1、APOPTOSIS,What is it?Why is it important?How is it controlled?What is its role in age-related disease?,APOPTOSIS,Programmed cell deathOrderly cellular self destructionProcess: as crucial for survival of multi-cellular organisms as cell divisionMULTIPLE FORMS?,Forms of cell death,“Classic“ Necrosis A
2、poptosis Mitotic catastrophePassive Active PassivePathological Physiological or PathologicalpathologicalSwelling, lysis Condensation, Swelling, lysiscross-linking Dissipates Phagocytosed DissipatesInflammation No inflammation InflammationExternally induced Internally or Internally inducedexternally
3、induced,APOPTOSIS,Evolutionarily conservedOccurs in all multicellular animals studies (plants too!)Stages and genes conserved from nematodes (worms) and flies to mice and humans,STAGES OF CLASSIC APOPTOSIS,Healthy cell,DEATH SIGNAL (extrinsic or intrinsic),Commitment to die (reversible),EXECUTION (i
4、rreversible),Dead cell (condensed, crosslinked),ENGULFMENT (macrophages, neighboring cells),DEGRADATION,STAGES OF CLASSIC APOPTOSIS,Genetically controlled: Caenorhabditis elegans soil nematode (worm),Healthy cell,Dead cell,Committed cell,ces2,ces1,ced9,ced3,4,BCL2,Caspases (proteases),C. elegans gen
5、es = mammalian genes,Cells are balanced between life and death,DAMAGE,Physiological death signals,DEATH SIGNAL,PROAPOPTOTIC PROTEINS (dozens!),ANTIAPOPTOTIC PROTEINS (dozens!),DEATH,APOPTOSIS: important in embryogenesis,Morphogenesis (eliminates excess cells):,Selection (eliminates non-functional ce
6、lls):,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):,Virgin mammary gland,Late pregnancy, lactation,Involution (non-
7、pregnant, non-lactating),Apoptosis,Apoptosis,- Testosterone,Prostate gland,APOPTOSIS: important in adults,Tissue remodeling (eliminates cells no longer needed):,Resting lymphocytes,+ antigen (e.g. infection),- antigen (e.g. recovery),Apoptosis,Steroid immunosuppressants: kill lymphocytes by apoptosi
8、sLymphocytes 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 normal cells restricts how many times this can occur before tissue renew
9、al declines),APOPTOSIS: control,Receptor pathway (physiological):,Death receptors: (FAS, TNF-R, etc),FAS ligand,TNF,Death domains,Adaptor proteins,Pro-caspase 8 (inactive),Caspase 8 (active),Pro-execution caspase (inactive),Execution caspase (active),Death,MITOCHONDRIA,APOPTOSIS: control,Intrinsic p
10、athway (damage):,Mitochondria,Cytochrome c release,Pro-caspase 9 cleavage,Pro-execution caspase (3) cleavage,Caspase (3) cleavage of cellular proteins, nuclease activation, etc.,Death,BAX BAK BOK BCL-Xs BAD BID B IK BIM NIP3 BNIP3,BCL-2 BCL-XL BCL-W MCL1 BFL1 DIVA NR-13 Severalviralproteins,APOPTOSI
11、S: 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,TOO LITTLE: Hyperplasia,Neurodegenerat
12、ion Thin skin etc,Cancer Athersclerosis etc,APOPTOSIS: Role in Disease Neurodegeneration,Neurons are post-mitotic (cannot replace themselves; neuronal stem cell replacement is inefficient)Neuronal death caused by loss of proper connections, loss of proper growth factors (e.g. NGF), and/or damage (es
13、pecially oxidative damage)Neuronal dysfunction or damage results in loss of synapses or loss of cell bodies (synaptosis, can be reversible; apopsosis, irreversible)PARKINSONS DISEASE ALZHEIMERS DISEASE HUNTINGTONS DISEASE etc.,APOPTOSIS: Role in Disease Cancer,Apoptosis eliminates damaged cells (dam
14、age = mutations = cancerTumor suppressor p53 controls senescence and apoptosis responses to damageMost cancer cells are defective in apoptotic response (damaged, mutant cells survive)High levels of anti-apoptotic proteins or Low levels of pro-apoptotic proteins = CANCER,APOPTOSIS: Role in Disease AG
15、INGAging both too much and too little apoptosis (evidence for both)Too much (accumulated oxidative damage?) - tissue degenerationToo little (defective sensors, signals? - dysfunctional cells accumulate hyperplasia (precancerous lesions),OPTIMAL FUNCTION (HEALTH),APOPTOSIS,APOPTOSIS,AGING,Neurodegeneration, cancer, ,
