer 6

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

Question 7

relatively how long is the M phase *

Answer 7

quick becasue cell is vulnerable here

Question 8

what are the phases of interphase *

Answer 8

G0

G1

S

G2

Question 9

describe G0 *

Answer 9

cell machinery is dismantled

where most cells are - doing their function

Question 10

describe G1 *

Answer 10

gap phase

decision point - check that everything has been done so the cell can move onto the next step

ie check mitochondria etc

Question 11

describe s phase *

Answer 11

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

Question 12

describe G2 phase *

Answer 12

gap

decision point - check DNA has replicated and sorts any mutations

Question 13

what is the centrosome organisation *

Answer 13

made of 2 centrioles - double barrels of 9 triplet microtubules, barrels at 90degrees - held together by dense protein material

Question 14

illustrate the cell cycle *

Answer 14

Question 15

function of the centrosome *

Answer 15

coordinates chromosomal movement

they form the microtubule organising centre - form highways of microtubles that control chromosome movement

Question 16

describe the life cycle of centrosomes during the cell cycle *

Answer 16

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

Question 17

what are the 6 phases of mitosis *

Answer 17

prophase

pro-metaphase

metaphase

anaphase

telophase

cutokinesis

Question 18

describe prophase *

Answer 18

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

Question 19

describe chromosome condenstion *

Answer 19

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

Question 20

describe late prophase*

Answer 20

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

Question 21

describe spindle formation *

Answer 21

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

Question 22

describe metaphase *

Answer 22

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

Question 23

describe early prometaphase *

Answer 23

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

Question 24

describe late prometaphase *

Answer 24

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

Question 25

describe anaphase *

Answer 25

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

Question 26

describe anaphase a *

Answer 26

breakdown cohesin

microtubules get shorter

daughter chromosomes are pulled to opposite spindle poles

Question 27

describe anaphase b *

Answer 27

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

Question 28

describe telophase *

Answer 28

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

Question 29

describe cytokinesis *

Answer 29

actin-myosin ring contracts

midbody begins to form, new membrane is inserted

when cells are separated, midbody is still between them

Question 30

describe the spindle assembly checkpoint *

Answer 30

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

Question 31

describe how mis-attachment of microtubules to kinetochores can lead to aneuploidy *

Answer 31

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

Question 32

descrieb how aberrent centrosomes/DNA duplication leads to aneuploidy *

Answer 32

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

Question 33

explain anti-cancer therapy by introducing gross chromosome mis-segregations

Answer 33

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

Question 34

mechanism of taxanes and vinca alkaloids for breats and ovarian cancers*

Answer 34

alters microtubule dynamics, produces unattached kinetochores = long term mitotic arrest

cells are vulnerable in this position so die

Question 35

what happens when something goes wring in cell cycle eg cell not big enough/DNA damage *

Answer 35

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

Question 36

describe the cell cycle checkpoints *

Answer 36

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

Question 37

how do tumours affect the cell cycle checkpoints *

Answer 37

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

Question 38

other than effecting checkpoints, how else can tumors affect the cell cycle *

Answer 38

they block cells entering Go so they keep dividing in the cycle

Question 39

what signals a cell to enter the cell cycle and divide *

Answer 39

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

Question 40

describe signalling through peptide GF *

Answer 40

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

Question 41

describe kinase cascades *

Answer 41

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

Question 42

when do cells enter Go *

Answer 42

when there is no stimulus