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Hayflick's Limit

  • Cultured normal human cells have a limited capacity for replication
  • This is around 50 replications, after which cells enter a phase called senescence

Life and Death for Cells

  • Once formed cells can:
    • Continue to grow and divide
    • Differentiate into a into a specialised cell type and cease dividing
    • Enter senescence (continue to exist and be active, but never replicate - most cells)
    • Die
      • Necrosis (response to acute cell injury)
      • Apoptosis (programmed cell death)

Cell Death

  • Why do cells die?
    • To remove:
      • unwanted cells (especially during embryogenesis)
      • damaged or aged cells
  • How do cells die?
    • Two mechanisms:
      • Necrosis – death by injury
      • Apoptosis – death by suicide

Necrosis

  • Death by injury or accident (e.g. hypoxia, poisoning)
    • Membranes begin to disrupt due to osmotic lysis, shear stress, loss of ATP, and so cell swells
    • Plasma membrane ruptures
    • Cellular material (including degradative enzymes) spills out into the extracellular environment
    • This causes an inflammatory response (NOT good!)
    • Affects a contiguous group of cells

Apoptosis

  • Death by design - genetically programmed cell death/cell suicide
    • Cell dies in response to external signals (e.g. during development) or internal damage
    • Important for development, elimination of tumour cells
    • Does not induce an inflammatory response
    • Affects individual cells only

Apoptosis vs Necrosis

Apoptosis Necrosis
Chromatin condensation Nuclear swelling
Preservation of membranes and organelles Disruption of organelles
Rapid engulfment by neighbouring cells Rupture of cell and release of cellular contents
DNA Fragmentation Inflammatory response


Apoptosis during embryogenesis

  • Apoptosis ensures that the number of developing nerve cells matches the number of target cells and hence all the target cells are connected by nerve cells

Why Apoptosis?

  • What makes a cell decide to commit suicide?
    • Normal development as well as protection from damage
  • Intrinsic - generated by signals arising within the cell
  • Extrinsic - triggered by external signalling molecules

2 Mechanisms of Apoptosis

Intrinsic

  • Generated by signals arising within the cell
  • Usually the result of stressors, such as those that damage DNA
    • Oxidants within the cell
    • UV, x-rays, chemotherapeutic drugs
    • Hypoxia

Extrinsic

  • Triggered by external signalling molecules often referred to as death activators
    • Specific molecules (death activators) that bind to receptors on the cell surface, e.g. TNF-alpha, B
    • Other molecules such as: toxins, hormones, cytokines, nitric oxide
    • These signals may positively (i.e. trigger) or negatively (i.e. repress) affect apoptosis

Caspases

  • Caspases are proteases
  • Their activation initiates apoptosis
  • Family of over a dozen caspases.
  • They contain contain a cysteine residue at the active site and cleave mostly at aspartic acid (Asp) residues.

Caspase Targets

  • Protein kinases e.g focal adhesion kinase (FAK) which disrupts cell adhesion and so releases cell from its neighbours
  • Lamins - nuclear envelope proteins - loss causes nucleus to shrink and breakup
  • Cytoskeleton proteins - leads to loss of cell structure
  • Endonuclease - caspase activated DNase (CAD) - inhibitor is cleaved so CAD can move into nucleus and degrade DNA

Hallmarks of Cancer

  • Evading growth suppressors
  • Deregulating cellular energetics
  • Sustaining proliferative signalling
  • Enabling replicative immortality
  • Genome instability and mutation
  • Activating invasion and metastasis
  • Tumour-promoting inflammation
  • Inducing angiogenesis
  • Resisting cell death
  • Avoiding immune destruction

Evasion of apoptosis is one of the hallmarks of cancer cells

  • Cells that have sustained irreparable genetic damage should undergo apoptosis
  • Successful cancer cells have developed mechanisms to avoid apoptosis
  • This can enable them to elude the effects of therapeutic radiation and chemotherapy

Intrinsic Pathway

  • Cellular stress causes a protein such as Bax to be insterted in the mitochondrial membrane
  • This allows cytochrom c to be released from the mitochondria
  • This binds to Apaf-1 and causes the activation of the initiator caspase.

Extrinsic Pathways

  • The TNF receptor is an integral membrane protein with its receptor domains exposed at the surface of the cell
  • Binding of the complementary death activator (TNF) transmits a signal to the cytoplasm that leads to the activation of caspase 8 which initiates a cascade of caspase activation.