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Molecular Exam 3 > Apoptosis > Flashcards

Apoptosis Flashcards

1
Q

Apoptosis

A

Programmed cell death

Routine controlled cell death that minimizes spread of damage and or inflammation

Eliminates unwanted cells (tadpole tail)

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2
Q

Necrosis

A

Accidental cell death

Eg- carrying Petri dish of cells, accidentally drop and step on them

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3
Q

Phenotype of Apoptosis

A
  • overall shrinkage of cell volume and nucleus
  • loss of adhesion to neighboring cells
  • formation of blebs on surface
  • DNA fragmentation
  • cytoskeleton collapses
  • Nuclear envelope disassembles
  • rapid engulfment of dying cell by phagocytosis (macrophages)
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4
Q

What roles do apoptosis play/what is the importance of apoptosis?

A
  • programmed cell death important for certain cells: abnormal, non functional, potentially dangerous
  • eliminate lymphocytes after they destroy and ingest microbes
  • organs can be kept correct size (liveR)

DNA damaged cells are destroyed if there is enough damage

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5
Q

Biochemistry of Apoptosis

A

An endonuclease cleaves DNA into a ladders of fragments in distinctive sizes
Cleavages occur in linker regions of chromosome
Agarose gel will show this pattern (a smear vs ladder indicates random cleavage)

Cytochrome C is release from mitochondria during apoptosis (apop marker)

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6
Q

Caspases (Cysteine ASPartyl specific proteASE)

A

Proteases that mediate the apoptotic cascade intracellularly

Activation is key
Cysteine in active site

Targets proteins and cleaves them in sequence where Asp AA occurs

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7
Q

Pro caspases

A

Caspases synthesized first as inactive prescursors

Becomes activated by protease cleavage

Cleaves at specific sites to form large and small subunits. These form a heterodimer which can be activated to a caspase by another caspase

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8
Q

Initiator Caspase

A

Initiates apoptosis

Caspase-8 and Caspase-9

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9
Q

Executioner Caspases

A

Destroy actual targets- execute process of apoptosis (caspase-3)

Cleaves downstream proteins, inactive endonuclease

Targets cytoskeleton
Attacks cell adhesion proteins- cells roll up in a ball

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10
Q

The Caspase Cascade

A

Irreversible

There specific caspases: knockout of caspase-3 in mice reduces apoptosis in developing brain and fetus dies with deformation

The machinery for this process is always there

Initiator caspase auto-activates itself

Executioner caspases cleaves cellular targets

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11
Q

Differentiate the two Apoptotic Pathways

A

Internal and External

Depend on where the stimuli come from

I- Mitochondrial dependent
E- mito independent

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12
Q

Intrinsic Pathway

A

Cells active apoptosis from inside cells

In response to injury, DNA damage and lack of O2, nutrients, or extra cellular survival signals

Translocation of cytochrome C from intermediate space of mito
It is release to cytosol and binds to adaptor protein (Apaf-1) to activate procaspases

Apoptosome forms (by of Apaf1) activating caspase-9. 9 activates downstream executioner caspase-3

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13
Q

About the Extrinsic Pathway

A

Extracellular signals bind to cell surface death receptors and trigger pathway (transmembrane proteins)

3 domains:

  • extracellular domain
  • single transmembrane domain
  • intracellular death domain

Receptors are homotrimers

Activates downstream executioner caspases, but there are inhibitory proteins that retrain it. Decoy receptors: FLIP

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14
Q

Homotrimers

A

Three proteins of the same type (members of tumor necrosis factor family of proteins)

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15
Q

Decoy Receptors

A

Have ligand binding domain but no death domain.

can bind death ligand but does not trigger apoptosis

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16
Q

FLIP

A

Protein that resembles initiator procaspases with no proteolytic domain

Competitive inhibitor against procaspases-8 and procaspase-10 (prevents apoptosis)

17
Q

Describe the process of the Extrinsic Pathway

A

Fans binds to Fas Death Receptor - ligand form homotrimers

Adaptor proteins are recruited: FADD adaptor (Fas associated death domain) and Procaspase-8 with death effector domain

Formation of trimers: brings death domains together to form DISC (death inducing signal complex)

Activates caspase-8 or -10
Activates downstream executioner caspases - caspase-3 **

18
Q

Bcl2 family of proteins

A

Regulate intrinsic apop pathway

Bcl2 controls release of cytochrome C into cytosol

2 types of Bcl2: anti and pro apoptotic
(3 classes, anti, pro BH123, pro BH3)

19
Q

Anti-apoptotic (prosurvival) Bcl2

Pro-apoptotic Bcl2

A
  • blocks release of cytochrome C (Bcl2 example)
  • 4 domains within Bcl2 BCl Homology domains
  • Promotes release of cytochrome C
  • BH123 protein + BH-3 only protein
20
Q

What are the three classes of Bcl2 proteins?

A

1) anti-apoptotic Bcl2 protein
2) pro-apoptotic BH123 protein
3) pro-apoptotic BH3 protein

21
Q

BH123 protein

A

Pro-apoptotic

Stimulus triggers intrinsic pathway

Become activated in outer mitochondrial membrane and induce release of cytochrome C.
Then apoptosome is formed by binding to Apaf1

22
Q

Anti-apoptotic Bcl2 Proteins

A

Bcl2 and BCl-XL

Mainly located on cytosolic surface of outer mitochondrial membrane

These proteins prevent apoptosis by binding to pro-apoptotic proteins (BH123) and prevent aggregation into active form

23
Q

Inactive Intrinsic Pathway/Inhibition

A

Active anti-apoptotic Bcl2 protein is stopping BH123.

Cytochrome C trapped in outer mitochondrial membrane space

Can be stopped by BH3-only

Prevents spread out BH123 proteins from coming together to form allow passage of cyto c and intermembrane proteins

24
Q

BH3 only protein

A

Pro-apoptotic, cytosolic protein

Translocated into mito after apoptotic signals activate it.

Inhibits Bcl2 protein from inhibiting aggregation to release cytochrome c (allows BH123 to come together and form channel)

25
Q

IAPs (inhibitors of apoptosis)

A

Bind to and inhibit caspases

Some IAPs add ubiquitin to caspases marking them for proteosomal destruction

Block apoptosis by binding caspases

This is GOOD because it can stop the caspases from auto-activating!

26
Q

Anti-IAPs

A

Proapoptotic

If apoptotic stimulus is present anti-IAPs are released from mitochondria to block IAP activity so that executioner caspases can be activated

Neutralize IAPs, free/liberate caspases

27
Q

Disease related to insufficient apoptosis

A

B Cell Lymphoma

Chromosome translocation causing excessive Bcl2 to be made can over-inhibit apoptosis. This means even severely damaged cells are not rid of.
This can result in cancer.

28
Q

P53 mutation

A

P53 is a tumor suppressor gene.

Mutation of p53 means it can no longer arrest cell cycle
It becomes insufficient and does not promote apoptosis
Cells with DNA damage stick around, thus cancer can be generated

29
Q

Excessive apoptosis

A

Heart attacks and strokes

Excessive cell death leading to organ failure

Molecular Exam 3 (5 decks)

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