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MOD > Chapter 2 Part 3 > Flashcards

Chapter 2 Part 3 Flashcards

1
Q

Define apoptosis

A

pathway of cell death that is induced by tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear and cytoplasmic proteins

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2
Q

When does apoptosis occur as a physiological condition?

A
  • destruction of cells during embryogenesis
  • involution of hormone-dependent tissues upon hormone withdrawal
  • cell loss in proliferating cell populations
  • elimination of potentially harmful self-reactive lymphocytes
  • death of host cells that have served their useful purpose
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3
Q

When does apoptosis occur in a pathologic condition?

A
  • DNA damage
  • accumulation of misfiled proteins
  • cell death in certain infections
  • pathologic atrophy in parenchymal organs after duct obstruction
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4
Q

Morphologic features associated with apoptosis

A
  • cell shrinkage
  • chromatin condensation
  • formation of cytoplasmic blebs and apoptotic bodies
  • phagocytosis of apoptotic cell or cell bodies, usually by macrophages
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5
Q

Apoptosis results from the activation of…

A

caspases (cysteine proteases that cleave proteins after aspartic residues)

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6
Q

What two phases are the process of apoptosis divided into?

A

1) initiation phase- during which some caspases becomes catalytically active
2) execution phase- during which other caspases trigger the degradation of critical cellular components

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7
Q

What two distinct pathways converge on caspase activation?

A

1) mitochondrial pathway

2) death receptor pathway

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8
Q

What occurs during the mitochondrial (intrinsic) pathway?

A

-results from increased permeability of the mitochondrial outer membrane with consequent release of death inducing (pro-apoptotic) molecules from the mitochondrial inter membrane space into the cytoplasm

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9
Q

What controls the release of mitochondrial pro-apoptotic proteins?

A

BCL2 family of proteins

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10
Q

What are the 3 groups the BCL family is divided into?

A

1) anti-apoptotic: BCL2, BCL-XL, MCL1
2) pro-apoptotic: BAX and BAK
3) Sensors: BAD, BIM, BID, Puma, Noxa

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11
Q

Anti-apoptotic protein functions

A

keep mitochondrial outer membrane impermeable and prevent leakage of cytochrome c and other death inducing proteins into cytosol

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12
Q

Pro-apoptotic protein functions

A

promote outer mitochondrial membrane permeability allowing the leakage of cytochrome c from the inter membranous space

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13
Q

Function of sensors

A

sensors of cellular stress and damage, regulate the balance between the other two groups

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14
Q

What does cytochrome c bind to once released into the cytosol?

A

APAF-1 (apoptosis activating factor 1) forming a multimeric structure called the apoptosome

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15
Q

What does the apoptosome complex do?

A

bind caspase 9 to initiate the mitochondrial pathway and sets up an auto amplification process

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16
Q

Mitochondrial (intrinsic) pathway overview

A

1) cell injury (growth factor withdrawal, DNA damage, protein misfolding)
2) triggers BCL2 family sensors
3) signal BCL2 effectors (BAX and BAK) to promote membrane permeability
4) release of cytochrome c and other pro-apoptotic proteins from the mitochondria
5) singnals initiator caspases (formation of apoptosome)
6) executioner caspases either activate endonucleases leading to nuclear fragmentation of breakdown the cytoskeleton
7) formation of cytoplasmic bleb
8) cytoplasmic bleb becomes apoptotic body
9) apoptotic body binds to phagocytic cell receptors

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17
Q

How is cell viability maintained?

A

1) survival signal (growth factor) binds to receptor protein
2) production of anti-apoptotic proteins (BCL2, BCL-XL)
3) no leakage of cytochrome c

18
Q

How is the extrinsic (death receptor initiated) pathway initiated?

A

engagement of plasma membrane death receptors on a variety of cells

19
Q

Describe the interactions that occurs during the activation of the extrinsic pathway of apoptosis

A

1) FasL expressed in T cells binds to Fas, which is a death receptor expressed in many cell types
2) 3 or more molecules of Fas are brought together and their cytoplasmic death domains form a binding site for FADD (Fas-associated death domain)
3) FADD attached to the death receptor binds an inactive caspase-8
4) multiple pro-caspase-8 molecules are brought into close proximity and cleave one another to generate active caspase 8
5) follow the rest of the mitochondrial pathway

20
Q

What protein inhibits the extrinsic pathway?

A

FLIP- binds to pro-caspase-8 but cannot activate it

21
Q

The mitochondrial pathway leads to an activation of what caspase?

A

9

22
Q

The death receptor pathway leads to an activation of what caspases?

A

8 and 10

23
Q

What are the two executioners caspases?

A

3 and 6

24
Q

What are examples of changes that occur in the membranes of apoptotic cells and fragments to promote phagocytosis?

A
  • phosphatidylserine flips to outer leaflet
  • secretion of soluble factors that recruit phagocytes
  • coated with thrombospondin
  • coated with natural antibodies and proteins of complement system (C1q)
25
Q

What accumulates in cells when DNA is damaged?

A

p53; arrests cell cycle at G1 phase to allow for time to repair

26
Q

What does p53 do if damage is too great to be repaired successfully?

A

triggers apoptosis

27
Q

What control the proper folding of newly-synthesized proteins

A

chaperones in the ER

28
Q

What happens with mid folded polypeptides?

A

ubiquitinated and targeted for proteolysis in proteosomes

29
Q

Unfolded protein response

A

buildup of unfolded or misfiled proteins that accumulate in the ER; activates pathways that increase production of chaperones, enhance degradation of abnormal proteins, and slow protein translation

30
Q

Cytotoxic T Lymphocyte Mediated Apoptosis

A

recognize foreign antigens on surface of host cells and secrete perforin to promote entry go granzymes; granzymes activate variety of cellular caspases and induce effector phase of apoptosis

31
Q

Examples of disorders associated with defective apoptosis and increased cell survival

A
  • cancer (mutations in TP53)

- autoimmune disorders (failure to eliminate harmful cells)

32
Q

Examples of disorder associated with increased apoptosis and excessive cell death

A
  • neurodegenerative diseases
  • ischemic injury
  • death of virus infected cells
33
Q

How is necroptosis similar to necrosis?

A

morphologically; loss of ATP, swelling of cell and organelles, generation of ROS, release of lysosomal enzymes and rupture of plasma membrane

34
Q

How is necroptosis similar to apoptosis?

A

mechanistically; triggered by genetically programmed signal transduction events that culminate in cell death

35
Q

How does necroptosis differ from apoptosis in its activation?

A

does not result in caspase activation

36
Q

Necroptosis overview

A

1) linking of TNFR1 receptor with ligand TNF
2) recruitment of RIP1-RIP2 complex
3) failure to activate caspase 8
4) formation of necrosome
5) metabolic alterations leading to decreased ATP and increased ROS
6) bioenergetic breakdown, protein oxidation, DNA damage
7) loss of cell and organelle integrity
8) cell death

37
Q

Cystic Fibrosis

A

Protein: CFTR
Pathogenesis: loss of CFTR leads to defects in chloride transport

38
Q

Familial Hypercholesterolemia

A

Protein: LDL receptor
Pathogenesis: loss of LDL receptor leading to hypercholesterolemia

39
Q

Tay-Sachs Disease

A

Protein: Hexosaminidase B subunit
Pathogenesis: lack of lysosomal enzyme leads to storage of GM2 gangliosides in neurons

40
Q

Alpha 1- antitrypsin deficiency

A

Protein: a1-antitrypisin
Pathogenesis: storage of non-functional protein in hepatocytes causes apoptosis; absence of enzymatic activity in lungs causes destruction of elastic tissue giving rise to emphysema

41
Q

Creutzfeld-Jacob Disease

A

Proteins: prions
Pathogenesis: abnormal folding of PrPsc causes neuronal cell death

42
Q

Alzheimer Disease

A

Protein: AB peptide
Pathogenesis: abnormal folding of AB peptides causes aggregation within neurons and apoptosis

MOD (34 decks)

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