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					      APOPTOSIS
 Programmed Cell Death
A genetically controlled cell suicide
              pathway
    The History of the Cell Death Study

•   First observed in 1842 by a German scientist Carl Vogt in Jent und
    Gassman, Solothurn 1842; 130
     He wrote “The role of the core of the notochord in the formation of the vertebrae is quite simply that its cells are
    resolved , beginning when the proliferation of the surrounding cartilage exerts pressure on the notochore”. “The light
    vesicular nuclei of the embryonic cells have disappeared; at least I could not detect any trace of them”.

•   1951, Glucksmann, A (in Cambridge Philosophical Society of bilogical
    review 26, 59) reviewed and rediscovered developmental cell deaths in
    embryological tissues
•   1964, Lockshin, RA and Williams, CM first used the term of “programmed
    cell death” to describe the breakdown of the intersegmental muscles of
    silkworms
•   1972, three British scientists Kerr, Wyllie and Currie proposed the term of
    “apoptosis” for morphology of naturally occurring or physiological cell
    deaths. They recognized the importance of apoptosis and suggested that
    it is a basic biological phenomenon with wide-ranging implications in
    tissue kinetics.
The Morphology of Apoptosis




Cytoplasm shrinks
Chromosomes condense and fragment
Nuclear membrane breaks down
Apoptotic body formation
Engulfment of the cell corpse
             Classification of cell death


                              Cell death


 Necrotic                   Physiological


            apoptosis        autophagic          other


    Caspase-dependent         Caspase-independent


receptor-caspase 8      mitochondria-caspase 9
           APOPTOSIS

              What is it?

         Why is it important?

         How is it controlled?

What is its role in age-related disease?
               APOPTOSIS
            Programmed cell death

        Orderly cellular self destruction

Process: as crucial for survival of multi-cellular
          organisms as cell division
                     Forms of cell death

Necrosis                 Apoptosis         Mitotic catastrophe

Passive                    Active            Passive

Pathological           Physiological or    Pathological
                        pathological

Swelling, lysis         Condensation,        Swelling, lysis
                         cross-linking

Dissipates             Phagocytosed         Dissipates

Inflammation           No inflammation      Inflammation

Externally induced      Internally or       Internally induced
                      externally induced
Difference Between Apoptosis
         and Necrosis
• Necrosis (pathological cell death): dying
  cells swell and lyse; toxic contents leak
  out and result in inflammatory response.

• Apoptosis (physiological or programmed
  cell death): dying cells shrink, are
  engulfed by other cells, leave no trace,
  and don’t result in harmful outcomes
              APOPTOSIS

           Evolutionarily conserved

  •Occurs in all animals studies (plants too!)

•Stages and genes conserved from nematodes
             and flies to humans
STAGES OF APOPTOSIS
        Healthy cell

   DEATH SIGNAL

       Commitment to die (reversible)

   EXECUTION (irreversible)

       Dead cell (condensed, crosslinked)
   ENGULFMENT




       DEGRADATION
                STAGES OF APOPTOSIS


      Genetically controlled: Caenorhabditis elegans
                  Soil nematode (worm)


               ces2   ces1                    ced9   ced3,4

Healthy cell                 Committed cell               Dead cell



                                              BCL2    Caspases

           C. Elegans genes == mammalian genes
Cells are balanced between life and death
   DAMAGE                  Physiological death signals




                    DEATH SIGNAL



     PROAPOPTOTIC                     ANTIAPOPTOTIC
       PROTEINS                         PROTEINS
 APOPTOSIS: important in embryogenesis

Morphogenesis (eliminates excess cells):




Selection (eliminates non-functional cells):
 APOPTOSIS: important in embryogenesis

Immunity (eliminates dangerous cells):
                 Self antigen
               recognizing cell




Organ size (eliminates excess cells):
           APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):



                                                       Apoptosis
Virgin mammary gland       Late pregnancy, lactation                   Involution
                                                              (non-pregnant, non-lactating)




                             - Testosterone
                              Apoptosis

          Prostate gland
          APOPTOSIS: important in adults
Tissue remodeling (eliminates cells no longer needed):


                                                Apoptosis



   Resting lymphocytes    + antigen (e.g. infection)    - antigen (e.g. recovery)




                  Steroid immunosuppressants: kill
                      lymphocytes by apoptosis

              Lymphocytes poised to die by apoptosis
        APOPTOSIS: important in adults
Maintains organ size and function:



                         Apoptosis
                         + cell division




    Cells lost by apoptosis are replaced by cell division

      (remember limited replicative potential of cells)
                  APOPTOSIS: control
Receptor pathway (extrinsic, physiological):
                                                FAS ligand     TNF



      Death receptors:
     (FAS, TNF-R, etc)
                                                     Death
                                                    domains

                                                              Adaptor proteins




                         Pro-caspase 8 (inactive)              Caspase 8 (active)




                         Pro-execution caspase (inactive)
                                                                 Execution caspase (active)




                                MITOCHONDRIA                                        Death
               APOPTOSIS: control
Intrinsic pathway (damage):

            Mitochondria


   BAX                Cytochrome c release               BCL-2
   BAK                                                   BCL-XL
   BOK                                                   BCL-W
   BCL-Xs           Pro-caspase 9 cleavage               MCL1
   BAD                                                   BFL1
   BID                                                   DIVA
   B IK                                                  NR-13
   BIM        Pro-execution caspase (3) cleavage         Several
   NIP3                                                   viral
   BNIP3                                                  proteins

            Caspase (3) cleavage of cellular proteins,
                     Nuclease activation,
                             Etc.

                                                          Death
        APOPTOSIS: control

  Physiological                   Intrinsic
receptor pathway               damage pathway


          MITOCHONDRIAL SIGNALS


              Caspase cleavage cascade


         Orderly cleavage of proteins and DNA


   CROSSLINKING OF CELL CORPSES; ENGULFMENT
                (no inflammation)
APOPTOSIS: Role in Disease


 TOO MUCH: Tissue atrophy
       Neurodegeneration
           Thin skin
              etc

  TOO LITTLE: Hyperplasia

            Cancer
         Athersclerosis
              etc
         APOPTOSIS: Role in Disease
                Neurodegeneration

   Neurons are post-mitotic (cannot replace themselves)

   Neuronal death caused by loss of proper connections,
         loss of proper growth factors (e.g. NGF),
          damage (especially oxidative damage)

Neuronal dysfunction or damage results in loss of synapses
                  (synaptosis; reversible)
                  apopsosis (irreversible)

               PARKINSON'S DISEASE
               ALZHEIMER'S DISEASE
             HUNTINGTON'S DISEASE etc.
     APOPTOSIS: Role in Disease
                    Cancer

      Apoptosis eliminates damaged cells
       (damage => mutations => cancer

  Tumor suppressor p53 controls senescence
     and apoptosis responses to damage

Most cancer cells defective in apoptotic response


      High levels of anti-apoptotic proteins
                       or
      Low levels of pro-apoptotic proteins
                ===> CANCER
       APOPTOSIS: Role in Disease
                    AGING

Aging --> both too much and too little apoptosis
              (evidence for both)

 Too much (accumulated oxidative damage?)
          ---> tissue degeneration

     Too little (defective sensors, signals?
      ---> dysfunctional cells accumulate
      hyperplasia (precancerous lesions)
     Functions of apoptosis
Sculpt body structures, e.g. hand digit



Serve some function but no longer needed
e.g. tadpole tail of frog.

Needed in one sex but not another
e.g. Mullerian duct important for female
is eliminated in males by apoptosis.

Produced in excess, e.g. extra neurons are
removed by apoptosis during neurogenesis.

Serve in immune system as a defense
mechanism to get rid of harmful or
damaged cells.