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Year 2 MCD Cancer > 6: Apoptosis > Flashcards

6: Apoptosis Flashcards

1
Q

What are the resons why apoptosis takes place?

A
  1. Harmful cells (e.g. cells with viral infection, DNA damage).
  2. Developmentally defective cells (e.g. B lymphocytes expressing antibodies against self antigens).
  3. Excess / unnecessary cells (embryonic development: brain to eliminate excess neurons; liver regeneration; sculpting of digits and organs).
  4. Obsolete cells (e.g. mammary epithelium at the end of lactation)

–> Can be Exploited therapeutically - Chemotherapeutic killing of cells

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2
Q

What are the characteristics of necrosisi?

A
  • unregulated cell death
  • normally due to trauma
  • there is cellular disruption
  • associated with inflammation (due to release of intracellular contents)
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3
Q

What are the characteristics of apoptosis?

A
  • programmed, regulated cell death
  • controlled dissembly of contents without membrane disruption
  • no inflammation
  • ATP dependant
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4
Q

How many different types of cell death are ther?

A

Many many types of cell death, ranging from Necrosis on the one end to Apoptosis on the other hand –> many are in the middle and have characteristics of both

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5
Q

Explain the process of necrosis

A
  1. Plasma membrane becomes permeable
  2. Cell swelling and rupture of cellular membranes
  3. Release of proteases and intracellular contents leading to autodigestion and dissolution of the cell
  4. Localised inflammation
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6
Q

What are the two phases of Apoptosis?

What are theri characteristics?

A
  1. Latent phase
    • apoptosis pahtways activated but no morphological change in cell
  2. Execution phase
    • morphologican changes and destruction of cell
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7
Q

What happens in the latent phaese of apoptosis?

A

death pathways are activated, but cells appear morphologically the same

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8
Q

Explain the processes that take place during the execution phase of apoptosis?

A

Example of epithelial cells

  • loss of microvilli and intracellular junctions
  • cell shrink
  • loss of plasma membrane assymetry (important in normal function, can be seen e.g. by phosphatidylserine lipid appearing on surface)
  • Chromatin and nuclear condensation
  • DNA fragmentation
  • Formation of memrane bleps
  • Fragmentation into membrane-enclosed bodies (get phagocytosed by macrophages etc)
    • no release of cell contents
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9
Q

What happens to the DNA during apoptosis?

A

•Chromatin and nuclear condensation

• DNA fragmentation

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10
Q

Explain the characteristics of Apoptosis-like PCD (programmed cell death)

A

some, but not all, features of apoptosis. E.g. Display of phagocytic recognition molecules before plasma membrane lysis

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11
Q

Explain the characteristics of Necrosis-like programmed cell death (PCD)

A

Variable features of apoptosis and necrosis before cell lysis present; “Aborted apoptosis”

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12
Q

Which proteins mainly execute Apoptosis?

A

Cysteine-dependent aspartate-directed proteases (Caspases)

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13
Q

Summarise the role and activation of caspases (briefly!)

A

Are the executers of apoptosis

  1. Get activated by cleavage (proteolysis) by another protease
  2. Set of a cascade of other activators
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14
Q

What two types of caspades are there?

What is their characteristic and function?

A

There are two types

  1. Initiator caspases
    • get activated directly by intrinsic/extrinsic pathways
  2. Effector caspases
    1. get activated by initiator caspases, set off futher routes
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15
Q

What are the protien domains that all caspases have in common?

What are the additional domapins the different initiator capsades have?

What is their function?

A

All have in common: p20 and p10 domain

  • Caspase 9+2 also have a CARD domain (caspase recruitement domain –> will localise the caspases at specific sites in the cell)
  • Caspase 10+8 also have a DED domain (Ceath effector domain) –> binds to adaptor protein and involved in activation of the capsase
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16
Q

What is meant by the term of caspase maturation?

Explain the process

A

It is the activation of a procaspase to the active form

  1. Pro-domain and SS domain of caspase are cleaved (proteolysis)
  2. Dimer formation of one Large (L) and one small(2 chain)
  3. 2 dimers come together to form the active heterotetramer, consisting of 2L2S
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17
Q

What are the main functions of activatio of the caspase cascade?

A
  • amplification of the apoptotic signal
  • divergent responses –> spread responses
  • regulation
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18
Q

What are the different concepts by which the effector caspases can execute the apoptotic program?

(what do they do to proteins?)

A
  1. Inactivate by proteolysis (cleavage of proteins)
    • single proteins
    • protein complexes
  2. Activate enzymes by cleavage
    • direct activation
    • indirect by destruction of inhibitory molecules
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19
Q

Name an example of how caspase induced inactivation of an enzyme/protein can lead to apoptosis

A

E.g. Inactivation of nuclear lamins leading to nuclear breakdown

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20
Q

Name an example of how caspase induced activation of an enzyme/protein can lead to apoptosis

A

incl. protein kinases; nucleases, e.g. Caspase-Activated DNAse, CAD

21
Q

What are the two pathways that can induce apoptosis?

How are they induced?

A
  1. Extrinsic pathways
    • by binding to extracellular receptors
  2. Intrinsic pathways
    • by mitochondria (cellular stress leading to the less ot mitochondrial membrane potential)
22
Q

What are “death receptors”?

What is their stucture, and what do they all have in common?

A

Transmembrane receptors that all

  • form trimers when activated
  • have an intracellular DD (death domain)
23
Q

Explain the structure of FADD

What is it and what is its function?

A

FADD= an adaptor protein binding to the death receptors

  • Has one DED(death effector domain) and one DD(death domain)
  • it activates the apoptotic programm
24
Q

Explain the structure of FLIP

What is it and what is its function?

A

FLIP is an adaptor protein that binds to the death receptors and inactivates the apoptotic programm

  • has only DED (Death effector domains)
25
Explain the activation of the death receptor at the example of FAS
A ligand (e.g. FAS-L on lmyphocyte) will bind to FAS --\> leads to receptor trimerisation --\> recruitement of adaptor protein
26
Explain the processe that happens after trimerisation of the death receptor at the example of FAS
* adaptor Protein (FADD) will bind to FAS via the Death domain (they both have)
27
What happens after FADD binds to FAS via the DD?
This will lead to an recruitement of caspase 8 that binds to FADD via the DED (both have it) and will lead to oligomerisation that activated caspase
28
Explain how oligomerisation of caspases lead to their activation
1. Oligodimerisation leads to conformational change of proteins 2. some caspases need transcleavage to be activated Concept of Transcleavage: * FAS is a trimeric receptor * 3 FADD molecules with 3 DED bind to it * 1 caspase (8?) binds to each of them--\> 3 caspases * Crosscleave each other leading to acitvation and * **Release of activtive initiator caspase 8 (tetramer) --\> at least 2 caspases required**
29
Explainn how FLIP inactivates the apoptotic pathway
It inhibits the activation of caspases competitevely * Binds to the DED ends of FADD * but has no proteolytic funtion--\> no caspase tetramer formation
30
Explain the caspase cascase (which caspase activated which
31
Explain the intrinsic activation of apoptosis
1. Cellular stress leads to 2. loss of mitochondrial membrane potential 3. Leading to release of cytochrome c and other factors 4. Cause apoptosome formtation
32
Which proteins/facotrs are required in the formation of teh apoptosome?
Apaf-1 (Apoptotic activating factor-1), Cytochrome c, ATP, procaspase 9
33
Explain the formation and structure of the apoptosome
1. Apaf-1 (Apoptotic activating factor-1) come together at the **CARD domain** and form a heptamer (7) 2. Outside: there is the WD-40 domain that interactis with **cytochrome c** 3. When cytochrome c bound--\> **caspase 9** (several, each Apaf-1 can bind one) bind to CARD of apoptosome and gets activated (oligomerisation and trans-cleavage) 4. Caspase 3 recruitement 5. Activation leading to caspase cascade acivation
34
How are the intrinsic and extrinsic pathways of apoptosis initiation connected?
1. When Extrinsic pathway is activated: 2. Bid protein gets activated by caspase 8 and triggers mitochrondrial release of mitochrondrial proteins 3. --\> activation of intrinsic pathway
35
What are the two classes within the Bcl-2 protein family? Where are they located?
There are 1. Anti-apoptotic molecules in the mitochondrium * Bcl-2 * Bcl-xL 2. Pro-apoptotic molecules that travel between cytocsol and mitochondrium * Bid * Bad * Bax * Bak
36
What are proteins from the Bcl-2 family?
Proteins that are involved in regulation and modulation of apoptosis (can be pro-apoptotic and anti-apoptotic) * differnet groups/proteins with different domains but all: BH3 as dimerisation motif
37
What are the anti-apoptotic proteins in the Bcl-2 protein family?
Bcl-2 Bcl-xL
38
Explain the role of Phosphatidylinositol 3’-kinase (PI3’-K) in the cell survival
Phosphatidylinositol 3’-kinase (PI3’-K) is a lipid kinase that promotes cell survival * gets activated by Growth factor receptor * converts PIP2 into PIP3 * PIP3 Activates protein kinase PKB/Akt which is anti-apoptotic
39
Explain the consequence of activation of protein kinase PKB/Akt
Its activation is anti-apoptotic because it * phosphorylates and inactivated bad * inactivation of caspase 9 * inactivation of pro-apoptotic Transcriptionfactor FOXO * Indirect: Other, e.g. stimulates ribosome production and protein synthesis
40
Explain the relationship between the PKB/Akt pathway and the Bcl-2 proteins
1. PKB/Akt are activated via the GF/PI3'-K pathway during growth factor binding 2. they inactivate BAD 3. which then means, that the heterodimers on the mitochondrium are inactive and and don't cause activation of the intrinsic pathway
41
Explain how the absence of GF might lead to apoptosis
If there is no GF --\> no activation of PKB/Akt (PI3’-K, GF pathways) * no inhibition of Bad * displaces Bax/BAc from Bcl-2/-xL binding site (all bind together via BH3) * Bax/Bac are now released and form the Bax/Bac Pore -\> Apoptosis via activation of the intrinsic pathway
42
Explain the role of PTEN in the regulation of apoptosis
PTEN can induce apoptosis by inhibiting the phosphorylation of PIP2 into PIP3 (and thereby the pro survival(phosphoinositide 3 kinase (PI3K) ) signaling) * disinhibition of apoptosis
43
Explain the role of Inhibitor of Apoptosis Proteins (IAPs) in the regulation of apoptosis How do they do it?
They inactivate apoptosis inthe extrinstic pathway by: * Bind to procaspases and prevent activation * •Bind to active caspases and inhibit their activity
44
Which molecules regulate and increase cell survival in the intrinstic pathway?
Mainly the pro survival Bcl-2 family proteins * Bcl-2, * Bcl-xL
45
Which molecules promote cell survival by inhibiting/modulating the apoptosis pathway?
* FLIP (competitively inhibits the activation of caspases) * IAPs Inhibitor of Apoptosis Proteins (directly inhibits caspase activation and already activated caspases)
46
How can apoptotical pathways be therapeutically useful?
* Harmful (oncogenic) cells (e.g. cells with viral infection, DNA damage) * Chemotherapeutic killing of tumour cells, e.g. Dexamethasone stimulates DNA cleavage
47
What is the Role of PI3 Kinase and FOXO?
PI-3’-kinase phosphorylates PIP2 to PIP3 thus activating PDK1 and Akt/PKB Akt phosphorylates FOXO transcription factors and inactivates it by moving the transcription factors to the cytoplasm --\> no expression of negative cell cycle regulators p27Kip and apoptotic protein Fas ligand. FOXO is apoptotic and anti-proliferative, so the PI3-kinase cascade increases proliferation and reduces apoptosis.
48
What are the effects of AKT (activated by PI3'-Kinase)
* inactivates FOXO (pro-apoptotic) * AKT phoyphorylates BAD * inhibits caspase 9 * Overall: anti-apoptotic!
49
How does PI3'K promotes cell cycle progression?
* it inacitvates GSK3b * normal function is to inactivate cyclins/CDK complexes leading to cell cylcle arrest

Year 2 MCD Cancer (17 decks)

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