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Year 2 - Cancer > Cancer 6 > Flashcards

Cancer 6 Flashcards

1
Q

why do we need cell death?

A

in order to remove

  • harmful cells (e.g. cells with viral infection, DNA damage)
  • Developmentally defective cells (e.g. B lymphocytes expressing antibodies against self=antigens)
  • Excess/unnecessary cells eg. Embryonic development e.g. brain to eliminate excess neurons; liver regeneration; sculpting of digits and organs
  • Obsolete organs (e.g. mammary epithelium at the end of lactation)
  • Exploitation ( eg. chemotherapeutic killing of cells)
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2
Q

define necrosis :

A
  • unregulated cell death associated with trauma, cellular disruption and an INFLAMMATORY RESPONSE
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3
Q

define apoptosis:

A
  • programmed cell death
  • regulated cell death; controlled disassembly of cellular contents without disruption O NO INFLAMMATORY RESPONSE
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4
Q

what is the process of necrosis?

A
  • The plasma membrane becomes permeable
  • There is cell swelling and rupture of cellular membranes
  • Proteases are released leading to autodigestion and dissolution of the cell
  • Localized inflammation
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5
Q

what is the process of apoptosis?

3 phases

A
  • Latent Phase = death pathways are activated, but cells appear morphologically the same
  • Execution Phase =
  • Loss of microvilli and intercellular junctions
  • Cell shrinkage
  • Loss of plasma membrane asymmetry

(normally the top of the cell is very asymmetrical to the bottom, in apoptosis the lipids change, phosphatidylserine lipid appears in the outer leaflet )

  • Chromatin and nuclear condensation
  • DNA fragmentation
  • Formation of membrane blebs
  • Fragmentation into membrane=enclosed apoptotic bodies
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6
Q

what is an important feature of apoptosis?

A
  • plasma membrane stays intact
  • there is no inflammation
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7
Q

what does the DNA modification during apoptosis result in?

A
  • Fragmentation of DNA ladders (seen in agarose gel)
  • Formation of more ‘ends’, which are labelled by adding an extra fluorescently-tagged base in a TUNEL assay
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8
Q

where do the dead cells go after apoptosis?

A
  • they are taken up by phagocytosis by macrophages
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9
Q

what is Apoptosis- like programmed cell death?

A
  • has some, but not all, features of apoptosis
  • Display of phagocytic recognition molecules before plasma membrane lysis
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10
Q

what is necrosis like programmed cell death?

A
  • displays variable features of apoptosis before cell lysis
  • this is like abandoned apoptosis that ends up being like necrosis
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11
Q

what is the nature of apoptosis and necrosis?

A
  • So cells quite often die of something that is in between necrosis and apoptosis
  • it is a graded response
  • with apoptosis at one end and necrosis at the other
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12
Q

what are caspases?

what is their structure?

what are they initiated by?

what is their function?

A
  • Caspase = Cysteine=dependent aspartate=directed proteases
  • They have a cysteine residue in their active site that is required for their activity
  • They are activated by proteolysis
  • They cut proteins just after their aspartate residue
  • They take part in a cascade of activation
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13
Q

what are the classes of caspases?

A
  • initiator caspases
  • effector caspases
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14
Q

in total what are the initiator caspases?

A

2 and 9

8 and 10

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15
Q

what are the initiator caspases?

what are they characterised by?

A
  • 2, 9
  • they have very defined domains
  • they are homologous throughout the whole family
  • at the end terminus, they have a CARD domain
  • CARD = Caspase Recruitment Domain
  • this domain will place the caspase at particular subsites inside the cell
  • consists of P20 and P10
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16
Q

what do caspase 8 and 10 have additionally?

A
  • DED = Death Effector Domain
  • DED is positioned before the P20 and P10
  • they do not have CARD
  • they undergo homotypic protein-protein interactions
  • (this means caspase 8 can only interact with caspase 8 ect.)
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17
Q

what are the effector caspases?

A
  • caspase 3, 6 , 7
  • they mainly consist of P20 and P10
  • The subunits are released by proteolytic cleavage during maturation
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18
Q

what is caspase maturation?

A
  • capsases are synthesised as PROCAPSES
  • Procaspases (zymogens) are single chain polypeptides
  • To become activated, the procaspases must undergo proteolytic cleavage to form large and small subunits
  • After the cleavage, you get folding of 2 large and 2 small chains to form an active L2S2 heterotetramer
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19
Q

what is the purpose of a caspase cascade?

A
  • Amplification
  • Divergent responses
  • Regulation

once apoptosis is triggered, the initiator caspases cleave and activate the effector caspases

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20
Q

what are initiator caspases responsible for?

what are effector caspases responsible for?

A

initiator caspases :

triggers apoptosis by cleaving and activating

effector caspases :

carries out actual apoptosis

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21
Q

how do the effector caspases execute the apoptotic program?

A
  • Cleaving and inactivating various proteins and complexes
  • Activating enzymes by direct cleavage, or cleavage of inhibitor molecules
22
Q

what are the two mechanisms of caspase activation?

A
  • Death by design = receptor-mediated (extrinsic) pathways
  • Death by default = mitochondrial (intrinsic) death pathway
23
Q

explain death by design:

A
  • All cells have death receptors on their surface
  • Death receptors consist of
  • Extracellular cysteine- rich domain
  • Single transcellular domain
  • Cytoplasmic tail (with a death domain)
  • These receptors are only activated when they encounter secreted or transmembrane trimeric ligands (e.g. TNF-alpha or Fas)
  • these are called death ligands
24
Q

what adaptor proteins are important in the death by design pathway?

A
  • FADD
  • FLIP
25
Q

what does DD and DED stand for?

A

DD = death domain

DED = death effector domain

26
Q

what are the features and functions of FADD?

A
  • FADD = POSITIVE regulator (required for the death pathway to become activated) and promotes cell death
  • FADD = DED + DD
27
Q

what are the features and functions of FLIP?

A
  • FLIP = negative regulator (inhibits the death pathway and allows it to be regulated)
  • FLIP = DED + DED
28
Q

how to signal through the death receptors? (Fas/Fas- ligand)

A
  • Fas is a death receptor that is upregulated if apoptosis is required
  • The Fas ligand binds to the Fas receptor on the surface of cytotoxic T lymphocytes
  • The Fas receptors then undergo trimerisation, which brings the three cytoplasmic DD domains together
  • The trimerised death domains recruit the positive adapter protein FADD by its own DD
  • The binding of FADD causes recruitment and oligomerisation of procaspase 8 through its DED to the FADD’s DED
  • The binding of procaspase 8 to FADD forms a Death-Inducing Signalling Complex (DISC)
  • This brings three initiator procaspase 8s into close contact, which allows cleavage
  • DISC formation results in cross-activation of procaspase 8, whereby they cleave each other within the complex
  • This releases the active initiator caspase 8 tetramer
29
Q

what inhibits the death receptor activation of procaspase 8?

A
  • inhibited by FLIP
  • it is homology but It has no proteolytic activity
  • there are two FLIPs a short one and a short one
  • once the procaspase 8 has been inhibited it can no longer be activated
30
Q

what does activation of caspase 8 result in?

A
  • Caspase 8 activates downstream effector caspases
  • the effector caspases go on to carry out the apoptotic programme
31
Q

explain death by default :

A
  • This is the intrinsic pathway whereby cellular stresses cause a loss of mitochondrial membrane potential
  • This results in the release of cytochrome C and other apopotosis=inducing factors
  • These stimulate the formation of an apoptosome complex
32
Q

what cellular stresses might cause death by default

A
33
Q

what does the apoptosome consist of?

A

the apoptosome consists of

  • APAF - 1
  • Procaspase 9
  • ATP
  • cytochrome C
34
Q

how does the apoptosome wheel of death work?

A
  • at one end of APAF-1 there is a number of WD-40 repeats that are involved in protein- protein interactions
  • There is also an ATPase domain within APAF- 1
  • At the other end of APAF- 1 there is a caspase recruitment domain (CARD) this is found in some initiator caspases eg 9
  • When cytochrome C binds to the WD=40 repeats on APAF=1, it forms a heptamer (the apoptosome)
  • This process also requires ATP
  • The CARD domains at the centre of the apoptosome can interact with the CARD domains on procaspase- 9
  • this means 7 procaspase 9s can bind to the apoptosome
  • the close proximity of the procaspase 9s that bind to the CARD domains of the apoptose can cross cleave activate eachother to produce caspase 9
  • The activated caspase 9 is then released, which is able to trigger the caspase cascade, which leads to apoptosis
35
Q
A
36
Q

does apoptosis require energy?

does necrosis require energy?

A

apoptosis needs energy

necrosis does not need energy

37
Q

how are the two apoptosis pathways linked?

A
  • Bid links the receptor- mediated and mitochondrial death pathways
  • When one pathway is triggered, it can trigger the other pathway
  • Caspase 8 from the receptor- mediated pathway can cleave Bid, which enhances release of mitochondrial proteins, thus engaging the intrinsic pathway
  • Bid promotes the release of cytochrome C from the mitochondrion, which triggers the mitochondrial death pathway
38
Q

what is the difference in energy requirement between the two apoptosis pathways?

A
  • the mitochondrial pathway requires ATP
  • the receptor-mediated pathway does not need ATP
39
Q

what are the modulators of apoptosis?

A
  • these are called Bcl - 2 proteins
  • there are three main groups of Bcl- 2 proteins
  • they all contain BH3 domains
  • Some of the proteins contain other domains including a transmembrane domain
40
Q

what is BH3?

A
  • BH3 is a dimerisation motif
  • this allows proteins in the Bcl - 2 family to associate and dimerise with each other
41
Q

what are the two groups within the Bcl-2 family?

A
  • Anti- apoptotic proteins =

localised to the mitochondrial membrane

INHIBIT apoptosis

  • Pro - apoptotic proteins=

move between the cytosol and the mitochondrial membrane and they PROMOTE apoptosis

42
Q

how do growth factors influence apoptosis regulation?

A
  • Growth factors may activate TWO growth factor pathways associated with anti- apoptotic effects
    1. Ligand binding causes dimerisation and cross- phosphorylation of the tyrosine kinase receptors
    2. Phosphorylation of the tyrosine kinase receptor initiates signal transduction pathways and creates docking sites for adapter proteins (e.g. Grb2), which can bind and mediate the protein- protein interactions within the pathways (eg. activating Ras)
43
Q

what is the PI3 - Kinase pathway?

what is it involved in?

A
  • Another phosphorylation site on the tyrosine kinase receptors
  • involved in cell survival and has anti- apoptotic effects
44
Q

what is the structure of PI3 kinase?

A
  • PI3 kinase is a lipid kinase involved in growth control and cell survival
  • its three main subunits =

Targeting subunit

Adapter subunit

Catalytic subunit

45
Q

how does PI3-K work?

A
  • It phosphorylates PIP2 to PIP3
  • this is then recognized by the adapter subunit of PKB/Akt (protein kinase B)
  • PKB is then recruited to the cell membrane and it is activated (it has anti-apoptotic effects)
  • PKB phosphorylates and inactivates Bad

(bad= pro-apoptotic)

  • Other pro-apoptotic proteins (such as Bax and Bak) are held in their inactive heterodimers (by their BH3 domains) to the anti-apoptotic Bcl - 2/xL proteins
  • As the pro-apoptotic proteins are held in the inactive heterodimers, cell survival and proliferation are promoted
46
Q

what happens to the PI3 pathway if the growth factors are absent ?

A
  • When growth factors are ABSENT, the PI3=kinase pathway is not activated
  • PIP3 is NOT generated
  • PKB is NOT recruited to the cell membrane and activated
  • This means that Bad can NOT be phosphorylated and held in an inactive heterodimer
  • So the Bad is dephosphorylated and released from the heterodimer
  • Bad can then go through the mitochondrial membrane where it binds through its BH3 domain to the BH3 domains of the anti-apoptotic Bcl-2 family members, therefore, DISPLACING the pro-apoptotic Bcl-2 family members.
  • Once the pro- apoptotic Bcl- 2 family members (e.g. Bax and Bak) are released from inhibition, they form a pore in the mitochondrial membrane which allows cytochrome C to escape into the cytosol and induce apoptosis
47
Q

what is the function of PTEN?

A
  • PTEN is a lipid phosphatase that counteracts the production of PKB, therefore reducing the regulation of cell survival and promoting apoptosis
48
Q

what are IAPs? (Inhibitor of Apoptosis Proteins)

A
  • IAPs bind to procaspases and prevent activation
  • IAPs also bind to active caspases and inhibit their activity
49
Q

what are the two cytoprotective pathways?

A
  • Bcl=2, Bcl=xL = intrinsic pathway
  • FLIP, IAPs = extrinsic pathway
  • Growth factor pathways via PI3=kinase and PKB/Akt
50
Q

how do cancer cells avoid apoptosis?

A
  • Bcl=2 (oncogene = because over=expression of Bcl=2 will promote cancer)
  • PKB/Akt (oncogene = because over=expression of PKB/Akt will promote cancer)
  • PTEN (tumour suppressor = because inactivation of this gene promotes cancer)

Year 2 - Cancer (15 decks)

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