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cells grow by:
- replicating DNA (DNA synthesis- S phase)
- Cell Division (Mitosis- M phase)
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4 Phases of Cell Cycle
- M Phase (mitosis)
- G1 (gap phase)
- S phase (DNA synthesis)
- G2 (gap phase)
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Cell division rate
- some never divide (nerve, lens, cardiac muscle)
- some are non dividing until need to replace dead/injured cells (skin fibroblasts, smooth muscle, endothelial cells)
- come divide rapidly (epithelial skin and intestinal cells)
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quiescent
- G0 phase cells are called quiescent - non-dividing
- include: neurons and skeletal muscle cells
- they are metabolicly active but not dividing and may be permanently there or temporary
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Properties of G0
- Non-dividing state
- Metabolically and functionally active state
- permanent
- temporary
- most adult cells are in G0 (other than intestinal and epithelial)
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extracellular regulation of cell cycle
- mitogerns: growth factors (platelet derived growth factors, insulin growth factor, epidermal growth factore), hormones (growth hormone, estrogen), cell-cell interaction.
- nutrition supply and cell size (if nutrition is low- cell will enter G0)
- ***cells are only responsive to mitogens in G1*****
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Control progression through the cell cycle
- progress through the cell cycle is controlled by protein kinases (Cyclin dependent kinases- CSK, cyclin proteins)
- monitored at various checkpoints
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Cyclin Dependent Kinases (CDK)
- enzymes that cause phosphorylation (addition of phosphate groups)
- each phase has a specific CDK which is activated (always present in an inactive state in cells)
- CDK's on their own are not active
- Require cyclin to be active
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Cyclin proteins
- are synthesised and degraded in a phase specific manner (G1, G2, and S specific)
- when synthesised cyclins complex with and activate CDKs
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CDK + Kinase
- causes phosphorylation of threonine and serine residues of target proteins
- transfer of the terminal phosphate of ATP to a hydroxyl group of specific amino acids (see power point)
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cyclin dependant kinase inhibitors
inhibit the action of CSKs-cyclin complexes (example: p21)
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Phase specific cyclins:
- G1: CDK 4 & 6- cyclin D, CDK 2- cyclin E
- S: CDK2- cyclin A
- G2- M: CDK1- cyclin B & A
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Restriction point control: G1-S
- Cyclin D synthesised in response to mitogens
- cyclin D complexes with CDK4/CDK6
- CDK holoenzyme phosphorylates the retinoblastoma protein (pRb)- releasing E2F transcription factor
- pRb serves as the R point switch
- E2F initiates transcription of genes involved in cell cycle progression
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Cell Cycle checkpoints- intrinsic control
- G1 checkpoint- recognizes DNA damage
- G2 checkpoint- recognises if DNA has not been replicated
- M Checkpoint- monitors alignment of chromosomes on mitosis spindle, ensures complete set of chromosomes are distrubuted accurately
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G1 checkpoint
- if DNA damage in daughter cells there will be a stabilization in p53 which can activate transcription to either send cell cycle to arrest or apoptosis
- p53 (tumor suppresor protein)
- or p53 can activate p21 CDK inhibitor which can inactivate the CDK complex to stop the cell from going to the S phase
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loss of cell cycle control/cancer
- cancer is abnormal unregulated cell proliferation
- loss of checkpoints allows for uncontrolled cell growth
- p53 function is lost in >50% cancers
- pRb function is also lost in cancers
- CDKs, cyclins, and CDKi can be deregulated
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cellular senescence
- cells do not divide indefinetly
- limited replicative lifespan- after they enter senescence
- irreversible arrest of cell growth (not G0)
- regulated by chromosome structures telomeres
- ("aged cells")
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Telomeres
- DNA protein that cap the ends of chromosomes
- consists of multiple TTAAGGG repeats
- protective function (stop chromosomes from fusing together)
- act as mitotic clock- determines the number of cell divisions a cell can go through
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Normal vs cancer cells (telomere length)
- Normal cell- shorter telomere after each division- a short telomere will signal for cell to stop dividing
- Cancer- telomere will not shorten after division- no telomere loss does not signal to stop dividing (male germ cells don't lose telomeres either)
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Telomerase
- enzyme can synthesise telomere DNA
- telomere are maintained- senescence is prevented
- activity is present in 95% of cancer cells
- allows cells to divide w/o limit- immortality
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Necrosis
- response to injury (mechanical damage, exposure to toxic chemicals, hypoxia, ischemia, etc)
- accidental form of cell death
- chromatin clumps
- mitochondra swell and rupture
- plasma membrane ruptures
- cell contents spill out
- affects neightbouring cells
- stimulates an inflammatory response
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Apoptosis
- Programmed cell death/cell suicide
- normal physiological process
- essential for development
- Examples: loss of webbing between fingers and toes as fetus, sloughing off of the inner lining of the uterus at menstraution
- needed to destroy cell that represent a threat to the integrity of the organism (damaged DNA, viruses)
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Caspases
- proteolytic enzymes (destroy/degrade protein) stored as inactive zymogens (must be stored inactive)
- induce apoptosis via cell surface receptors
- results in cleavage of key cellular substrates
- activate other egradative enzumes (proteases, DNases, RNases)
- results in distinct morphological changes
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characteristic changes apoptotic cells
- chromatic condenses
- DNA fragments (ordered)
- cytoplasm shrinks and membrane blebs
- contents are packed into membrane bound structures termed apoptotic bodies
- the phospholipid phosphatidylserine is exposed on the surface
- phagocytic cells engulf the call fragements
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reduced apoptosis (disease)
- cancers- loose the ability to apoptosis
- viral infections- some viruses degrade p53 function (HPV)
- neurodegenerative diseases increase apoptosis (alzheimers dz, parkinsons dz)
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