Cancer 4: The cell cycle and its regulation Flashcards
define cell cycle
what are the 3 stages involved?
Orderly sequence of events in which a cell duplicates its contents
and divides in two.
involves:
- Duplication
- Division
- Co-ordination
Why is the mitosis phase the most vulnerable period of the cell cycle?
- Cells are more easily killed (irradiation, heat shock, chemicals)
- DNA damage can not be repaired
- Gene transcription silenced
- metabolism
Describe the process of M-phase
phase where cells undergo mitosis
Describe what happens in interphase
longest time of cell life time = interphase
- where duplication occurs
Give the order if the eukaryotic cell cycle
M phase = mitosis
Interphase:
G0 phase = cell cycle machinery dismantled
G1 phase = decision point (to divide/ or not)
S phase = DNA/Protein synthesis
G2 phase = Decision point
then M phase –> G0 again
What happens in S phase ?
- DNA replication
- Protein synthesis occurs
- -> there is increase in initiation of translation + elongation of proteins
- replication of organelle
(for mito–> needs to coordinate w mitochondrial DNA)
–> because mitochondria has its own DNA
Describe the structure of centrosome, and its function
structure:
- has 2 centrioles (barrels of 9 x triplet microtubules)
function:
- acts as Microtubule organizing centre ( MTOC) + mitotic spindle
by __ phase, centrosomes are completely duplicated
by M phase they are completely duplicated
What are the 6 phases of mitosis?
- prophase
- pro metaphase
- metaphase
- anaphase
- telophase
- cytokinesis
What happens in prophase?
- condensation of chromatin (chromatin - has DNA wrapped in histones)
- becomes 30nm chromatin
- forms a chromosome scaffold
- condensed chromosome scaffold associated form
then goes on to form condensed chromosomes
condense chr = has 2 sister chromatids
- has centromere (constriction of sister chromatin) = DNA core
- kinetochore (belt like) = allows segregation of chromosome to occur smoothly
What happens between prophase pro metaphase ?
- Replicated chromosomes condense
- Duplicated centrosomes migrate –> to opposite sides of the nucleus + organize assembly of spindle microtubules
- Mitotic spindle forms outside nucleus (between the 2 centrosomes)
Describe the process of spindle formation.
- Radial microtubule arrays (ASTERS) form around each centrosome (MTOC)
- ASTERS meet in the middle –> form stable interactions
- Polar microtubules form
note: microtubules polymerase + depolymerize all the time
What is a characteristic of cell at metaphase?
Chromosomes = aligned at equator of spindle.
- centrosome = in opposite. poles
- microtubules = arranged in equator
What happens in early pro metaphase?
- Breakdown of nuclear membrane
- Spindle formation = mostly complete
- polar microtubules/spindles capture chromosomes –> by their constrictions (kinetochore)
note: microtubules only attach to the kinetochore
What happens in late pro metaphase?
- Microtubule from opposite pole = captured by sister kinetochore
- Chromosomes attached to each pole come to middle
- Chromosome slides rapidly towards center –> along microtubules
important factors involved:
CENP-E = centromere protein E
–> sense tension of cables
What happens in Anaphase?
What are the 2 parts of Anaphase?
- Paired chromatids separate to form two daughter chromosomes
- Cohesin holds sister chromatids together
2 parts of anaphase
- A
- B
What happens in Anaphase A ?
- cohesin= broken down
- Microtubules get shorter –>and pulls Daughter chromosomes
- toward opposite spindle poles
What happens in Anaphase B ?
1-Daughter chromosomes migrate towards poles
2-Spindle poles (centrosomes) migrate apart
–> to allow space for cells to divide
What happens in telophase of the cell cycle ?
- Daughter chromosomes arrive at spindle
- Nuclear envelope reassembles at each pole
- there is assembly of contractile ring (ring of actin –> squeezes 2 cells apart)
What happens in cytokinesis?
- actomyosin (contractile) ring contracts
- squeezes 2 cells apart
then when it is close enough, the memb fuses to form 2 distinct cells
How does the cell cycle transition out of metaphase? (spindle assembly checkpoint)
what is required for this to occur?
- control = done by kinetochore
- depends on attachment/unattachment of microtubules to kinetochore
- unattached kinetochore –> sends signal (generates checkpoint signals)
- when kinetochore = attached = no signaling –> can go onto next anaphase of cell cycle
requires:
- CENP-E
- BUB protein kinases
what are the 2 ways in which aneuploidy can occur?
1) mis-attachment of microtubules to kinetochores
a) defect of cohesion / synthetic attachment
- -> both sister chromatid will be at the same pole
b) merotelic attachement
- -> chromosome = lost at cytokinesis
2) aberrant centrosome/DNA duplication
describe how induction of gross chromosome mis segregation can act as an anti cancer therapy
check point kinase inhibitor –> inhibits attachment error correction mechanism
- holds cells at G2 phase
- then make cell think all cells = aligned
- lose chromosome –> cancer cells die
What happens if something goes wrong during the cell cycle?
a) cell cycle arrest
- -> at check points (G1 + Spindle check point)
- -> temporary (following DNA repair)
b) Apoptosis
- -> DNA damage = too great
- -> chromosomal abnormalities
- -> toxic agents
after a) + b) cells = aborted + destroyed
Cell cycle checkpoints and tumour progression
PCWT
at start = G1 check point (enter cell cycle) G2 checkpoint ( senses DNA damage) metaphase checkpoint (cells all align --> to see if sister chromatids are aligned)
tumours:
- acts on G1 CKPT –> prevents exits via G0 phase
- acts on G2 CKPT –> blocks sensing of DNA damage
- acts on metaphase CKPT –> makes cell think chromatid are aligned –> can lead to aneuploidy/defects
De-regulation of cell cycle during tumorigenesis
tumors:
- blocks exit from cell cycles
- -> doesn’t go into G0
- -> goes back into cell cycle –> proliferates again
What triggers a cell to enter the cell cycle and divide?
- no stimulus = cell go into G0 (quiescent phase)
- Exit from G0 requires growth factors + intracellular signaling cascades
what are the difference signalling cascade
Response to extracellular factors
Signal amplification
Signal integration
Modulation by other pathways
Regulation of divergent responses
How does signalling occur by peptide growth factors?
to trigger a cell to enter cell cycle
what happen upon activation of receptors?
e. g EGF + PDGF
- -> found in inactive state
- with ligand:
- -> receptors form dimers
- -> receptors are activated by cross phosphorylation (when 2 kinase domains = close enough)
- -> upon activation,
- kinase cascade = triggered
- triggers binding of adaptor proteins
What happens in protein phosphorylation to trigger a cell to enter cell cycle
- there is transfer of phosphate from ATP to a hydroxyl groups
- added Phosphate group
- -> alters protein function:
–> causes change in shape –> which causes change in acitivity
–> OR creates a docking site for another protein
(usually serine, threonine, tyrosine)
What is the significance of protein kinase cascades in triggering cell cycle?
- Leads to signal amplification, diversification and opportunity for regulation
- phosphorylation = occurs by kinase
- phosphorylation = reversed by phophatases
why is appropriate regulation of cell division important?
- 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)
- Perturbation of protein levels of cell cycle regulators is found in different tumours - abnormal mitosis
Contact inhibition of growth
Attacking the machinery that regulates chromosome segregation is one of the most successful anti-cancer strategies in clinical use
what action does CENP-E have on late pro metaphase?
important factors involved:
CENP-E = centromere protein E
–> sense tension of cables
