Molecular cellular aspects of apoptosis Flashcards
- What is the function of physiological cell death?
• It’s used for control, regulation and development. If not balanced, overactive apoptosis can cause stroke or neurodegenerative diease, underactive can cause cancer, but imbalanced apoptosis can be normal depending on the circumstance.
- What are the mechanisms of cell death?
- It can be intrinsic or extrinsic.
- Extrinsic: Through TNF family death receptor such as FAS, TRAIL, TNFR. All have a cytoplasmic death domain with death effector domain and death domain they form a DISC complex and recruit activator caspases all of them cleave the next caspase it recruits and finally they recruit the procaspase 8 which recruits effector caspases and commits the cell to apoptosis. TNFR can induce apoptosis through a different pathways.
- Intrinsic: Through APAF and BCL2 family, mitochondrial disruption occurs rectruiting effector caspases and inducing apoptosis.
- Finally phagocytes are recruited through chemokine signals and bind to them and finally engulf them./
- What are the mediators of cell death?
• death ligands binding to tnf family receptors and recruiting and starting a Caspase cascade that will end in apoptosis
• Mitochondrial release of cytochrome c which binds to APAF1 then recruits procaspase 9 and induces caspase cascade. Intrinsic pathway regulated by BCL2 famlily: are proteins found in the outer membrane of mitochondria.
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p53 induces apoptosis when there is DNA damage through BH3 family via p21.
- What are the consequences of cell death?
Phagocytosis, inflammation
- What are the molecular controls of cell death?
FLIP is an anti-apoptosis regulator that inhibits DISC formation.
ICAD inhibits DNA nuclease activity(CAD) when effector caspase activates it, and CAD cleaves ICAD.
Human apoptosis inhibitor-XIAP IT INHIBITS THE EFFECTOR CASPASES.
Anti-apoptotic factors- BCL2 family
- How is cancer associated with poor regulation of cell death?
Poor regulation of cell death is associated with many diseases such as cancer if the pro-apoptotic factors are reduced such as reduced BAX, APAF1 is found in different cancer and overexpression of XIAP is associated with chemotherapy resistance. Because there will be an abnormal accumulation of cells that can transform to cancer, on the other hand if there is too much cell death diseases such as stroke, NDG disease can occur.
- What are the role of cell death in disease?
Too little cell death is associated with many diseases such as many types cancer, autoimmune disease, in cancer if the pro-apoptotic factors are reduced such as reduced BAX, APAF1, FAS. But all pro-survival BCL2 proteins are oncogenes that accelerate proliferation. For example translocation of BCL-2 next to IG enhancer is associated with lymphoma. IAP overexpression associated with chemotherapy resistance and poor clinical outcome. Too much cell death is associated with NDD, stroke,CHD.
How does death ligands and death receptors mediate cell death?
death ligands binding to tnf family receptors and recruiting and starting a Caspase cascade that will end in apoptosis: pro-inflammatory, initiator(8,9) and effector caspases(3,6,7), each activate and recruits the next and cleaves after 4 AA, where aspartate is, tetrapide specific cleavage and cysteine is in active site, 2 cleavages are needed before the zymogen is activated. It has 2 domains, both monomers dimerize before it’s active. CEffector caspases work by cleaving DNA replication enzymes and structural protein.
How does death by mitochondria happen?
Bax like family anti-apoptotic regulate cytochrome c release. BH3 will inhibit BCL2 family and BAX will oligomerize form channels to ditrupt mitochondrial membrane potential, pro survival factors will be sequestered .Cytochrome c is released from mitochondria which binds to APAF1: ATP and cytochrome c dependent, 7 APAF OLIGOMERIZE AND FORM An apoptosome COMPLEX and then recruits procaspase 9 and induces caspase cascade.
