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38 Cards in this Set
- Front
- Back
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Learning Objectives
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• to appreciate that cell death is normal part of life of a cell as well asa pathological state • to recognise that there are distinct pathways involved in the processof cell death • to distinguish different forms of cell death •necrosis and apoptosis • to understand the role of caspases • to know the processes occurring in the intrinsic and the extrinsicpathways and their differences • to understand the role of key proteins involved in apoptosis |
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what is apoptosis known as? |
programmed cell death |
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what are the morphological features of apoptosis?
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• cell shrinkage
• heterochromatization of nucleus
• nuclear fragmentation
−DNA ladders
• no inflammation
• suicide program |
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describe apoptosis
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• different from necrosis • little inflammatory response • specific genes involved • distinct biochemical pathway • cells die when not needed • cell activates a suicide program • apoptosis is mediated by caspases • proteases • synthesized as procaspases • procaspases are activated by other caspases |
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What is a good example of apoptosis?
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• getting rid of neutrophils after an infection • in adult bone marrow most neutrophils produced die throughapoptosis • important biochemical feature is presence of phosphatidylserine (negatively charged phospholipid) to outer layer ofbilipid membrane • signal for phagocytic cells such as macrophages, to ingest theapoptotic cell |
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cellular pathways of apoptosis
the caspase cascade involved in apoptosis
describe the Procaspase activation by cleavage (Part A of procaspases that are activated by binding to adaptor proteins)
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each suicide protease is made as an inactive proenzyme (procaspase), which usually is activated by proteolytic cleavage by another member of the caspase family. as indicated, two of the cleaved fragments associate to form the active site of the caspase. the active enzyme is thought to be a tetramer of two of these units
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cellular pathways of apoptosis
the caspase cascade involved in apoptosis
describe the caspase cascade (Part B of procaspases that are activated by binding to adaptor proteins) |
each activated caspase molecule can claeve many procaspase molecules, therby activating them, and these can then activate even more procaspase molecules. in thsi way, an initial activation of a small number of procaspase molecules (called initiator caspases) can lead, via an amplyifing chain reaction (a cascade), to the explosive activation of a large number of procaspase molecules. some of the activated caspases (called effector caspases) then cleave a number of key proteins in the cell, including specific cytosolic proteins and nuclear lamins, leading to the controlled death of the cell
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what does the proteolytic cascade lead to?
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protein disposal in apoptotosis
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the proteolytic cascade pathway involves which enzymes?
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initiator caspases and executioner caspases
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what do caspases specifically target?
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the caspases specific target proteins eg cytoskeleton and cell-cell adhesion molecules expression of different caspases may be cell-specific |
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describe the types of caspases in humans
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in humans, initiator caspases are caspases 2, 8, 9 and 10and executioner caspases are caspases 3, 6 and 7 |
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what actually kills the cell during the proteolytic cascade of caspases? |
cleavage of the key proteins is what actually kills the cell |
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what pathways lead to apoptosis?
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There are two independent signalling pathways that lead to apoptosis
• extrinsic
• intrinsic |
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in summary describe the activation of apoptosis from outside the cell (Extrinsic pathway)
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extracellular activation. A killer lymphocyte carrying the Fas ligand binds and activates Fas proteins on the surface of the target cell.
Adaptor proteins bind to the intracellular region of aggregated Fas proteins, causing the aggregation of procaspase-8 molecules.
these then cleave one another to initiate the caspase cascade
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in summary describe the activation of apoptosis from inside the cell (Intrinsic pathway) |
involves intracellular activation. Mitochondria release cytochrome c, which binds to and causes the aggregation of the adaptor protein apaf-1. apaf-1 binds and aggregates procaspawse-9 molecules, which l.eads to the cleavage of these molecules and the triggering of a caspase cascade. other proteins that contribute to apoptoswis are also released from the mitocfhondrial intermembrane space.
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what does the extrinsic pathway of apoptosis require?
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requires extracellular signalling event |
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in the extrinsic path how are caspases activated?
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caspases are activated by binding of apoptosis signals todeath receptors |
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in the extrinsic path, what does the death receptors belong to?
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tumor necrosis factor receptorgene superfamily TNF' there are at least 10 receptors
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describe the Fas death receptor and its pathway
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• Fas receptor CD95 is best characterized death receptorand it isinvolved in
−deletion of activated T cells at end of immune response
−killing of virus-infected and cancer cells by T cells • killer lymphocytes produce a protein called Fas ligand which binds tothe death receptor on surface of target cell
• Fas recruits intracellular adaptor proteins which bind and aggregateprocaspase-8 molecules
• procaspase-8 activate other caspases which induce apoptosis |
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in the intrinsic pathway how can cells kill themselves? |
cells can kill themselves by activating caspases from inside themselves |
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in the intrinsic path, describe the actions of the cascade and what it involved |
• involves release of cytochrome c from mitochondria • in cytosol, cytochrome c activates Apaf-1, an adaptor protein • Apaf-1 binds to and activates procaspase 9 • caspase 9 activation leads to activation of other caspases and tocleavage of cellular proteins • this pathway used for DNA damage or lack of oxygen |
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what pathway is involved the DISC = death-inducing signaling complex |
extrinsic apoptotic pathway
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what pathway is involved in the CARD = caspase recruitment domain |
intrinsic apoptic pathway
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what are the main intracellular regulators of the cell death program?
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Bcl-2 family of intracellular proteins
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what does the Bcl2 family of proteins help regulate?
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the activation of procaspases of the intrinsic pathway
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how many classes of Bcl2 proteins are there?
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3 classes
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what are the three classes of Bcl2 proteins?
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how many classes of anti apoptic proteins does Bcl2 proteins have?
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one class of anti-apoptotic proteins |
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how many classes of pro-apoptic proteins does Bcl2 proteins have? |
two classes of pro-apoptotic proteins |
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what do all classes of Bcl2 proteins have? |
BH3 domains |
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what is the main anti-apoptotic protein?
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Bcl2 |
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what is Bax and Bak? |
they are main pro-apoptotic proteins that belong to the BH123class |
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what is another pro-apoptotic class of protein? |
BH3 |
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what is the significant of Bcl2 proteins shown by?
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Significance of Bcl2 proteins is shown by knockouts • Bcl2 knockout mice have defects in nervous system duringdevelopment
• Bax knockouts have increased numbers of neural cells |
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describe BH123 pro-apoptotic function |
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describe when the intrinsic pathway is inactive
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describe when the intrinsic pathway is active |
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what are apoptosis pathways linked with? |
growth and proliferative pathways |
