Term
| Provide examples of 4 physiological contexts where apoptosis occurs to eliminate unnecessary or damaged cells. |
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Definition
1) Pruning in developing nervous system
2) Maintaining tissue homeostasis in GI track and Immune system where cell turnover is common.
3) Elimination of immune cells such as self reactive T cells
4) Eliminating Virus-infected and tumor cells by cytotoxic T cells. |
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Term
True or False:
There is no acute inflammatory response in Apoptosis |
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Definition
True!
This response occurs only in necrosis
Apoptosis has Cell shrinkage, formation of apoptotic bodies, chromatin condensation, blebbing of PM, and exoplasmic exposure of phosphatidyl serine. |
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Term
True or False:
Necrosis is ATP-dependent, while Apoptosis is not |
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Definition
False, the opposite is true!
Apoptosis uses ATP and UTP released from apoptotic cells to activate and recruit phagocytic cells.
Necrosis involves pyknosis (nuclear condensation), Karyorrhexis (fragmentation) and Karyolysis (lysis) with an acute inflammatory response.
NOTE- both processes can occur within a given tissue at the same time |
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Term
| Why might mutations in the gene encoding lysosome-associated membrane protein type 2A (LAMP-2A) be of clinical concern? |
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Definition
LAMP-2A is important for chaperone-mediated autophagy.
LAMP-2A, along with chaperone proteins, enables unfolded proteins to be directly translocated into the lysosome |
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Term
| Distinguish between Microautophagy and Macroautophagy |
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Definition
1) Microautophagy occurs via the direct engulfment of cytoplasmic material via lysosomal invaginations
2) Macroautophagy involves double membrane vesicle called autophagosome, which fuses with lysosome to form autolysosome. |
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Term
| What is the role of caspases in apoptosis and how are they inhibited? |
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Definition
1) Initiators (8 and 10) and Executioners (3,6 and 7) both contain Cysteine within their active sites and cleave Aspartic acids on target proteins within tetrapeptide sequences.
2) Inhibitors of Apoptosis (IAPs) inhibit caspase activity or trigger their ubiquitylation. IAPs are inhibited by mitochondrial factors such as SMAC/DIABLO. |
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Term
True or False
Caspases are activated by cleavage and be involved in "initiation" or "effector" phases of apoptosis |
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Definition
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Term
| Explain how caspases interact with PARP and I-CAD. |
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Definition
1) PARP binds to DNA strand breaks and repairs them. Caspase 3 cleaves and inhibits PARP.
2) Caspases cleave I-CAD in cytoplasm and associated DNAse (CAD) is released to enter nucleus and cleave DNA within internucleosomal regions. |
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Term
| How does the Extrinsic Pathway of Caspase Activation work? |
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Definition
SHORT- Death receptors bind ligands and interact with DDs of adaptor molecules. The DEDs of these adaptor molecules with DEDs on pro-caspases and activate DISC. Activates initiator caspases activate executioner caspases and apoptosis occurs.
1) Death receptors, Fas (CD95) and Tumor Necrosis Factor Receptor (TNFR) bind Fas Ligand and TNF-a.
2) Death domains (DDs) within receptors interact with adaptors (FADD, MORT) that contain Death Efffector Domains (DEDs).
3) Adaptor DEDs interact with DEDs on procaspases activates Death-Inducing Signaling Complex (DISC)
4) Initiator caspases (8, 10) cleave and activate executioner caspases (1,3) which cleave proteins and cause apoptosis |
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Term
| What doe RIP1 have to do with ischemic brain injury? |
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Definition
| RIP1 is the non-apoptotic, "necroptotic"adaptor protein for TNFR/TNF-a. Inhibitors of this adaptor are protective in mouse models. |
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Term
| How does the Intrinsic Pathway of Caspase Activation work? |
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Definition
Signals that do not act through death receptors act through this mitochondria-dependent pathway.
1) Cytochrome c is released along with other proapoptotic factors from mitochondria
2) Cytoplasmic Cyt C associates with Apaf-1, dATP and procaspase 9 leading to the formation of the Apoptosome
3) Caspase 9 is activated and cleaves executioner. Caspase 3 |
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Term
| How are the intrinsic and extrinsic caspase pathways linked? |
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Definition
| Caspase 8-mediated cleavage of regulators of mitochondrial cytyochrome c release. |
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Term
| How can some Bcl-2 family members be anti-apoptotic and others be pro-apoptotic? |
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Definition
Anti-apoptotic members share common BH1-BH4 motifs (Bcl-2, Bcl-xL)
Pro-apoptotic members share common BH1-BH3 motifs (Bax, Bak) or contain a BH3 motif only (Bad, Bid, Bim)
REMEMBER, vertebrate homolouge is Ced-9 |
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Term
| How do Bcl-2 proteins activate/suppress apoptosis? |
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Definition
1) Anti-apoptotic members usually bind and inhibit BH123 (Bax, Bak) members to prevent apoptosis
2) Stress/damage activates BH3-only members (Bid, Bim, Bad) to interact with anti-apoptotic Bcl-2 proteins to relieve their inhibition of BH123 members at mitochondrial outer membrane.
3) "Death pore" forms with BH123 members leading to leakage of cytochrome C, Apoptosis Inducing Factor (AIF) or Endonuclease G from mitochondria. |
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