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Advanced Cellular and Molecular Biology > Apoptosis Intrinsic > Flashcards

Apoptosis Intrinsic Flashcards

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1
Q

What is the intrinsic pathway also known as?

A

The mitochondrial pathway of apoptosis

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2
Q

What does the intrinsic pathway of apoptosis require?

A

Release of proteins from the mitochondrial intermembrane space, specifically cytochrome C

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3
Q

How does the mitochondrial membrane release proteins?

A

Via mitochondrial outer membrane permeabilization (POMOP)

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4
Q

What happens when cytochrome C is released from the mitochondrial intermembrane space?

A

It binds Apaf-1 (apoptosis protease activating factor-1) and recruits initiator procaspase 9 to form the apoptosome

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5
Q

_____________ binds ___________________________ (Apaf-1) and recruits initiator procaspase 9 to form the ______________.

A

Cytochrome C

Apoptosis protease activating factor-1

Apoptosome

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6
Q

Which proteins enable MOMP?

A

Bcl2 proteins

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7
Q

What are the three groups of the Bcl2 protein family?

A

Anti-apoptotic (Bcl-2, Bcl-xL, Bcl-W, Mcl-1)

Pro-apoptotic (Bax, Bak, Bok)

BH3-only (Bid, Bim, Bad, Puma)

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8
Q

How is MOMP inhibited?

A

Bcl-2, Bcl-xL etc. bind the effector proteins on the outer membrane and inhibit the assembly of Bax and Bak

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9
Q

How is MOMP activated?

A

By assembly of Bax and Bak in the presence of BH3-only proteins

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10
Q

What proteins are required in order for Bak and Bax activation?

A

The BH3-only proteins (Bim, Bid, Bad, Puma)

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11
Q

What are the two primary ways to activate the intrinsic pathway of apoptosis?

A
  1. Decrease the expression and activity of anti-apoptotic proteins
  2. Increase expression and activity of BH3-only proteins
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12
Q

Most anti-apoptotic proteins are stably expressed and active in most cell types except for _____, which is degraded during prolonged mitotic arrest. Its degradation requires phosphorylation by _____ and ubiquination by ______.

A

Mcl-1

Cdk1

APC/C

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13
Q

What proteins function as the “trigger” for intrinsic apoptosis?

A

The BH3-only proteins because they are the only ones that seem to change

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14
Q

What are five ways to regulate BH3-only proteins?

A
  1. Transcription
  2. Phosphorylation
  3. Localization/sequestration
  4. Ubiquitin-dependent proteolysis
  5. Caspase-dependent proteolysis
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15
Q

What four things can activate intrinsic apoptosis?

A
  1. Exposure to the TNF of Fas ligand
  2. DNA damage
  3. Cell stress
  4. Loss of survival factors
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16
Q

What does TNF refer to?

A

Tumor necrosis factor

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17
Q

What types of things can cause DNA damage?

A

Mutagenic chemicals

UV exposure

Gamma radiation

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18
Q

What types of cell stress can activate instrinsic apoptosis?

A

DNA damage

Cytoskeletal damage

Osmotic stress

Hypoxic stress

Oxidative stress

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19
Q

What do we mean by “loss of survival factors”?

A

The cell requires growth factors and contact with other cells and extracellular matrices for survival

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20
Q

When the TNF or Fas ligand binds their receptors, _______________ 8 becomes cleaved into _____________ and activated. _________________ then cleaves ______ to form its active form _________, which stands for truncated Bid.

A

Procaspase 8

Caspase 8

Bid

tBid

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21
Q

What does tBid refer to?

A

Truncated Bid

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22
Q

What happens upon TNF or Fas ligand binding?

A

The death-inducing signaling complex (DISC) forms

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23
Q

___________ is a potent inducer of apoptosis.

A

tBid

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24
Q

The TNF and Fas ligand _________ the intrinsic pathway to the extrinsic pathway of apoptosis.

A

Connect

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25
Q

What do p38MAPK and JNK do?

A

Induce intrinsic apoptosis

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26
Q

JNK stands for _______________.

A

MAPK

c-Jun N-terminal kinases

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27
Q

What activates p38MAPK and JNK?

A

Cytokines, oxidative stress, genotoxic stress, UV irradiation

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28
Q

How do p38MAPK and JNK (c-Jun N-terminal kinases) induce intrinsic apoptosis?

A

Phosphorylate some Bcl-2 family members and phosphorylate transcription factors that increase expression of other pro-apoptotic proteins

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29
Q

___________ and ____________ phosphorylate some Bcl-2 family members and phosphorylate transcription factors that ________ expression of other pro-apoptotic proteins, thereby inducing intrinsic apoptosis.

A

p38MAPK

JNK (c-Jun N-terminal kinases)

Increase

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30
Q

What are three targets of JNK?

A

Anti-apoptotic proteins (Bcl-2, Bcl-xL)

BH3-only protteins (Bim, Bmf)

Transcription factor c-Jun

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31
Q

JNK (c-Jun N-terminal kinases) target anti-apoptotic proteins _____ and _____, inhibiting them via ________________; BH3-only proteins ____ and _____, activating them via _________________; and transcription factor ____, which increases expression of multiple pro-apoptotic proteins, including _____, TNF-alpha, and Fas ligand.

A

Bcl-2, Bcl-xL

Bim, Bimf

c-Jun

Bak

32
Q

Bad is not a direct target of ______, but _____ does target Bad’s sequestering protein _________.

A

JNK (c-Jun N-terminal kinases)

JNK

14-3-3

33
Q

What is the sequesting protein for Bad?

A

14-3-3

34
Q

Phosphorylation of ___________ by JNK releases Bad.

A

14-3-3

35
Q

Bad has a high affinity for anti-apoptotic proteins ___________, ____________, and ______________.

A

Bcl-2

Bcl-xL

Bcl-W

36
Q

How does Bad contribute to apoptosis?

A

It binds anti-apoptotic proteins and inhibits them

37
Q

Bim binds __________ light chain complex in association with microtubules, the phosphorylation of which leads to dissociation and apoptosis.

A

Dynein

38
Q

Bmf binds ______ Va in association with the actin cytoskeleton, phosphorylation of which leads to dissociation and apoptosis.

A

Myosin

39
Q

Bim binds ____________________________________ in association with ___________________, the phosphorylation of which leads to dissociation and _______________.

A

Dynein light chain complex

Microtubules

Apoptosis

40
Q

Bmf binds _____________________ in association with ______________________, the phosphorylation of which leads to dissociation and ________________.

A

Myosin Va

Actin cytoskeleton

Apoptosis

41
Q

Which chemotheraputic drug releases Bim and Bmf?

A

Taxol

42
Q

How does Taxol work?

A

It stabilizes microtubules and actin microfilaments, stabilizing them and thereby releasing Bm and Bmf from the cell

43
Q

Which pathway is decreased when growth factors are absent?

A

The Akt/PKB pathway

44
Q

Decreases in the Akt/PKB pathway lead to __________________ transcription of pro-apoptotic proteins.

A

Increased

45
Q

The absence of growth factors _____________ Akt/PKB activity, leading to ____________ transcription of pro-apoptotic proteins.

A

Decreases

Increased

46
Q

The Akt/PKB pathway __________ apoptosis.

A

Blocks

47
Q

The absence of growth factors decreases Akt/PKB activity and leads to __________________ of Bad, allowing it to detach from 14-3-3 and inactivate via binding anti-apoptotic proteins, Bcl-2, Bcl-xL, and Bcl-W.

A

Dephosphorylation

48
Q

Decreases in Akt/PKB activity leads to dephosphorylation of _________, which allows it to detach from its sequestering protein _________ and bind to and inactive anti-apoptotic proteins, ____, ____, and _____.

A

Bad

14-3-3

Bcl-2, Bcl-xL, Bcl-W

49
Q

Absence of growth factors __________ Akt/PKB activity and leads to ____________ of FOXO3 transcription factors, which then releases from its sequestering protein ______ and translocates to the nucleus where it _______ expression of BH3-only proteins Bim and PUMA.

A

Decreases

Dephosphorylation

Increases

50
Q

Absence of growth factors __________ Akt/PKB activity and leads to ____________ of _______ transcription factors, which then releases from its sequestering protein ______ and translocates to the nucleus where it _______ expression of _____ proteins Bim and PUMA.

A

Decreases

Dephosphorylates

FOXO3

14-3-3

Increases

BH3-only

51
Q

What decreases Akt/PKB activity?

A

Absence of growth factors

52
Q

How do decreases in Akt/PKB activity lead to apoptosis?

A
  1. Increases transcription of pro-apoptotic proteins
  2. Dephosphorylates Bad, which releases from 14-3-3 and inactivates Bcl-2, Bcl-xL, and Bcl-W (anti-apoptotic proteins)
  3. Dephosphorylates FOXO3 transcription factor, which releases from 14-3-3, translocates to nucleus, and increases expression of BH3-only proteins (Bim, Puma) required foor Bak and Bax activation
53
Q

Absence of growth factors decreases MAP kinase activity by leading to ___________________ and activation of proteins that inhibit inhibitors of apoptosis proteins (IAPs), thereby freeing up more pro-apoptotic proteins and decreasing expression of ________ proteins.

A

Dephosphorylation

Anti-apoptotic

54
Q

The loss of attachment to the extracellular matrix leads to a loss of signaling via ______ and other ECM binding proteins and ultimately leads to ______, which means “homeless.”

A

Integrins

Anoikis

55
Q

Bax and Bak are regulation via ________ proteins.

A

BH3-only

56
Q

What are the three models for regulation of Bax and Bak via BH3-only proteins?

A
  1. Activation model (BH3-only proteins directly activate Bax and Bak)
  2. Sensitizer model (BH3-only proteins indirectly activate Bax and Bak)
  3. De-repression/displacement model (BH3-only proteins indirectly activate Bax and Bak)
57
Q

The activation model of BH3-only regulation proposes that BH3-only proteins directly ______ and activate Bax and Bak, leading to their dimerization, oligomerization, and MOMP.

A

Binds

58
Q

Data showed that Bim, tBid, and Puma may only only _____ bind Bax and Bak, and none of the other BH3-only proteins bound to Bax and Bak at all, leading to the “___________” or “____________” hypothesis.

A

Weakly

Hit-and-run

Kiss-and-run

59
Q

What did the sensitizer model suggest?

A

Anti-apoptotic proteins sequester a subset of BH3-only proteins that are direct activators of Bim, tBid, and Puma that in turn activate Bax and Bak

60
Q

Data showed in the sensitizer model that Bad and Noxa bind different and non-overlapping members of the anti-apoptotic proteins while Bim, tBid, and ______ bind them all.

A

Puma

61
Q

The de-represion/displacement model suggests that anti-apoptotic proteins ____________ Bax and Bak, and BH3-only proteins bind these anti-apoptotic proteins, thereby displacing and releasing Bax and Bak.

A

Sequester

62
Q

Data shows that all anti-apoptotic proteins bind ____ and most bind Bak, and Bcl-xL causes retro-translocation of Bak from the mitochondrial outer membrane to the cytosol.

A

Bax

63
Q

The data shows that Bim, ______, and Puma bind all anti-apoptotic members, and these three are the most ______ inducers of apoptosis. The other two BH3-only members, Bad and Noxa, bind different and non-overlapping anti-apoptotic proteins, together matching the potency of the other three.

A

tBid

Potent

64
Q

Which three BH3-only proteins are the most potent inducers of apoptosis?

A

Bim, tBid, and Puma

65
Q

BH3-only proteins use their _____ domains to bind the hydrophobic groove in __________ proteins; therebying binding causes __________ of Bax and Bak, leading to apoptosis.

A

BH3

Anti-apoptotic

Apoptosis

66
Q

Why were previous studies regarding regulation of BH3-only proteins problematic?

A
  1. Each used different cell types with varying levels of expression
  2. Overexpression of proteins in cells may not be relevant to physiological conditions
  3. In-vitro binding assays used peptide fragments, not whole proteins; affinity-bindinig constants varied; and excluded effects of membrane association, which is critical for proteins with transmembrane domains
67
Q

What is the current model regarding BH3-only regulation?

A

The “embedded together” model

68
Q

What does the embedded together model propose?

A

The true functional interactions between the proteins only occur in and on membranes and that lipids are active participants in these interactions

69
Q

A G94A mutation of the BH3 domains of Bim and tBid disrupted their ability to bind Bax, but not their ability to bind anti-apoptotic proteins in mouse embryo fibroblasts and myeloid cells, thereby providing evidence against the direct activation model

A

The top panel confirms the creation of a mutant that is unable to bind to Bax but can bind everything else

The bottom panel (C) shows that when Bim and tBid were unable to bind Bax, apoptosis was not prevented; however, when Bim and tBid were unable to bind Bcl-2 members (anti-apoptotic), apoptosis was prevented

70
Q

Bax and Bak double knockout mice were resistant to UV irradation and etoposie-induced apoptosis, but the Bim and tBid double knockout mice were not resistant to UV irradiation and etoposide-induced apoptosis (A); meanwhile Bax is activated by etoposide even when Bim and tBid were knocked out in mice (B).

This provided evidence against the direct activation model. Why would Bim and tBid knockouts still undergo apoptosis when Bax and Bak were knocked outed?

A

Can Bax be activated without Bim or tBid?

71
Q

Noxa and Bad overexpression induced cytochrome C release (E); Noxa and Bad overexpression induced apoptosis in Bim and tBid double knock outs (D); these results provided evidence against the sensitizer model

A

Do sensitizers require Bim or tBid?

72
Q
  • Octa knock-outs lacking all BH3-only proteins do not respond to inducers of apoptosis (E)
  • Silencing both Bcl-xL & Mcl-1 in octaKO cells induces apoptosis (A)
  • Inhibiting both Bcl-xL & Mcl-1 in octaKO cells induces apoptosis (B)
  • These results provide even stronger evidence against the direct activation model with support for a de-repression model
A
73
Q

•Expression of Bax or Bak in Bcl-2 allKO cells induces apoptosis and depends on membrane association

–Occurs in the absence of both BH3-only proteins and anti-apoptotic proteins

–Strong evidence against all but a de-repression model

A
74
Q

•The kinetics of Bax-induced apoptosis are similar in Bcl-2 allKO cells and “2+5” KO cells and dependent on membrane association

–Indicates that endogenous BH3-only proteins do not contribute to Bax activation in the absence of anti-apoptotic proteins

–One last nail in the coffin for the sensitizer model

A
75
Q

The most current models proposes that BH3-only proteins bind anti-apoptotic proteins to displace Bax and Bak, which are then free to insert into the outer mitochondrial membrane (Bax) and to form homodimers and oligomers (Bax and Bak). This in turn leads to the formation of lipidic pores and the release of cytochrome C.

A
76
Q
A
77
Q
A

Advanced Cellular and Molecular Biology (7 decks)

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