Lecture 9b to post 2007 - Lecture 9a Review Apoptosis What...

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Lecture 9a Review • Apoptosis – What is it? – How was it discovered? • Two fundamental types of cell death – Apoptosis versus Necrosis – Differences in the morphological and biochemical characteristics • Importance of programmed cell death in metazoans • The role of apoptosis in anticancer treatment sensitivity • Major Mammalian Apoptotic pathways – Extrinsic (death receptor mediated) – Intrinsic (mitochondrial mediated) • Introduced caspases
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Lecture 9b Overview • Caspases – what are they? – Initiators versus executioners – activation –Func t ion • Extrinsic Pathway – Death receptor Mediated • Intrinsic Pathway – Mitochondrial Mediated –Bc
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Caspases: what are they? •c ysteine as partyl proteases : caspases active caspases are heterodimeric, consisting of large and small subunits generated by caspase-mediated cleavage of a common procaspase precursor protein caspase ‘cascades’ : amplification of apoptotic signals
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Pivotal role of caspases • specific inhibition or ablation of caspases in mammals is sufficient to block morphological effects of apoptosis and delay cell death
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Name Alternative name Caspase 1 ICE Caspase 2 ICH-1, Nedd-2 Caspase 3 CPP-32, Yama, Apopain Caspase 4 ICH-2, TX, ICE-rel-II Caspase 5 ICE-rel-III, TY Caspase 6 Mch2 Caspase 7 Mch3, ICE-LAP3, CMH-1 Caspase 8 FLICE, MACH, Mch5 Caspase 9 Mch6, ICE-LAP6 Caspase 10 Mch4, FLICE2 Caspase 11 ICH-3 Caspase 12 Caspase 13 ERICE Caspase 14 MICE Mammalian Caspases
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Caspases are critical effectors of all known apoptotic signaling pathways • apoptosis is irreversibly turned on by activation of caspase family of aspartate- specific proteases • upstream initiator caspases: caspases 2, 8, 9 and 10 • these caspases in turn activate other downstream caspases (effectors) e.g. caspase 3, 7 • downstream caspases responsible for cleavage of many other cellular proteins, leading to completion of apoptotic program
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Processing Of Caspase Substrates Dismantles And Deregulates Vital Cellular Function Various caspase substrates have been identified including: • Cytoskeleton proteins (such as actin and gelsolin) • Nuclear proteins (such as lamin A and B) • Proteins involved in DNA repair (such as PARP, RAD51, and DNA-PKcs) • Cell cycle proteins (such as p21, p27, and RB)
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DNA fragmentation: role of CAD/ICAD CAD: caspase-activated deoxyribonuclease degrades DNA during apoptosis Inhibitor of caspase-activated deoxyribonuclease Both normally in cytoplasmic fraction: ICAD acts as a chaperone for CAD, remaining complexed with CAD to inhibit DNase fragmentation in nuclei Caspases activated by apoptotic stimuli then cleave ICAD, allowing CAD to enter the nucleus and degrade chromosomal DNA
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This note was uploaded on 12/03/2010 for the course PHAMACOLOG pcl470 taught by Professor Arnot during the Fall '10 term at University of Toronto.

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Lecture 9b to post 2007 - Lecture 9a Review Apoptosis What...

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