Todays Topics

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Todays Topics

• Apoptosis
• programmed cell death
• p53

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Apoptosis vs. Necrosis

• Necrosis
• Cells swell and burst, releasing their
  intracellular contents
• Damaging to surrounding cells
• Causes inflammation

• Apoptosis
• Cells shrink and condense
• Release small membrane bound bodies
• Small fragments are engulfed by surrounding cells

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Apoptosis in development
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Caspases procaspases and adaptor proteins come
together to activate caspases in the cell these
leads to a caspase cascade, resulting in
cleavage of nuclear lamina, DNA and other
cellular proteins.
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p53

• Guardian of the Genome
• p53 signaling is normally off
• Activated by cell stress or damage
• p53 shuts down the multiplication of stressed
  cells and induces apoptosis

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Signaling that activate p53

• DNA damage (double strand breaks)
• Aberrant growth signals (such as overactivation
  of ras or myc)
• Drugs (chemotherapeutics) and UV light
• All 3 pathways inhibit the degradation of p53,
  allowing it to activate transcription of genes
  that induce cell death or inhibit cell division.

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How does p53 promote apoptosis?

• p53 is a transcription factor
• p53 promotes the transcription of BAX (and fas)
• BAX allows for the release of cytochrome C

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How does p53 inhibit cell cycle progression?
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Transforming viruses have found a way to attack
p53/Rb
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Can too much p53 be a bad thing???
J. Campisi, Science 2005
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p53-directed therapies

• Gene replacement therapy
• Adenoviral delivery of wildtype p53
• Inactivation of cellular control mechanisms
• Inactivation of MDM2
• Dangerous potential side effects premature aging.

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Genomic Instability Loss of DNA repair enzymes,
loss of telomeres, loss of p53
loss of p53