Apoptosis (Programmed Cell Death)

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Apoptosis(Programmed Cell Death)
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Apoptosis vs Necrosis

• Level of stress, change in environment

stress
apoptosis
necrosis
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Modes of Cell Death
Necrosis
Apoptosis

• A pathological response to injury
• Chromatin clumping
• Mitochondria swelling and rupture
• Plasma membrane lyses
• Cell contents spill out

• A normal physiological response to specific
  suicide signals
• Chromatin condenses
• Internucleosomal cleavage leads to laddering of
  DNA
• Cytoplasma shrinks without membrane rupture
• Blebbing of plasma and nuclear membranes
• No spillage

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Tumor Suppressor Genes

• Tumor-suppressor genes, function like brakes,
  keep cell numbers down, either by
• 1. Inhibiting progress through the cell cycle
  and thereby preventing cell birth, or
• 2. Promoting apoptosis
• When cellular tumor suppressor genes are rendered
  non-functional through mutation, the cell becomes
  malignant. Example pRb, p53, and p16INK4a.

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Oncogenes

• Oncogenes stimulate cells to grow (or refuse to
  die).
• Mutated oncogenes can stimulate cells even when
  they are not receiving growth signals. Example
  Ras, Akt, Survivin.
• Amplification of oncogenes is also found in
  cancer. Example MDM2.

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Apoptosis Signaling Pathway
Cell, 2002108153-64
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Tumor-derived mutations affecting apoptosis
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Tumor-derived mutations affecting apoptosis
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Tumor-derived mutations affecting apoptosis
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Tumor-derived mutations affecting apoptosis
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Tumor-derived mutations affecting apoptosis
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Role of p53 in Apoptosis

• p53 induces apoptosis through transcriptional
  activation of proapoptotic genes, such as Puma,
  Noxa, p53AIP, Bax, Apaf-1, etc.
• It can also directly induce apoptosis by
  localizing to mitochondria via interaction with
  Bcl-2 family protein.

Nat Rev Cancer, 20022594-604
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p53 in DNA Repair and Apoptosis
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Tumor Suppressor p53

• Mutated/inactivated in a majority of human
  cancers
• p53 -/- knockout mice embryos develop normally to
  term but after a few weeks the young mice develop
  numerous malignant tumors
• adenovirus introduced wild-type p53 markedly
  enhanced the anti-tumor effect of a common
  chemotherapeutic agent, cisplatin, in human
  non-small cell lung cancer cells, and in human
  colon cancer cells.
• Effectiveness of cancer therapy correlates with
  the ability to induce p53-dependent apoptotic
  response

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Thank You