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Foundations Exam 1 > Apoptosis, Autophagy, Necrosis > Flashcards

Apoptosis, Autophagy, Necrosis Flashcards

1
Q

two major pathways of apoptosis (programmed cell death)?

A

intrinsic: triggered by intracelular stress (oxidative damage, ischemia)

extrinsic: triggered by death ligand (tumor necrosis factor, TNF)

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2
Q

what is the basic progression of intrinsic pathway of apoptosis (naming molecules involved)?

A
  1. intracelular stress
  2. mitochondria cytochrome c
  3. APAF1
  4. caspase 9 (this step inhibited by Bcl-2)
  5. caspase 3
  6. apoptosis execution by DNA fragmentation
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3
Q

what is the basic progression of extrinsic apoptosis pathway? (naming molecules involved)

A
  1. extrinsic signal (death ligand such as TNF)
  2. FADD
  3. DISC formation
  4. caspase 8
  5. caspase 3
  6. apoptosis execution by DNA fragmentation
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4
Q

how do pro-apoptotic signals affect mitochondria in intrinsic apoptosis pathway?

A

pro-apoptotic stimuli increase permeability of outer membrane and promote mobilization of Cytochrome C (usually bound to cardiolipin, CL)

in cytosol, cytochrome C activates APAF1 and proteolytic maturation of caspase-9 and caspase-3

[reminder - cyt c functions as electron shuttle in ETC, but also functions as apoptosis signal]

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5
Q

how do Bcl-2 family proteins influence apoptosis in intrinsic pathway

A

B-cell lymphoma-2 (Bcl-2) superfamily:

pro-apototic: Bax, Bak - promote permeability of mitochondria and Cyt C release

anti-apoptotic: Bcl-2, Bcl-XL - bind Bax/Bak to inhibit

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6
Q

which Bcl-2 proteins are pro-apoptosis, which are anti-apoptosis?

A

Bax and Bak are PRO-apoptosis

Bel-2 and Bcl-XL are ANTI-apoptosis and bind/inhibit Bax/Bak

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7
Q

how is Bcl-2 implicated in cancer?

A

in follicular lymphoma, a chromosomal translation commonly occurs which leads to high levels of Bcl-2 expression

this causes decreased propensity to undergo apoptosis —> increased cancer growth

Bcl-2 overexpression linked to poor disease outcomes in several cancers

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8
Q

how does p53 function to prevent cancer formation? give 3 ways

A

initiates apoptosis (blocks anti-apoptosis Bcl-2 and Bcl-XL while promoting pro-apoteosis Bak/Bax)

activates DNA repair proteins

arrests growth by holding cell cycle at G1/S checkpoint

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9
Q

how does APAF1 function in intrinsic pathway of apoptosis

A

APAF1 = apoptotic protease activation factor 1

cytochrome C (released from mito) activates APAF1 by displacing it from CARD (CAspase Recruitment Domain)

CARD domains form cluster of 7 —> apoptosome

*apoptosome cleaves procaspase 9 to form caspase 9 (initiator caspase), which activates cas3/6/7 (executioner caspases)

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10
Q

the molecular “hitmen” are

A

caspases - enzymes that give rise to morphological and biochemical changes arising form apoptosis

must be CLEAVED to be active

regulated at post-translational level so they can be rapidly activated

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11
Q

group these into apoptosis initiators and effectors:
caspase
2, 3, 6, 7, 8, 9, 10

A

caspase initiators: 2, 8, 9, 10

caspase effectors: 3, 6, 7

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12
Q

what are the pro-apoptotic receptors in the extrinsic pathway? what do they bind?

A

DR4 and DR5

bind endogenous Apo2L (apoptosis-inducing ligand 2) and TRAIL (TNF-related apoptosis-inducing ligand)

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13
Q

after activation, what do DR4 and DR5 recruit? (extrinsic apoptosis) What steps occur next?

A

recruit FADD: Fas-associated death domain

FADD recruits Caspase 8 and/or 10 (initiator caspases) to the DISC (death-inducing signaling complex)

cas-8 and 10 are released into cytoplasm, activate effectors (cas3/6/7)

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14
Q

what are the ligands of each of these TNF-family death receptors of extrinsic apoptotic pathway?
a. FAS
b. DR5
c. TNFR1
d. DR3

A

FAS binds FasL (Fas ligand)

DR5 binds TRAIL/Apo2L

TNFR1 binds TNFalpha

DR3 binds Apo3L

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15
Q

T/F: extrinsic pathway stimulates apoptosis independently of p53 and mitochondria

A

TRUE

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16
Q

fill in the blanks of extrinsic apoptotic pathway:
1. ligands bind _____
2. ______
3. caspases _____
4. caspases _____

A
  1. ligands bind DEATH RECEPTORS
  2. FADD/DISC
  3. caspases 8, 10 (initiators)
  4. caspases 3, 6, 7 (effectors)
17
Q

where do extrinsic and intrinsic apoptotic pathways converge?

A

activation of effector caspases 3, 6, 7

18
Q

what is a distinctive feature of DNA degradation by caspase-activated DNase(CAD) when detecting apoptosis?

A

DNA laddering - biochemical marker of apoptosis

19
Q

what are 2 biochemical markers of apoptosis?

A
  1. DNA laddering
  2. caspase activation (can be measured via expression levels) - must be cleaved to become active
20
Q

how can TUNEL assay be used to detect apoptosis

A

TUNEL = Terminal Transferase dUTP Nick-End Labeling)

measurement of DNA fragmentation

TdT (terminal deoxynucleotidyl transferase) adds dNTPs to 3’ end of DNA molecules in absence of a template

in imaging, apoptotic cells appear as blebs

21
Q

macroautophagy vs. microautophagy vs. chaperone-mediated autophagy

A

macroautophagy: cytosolic components are sequester within double membrane organelle or autophagosome, which fuses with lysosome (forms autolysosome) for degradation

microautophagy: lysosomes DIRECTLY engulf cytosolic components via invagination

chaperone-mediated autophagy: chaperone protein and cytosolic protein form complex that is recognized by LAMP-2A which translocates it into lysosome

22
Q

what recognition protein is required for chaperone-mediated autophagy

A

LAMP-2A: translocates chaperone protein/ cytosolic protein complex to lysosome

23
Q

4 stages of autophagy

A
  1. induction
  2. autophagosome formation
  3. autophagosome-lysosome fusion
  4. autophagosome breakdown
24
Q

autophagy is inhibited by ___ conditions and stimulated by ____ conditions

A

starvation STIMULATES autophagy

nutrient-rich conditions INHIBIT autophagy

25
Q

a key regulator of autophagy induction (step 1) is ____

A

mTORC1 (mammalian target of rapamycin complex 1)

*pharmacological inhibition of mTOR leads to downstream phosphorylation events which ACTIVATES autophagy-related genes

26
Q

a new drug is developed that inhibits mTOR. What is the effect of this drug?

A

mTORC1 is a key regulator of autophagy induction (inhibits)

inhibiting mTOR leads to downstream dephosphorylation and ACTIVATION of autophagy-related genes

inhibit mTOR —> activate autophagy

starvation also inhibits mTORC1 (starvation stimulates autophagy

27
Q

what occurs during autophagosome formation (step 2 of autophagy) - be specific

A

formation of a membrane around the targeted portion of the cell

LC3 maturation and lipidation are required

28
Q

what proteins mediate autophagosome-lysosome fusion?

A

SNAREs: syntaxin17, SNAP-29, VAMP8

29
Q

the ____ is the garbage truck of autophagy, the ____ is the dump site

A

autophagosome = garbage truck, delivers garbage to

lysosome = dump site (incinerator)

30
Q

what are biological markers of autophagy events and clearance, respectively?

A

LC3 lipidation - marker of autophagy events

LOW levels of p62 - marker of autophagy clearance

31
Q

when is autophagy in neuro-degeneration protective?

A

neuro-degenerative disease cause impaired clearance of protein aggregates

autophagy tries to compensate

32
Q

5 types of necrosis

A
  1. coagulation necrosis - ischemia
  2. liquefactive necrosis - cell destruction leading to escape of hydrolases
  3. enzymatic fat necrosis - escape of lipases
  4. caseous necrosis - bacterial liquefaction
  5. gangrenous necrosis - ischemic + bacterial liquefaction
33
Q

what are the morphological features of necrosis? (describe early and late)

A

early necrosis: cell swelling, chromatin digestion, disruption of membranes

late necrosis: extensive DNA hydrolysis, vacuolation of endoplasmic reticular, organelle breakdown, cell lysis

release of intracelular content after rupture causes inflammation

34
Q

Which of these is correct? Fix the false statement or make it correct.
a. Proteins which regulate release of pro-apoptotic factors ALL contain BH3 domain
b. Cytochrome C interacts with APAF-1 to form the apoptotic body

A

TRUE: proteins that regulate pro-apoptotic factors all contain BH3 domain

statement b fixed:
Cytochrome C interacts with APAF-1 to form the APOPTOSOME

35
Q

Are any of these statements false? If so, which ones?
a. The bcl-2 gene translocation decreases apoptosis
b. Proteins which regulate release of pro-apoptotic factors all contain BH3 domain
c. p53-mediated activation of Bax and Bak leads to release of cytochrome c from the mitochondria

A

they’re all true yay!

36
Q

which is true of the TUNEL assay?
a. used for detecting apoptotic bodies
b. common method for detecting autophagosome formation
c. measures DNA fragmentation
d. a biochemical marker for apoptosis
e. used to demonstrate chromatin condensation

A

TUNEL Assay MEASURES DNA FRAGMENTATION

37
Q

Which of these is TRUE?
a. mTORC1 can induce autophagy
b. autophagosome breakdown requires lysosomal enzymes such as cathepsin A
c. autophagy impairment is associated with reduced apoptosis

A

TRUE: b. autophagosome breakdown requires lysosomal enzymes such as cathepsin A

Foundations Exam 1 (33 decks)

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