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2010-10-13 11:38:41
Biomolecular Science

Mammalian cell cycle
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  1. cells grow by:
    • replicating DNA (DNA synthesis- S phase)
    • Cell Division (Mitosis- M phase)
  2. 4 Phases of Cell Cycle
    • M Phase (mitosis)
    • G1 (gap phase)
    • S phase (DNA synthesis)
    • G2 (gap phase)
  3. 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)
  4. 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
  5. Properties of G0
    • Non-dividing state
    • Metabolically and functionally active state
    • permanent
    • temporary
    • most adult cells are in G0 (other than intestinal and epithelial)
  6. 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*****
  7. 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
  8. 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
  9. Cyclin proteins
    • are synthesised and degraded in a phase specific manner (G1, G2, and S specific)
    • when synthesised cyclins complex with and activate CDKs
  10. 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)
  11. cyclin dependant kinase inhibitors
    inhibit the action of CSKs-cyclin complexes (example: p21)
  12. Phase specific cyclins:
    • G1: CDK 4 & 6- cyclin D, CDK 2- cyclin E
    • S: CDK2- cyclin A
    • G2- M: CDK1- cyclin B & A
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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")
  18. 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
  19. 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)
  20. 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
  21. Cell Death
    • Necrosis
    • Apoptosis
  22. 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
  23. 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)
  24. 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
  25. 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
  26. 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)