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Wednesday, December 23, 2015

Mechanisms of Apoptosis

Apoptosis is programmed cell death. It is the result of activation of enzymes (caspases). The two pathways of apoptosis are the extrinsic pathway and the intrinsic pathway.

Extrinsic (death receptor) pathway

1.       Initiated when a TNF receptor (eg. CD95/Fas) binds to its ligand CD95L.
2.       Triggers multiple receptors to aggregate together at cell surface.
3.       This attracts an adapter protein FADD (Fas-Associated Death Domain).
4.       The protein recruits procaspase 8 to form the death-inducing signalling complex (DISC).
5.       Procaspase 8 is cleaved into active caspase 8.
6.       Caspase 8 activates caspase 3 (an executioner caspase) to initiate cell degradation.
7.       Caspase 8 also cleaves Bid protein to tBid (truncated Bid).
8.       tBid acts as a signal on mitochondria membrane to facilitate release of cytochrome c in the intrinsic pathway.

Intrinsic (mitochondria) pathway

1.       Triggered by stimuli such as deprivation of growth factors/survival signals/ exposure to agents that damage DNA/excessive accumulation of misfolded proteins.
2.       Sensors (BH3 proteins) of the Bcl2 family are activated, which in turn activate pro-apoptotic members called Bax and Bak.
3.       Bax and Bak cause cytochrome c and other mitochondrial proteins to leak out.
4.       These sensors inhibit anti apoptotic molecules Bcl2 and BclXL , enhancing leakage.
5.       Cytochrome c leaks into the cytosol where it binds to APAF-1 (apoptotic protease activating factor 1) forming an apoptosome which in turn activates caspase 9.
6.       Caspase 9 cleaves and activates the executioner caspase (caspase 3) that initiates degradation.
7.       The activation of caspase cascade leads to nuclear fragmentation.

References:
1. Kumar V, Abbas A. K, Aster J.C. Robbins Basic Pathology. 2013. 9th ed. Philadelphia: Elsevier Saunders.
2. http://www.scq.ubc.ca/apoptosis/