Cell Apoptosis

Cell going through anaphase Nerve cell Cell Schematic: Eukaryote ATP

Programmed Cell Death (PCD)

  1. Very important in developing a normal, functioning organism
  2. PCD is as important as cell proliferation
  3. PCD kills dangerous (eg. autoimmune) or unnecessary (eg. "webs" between digits) cells
  4. PCD is a choreographed programmed sequence of events
    1. Round up
    2. Outer membrane bulges
    3. Internal structures break down
    4. DNA breaks up
    5. Cell breaks into pieces - pieces are phagocytosed
  5. PCD is thought to have a role in aging and disease
    1. cancer, etc. is the failure of cell to die appropriately
    2. degenerative diseases (cells die too much)
  6. Human homologs
    1. Bax: homology unknown, but functions in pro-apoptosis
    2. ICE ~ ced 3
    3. Bcl2 ~ ced 9
    4. It appears that the Bcl2 / Bax ratio determines whether cell live or die
      1. Bcl2 / Bax > 1 cell lives
      2. Bcl2 / Bax < 1 cell dies
    5. The exact mechanism of how the products of these genes interact to affect cell survival or cell death is unknown at this time

  7. Cell cycle and cell cycle control
    1. Cdk's and cyclins
    2. Negative controls: cullins that destroy cyclins
  8. Apoptosis and PCD
    1. Signals from outside: growth factors
    2. Signals from within cells
      1. Telomers: structures found at ends of eukaryotic chromosomes in most organisms. Telomers are composed of variable numbers of simple repeat sequences... TTAGGG in vertebrates
      2. Telomers are synthesized by telomerase, a ribonucleoprotein which means it contains both a protein and a ribonucleotide (RNA) component. It uses the RNA as a template to synthesize the DNA repeat sequences [it is technically a reverse transcriptase]
      3. Telomers evolved to
        1. ensure complete replication of chromosome ends (not accomplished by the known DNA poymerases)
        2. protect ends of chromosomes from degradation or fusion
      4. Considerable attention has been given to telomere length (the number of repeat sequences) There appears to be a relationship between telomere length and both aging and cancer
      5. Telomere tract shortening has been associated with cell senescence (cell death). Perhaps a molecular "clock" to prevent oncogenesis. With out telomerase chromosomes would shorten with every cell and eventually dissrupting the genes
      6. Telomerase is undetectable in most somatic cell but is elevated in tumors --> telomere elongation might be important (essential?) for tumor development. This is a good target for cancer therapy because its activity is high in many types of cancer cells. The continuous division of which demands good telomere maintenance. How do cells measure telomere length and how do cell regulate telemere length and activity?
      7. In humans (TRF1) and yeast (Taz1p, Rap1p), recent discoveries include telomere repeat binding proteins that appear to function in telomere length regulation
      8. Proteins that bind to telomere repeats negatively regulate telomere elongation

      9. Hypothesis: a mechanism exists that senses the number of telomere repeat binding proteins on the ends of chromosomes. When this number exceeds a certain threshold, a signal is generated that blocks further elongation by telomerase.
      10. It has been shown that the binding proteins do not regulate the amount of telomerase, merely telomerase activity