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Cancer mechanisms and therapeutics > Apoptosis regulation > Flashcards

Apoptosis regulation Flashcards

1
Q

Why is the study of apoptosis so important?

A
  • provides diagnostic + prognostic markers
  • improve current therapies and specifically target cancer cells for destruction without affecting normal cells
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2
Q

What are the two pathways of apoptosis?

A
  • intrinsic (mitochondrial)
  • extrinsic (death receptor)
  • both involve caspases
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3
Q

What triggers and causes intrinsic apoptosis? (4)

A
  • cell stress
  • growth factor deprivation
  • cytotoxic drugs
  • regulated by the Bcl-2 family of proteins
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4
Q

What triggers and causes extrinsic apoptosis?

A

cell surface or secreted ligands that interact with death receptors on the cell surface

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5
Q

What are caspases?

A
  • family of cysteine-aspartic proteases
  • target nuclear and cytoplasmic proteins in reponse to death signals
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6
Q

What do caspases do?

A
  • cleave at aspartic acid residues that are followed by alanine or serine - very specific
  • cleave other proteins to acitvate them and allow them to cleave DNA - endonucleases
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7
Q

What is the human caspase family?

A
  • capases 1-10
  • 1, 4, + 5 are involved in inflammation
  • the rest are apoptosis
  • 3, 6 + 7 are executioner caspases that cleave cellular components
  • others activate these by acting upstream
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8
Q

How are caspases activated?

A
  • procaspases are cleaved
  • acttive caspase is a dimer formed of 2 large and 2 small sububnits
  • contains 2 active sites
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9
Q

How does caspase cleavage lead to apoptosis?

A

-capses cleave and inhibit many structural and regulatory proteins
- can cleave antiapoptotic proteins
- leads to loss of cell-cell contacts, cell matrix contraction, changes in shell shape and structure
- DNA cleaved

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10
Q

Give an example of a drug that induces apoptosis

A

daunorubian intercalates between DNA base pairs, damaging DNA and inhibiting DNA synthesis + causing apoptosis

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11
Q

How does apoptosis occur in an epithelium?

A
  • caspase enzymes cleave cell adhesion molecules early on
  • breaks cell-cell contacts and isolates the apoptotic cell
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12
Q

What is necrosis?

A
  • unprogrammed cell death
  • intracellular components such as the nucleus + mitochondria swell up + the cell lyses
  • causes an inflammatory response
  • less optimal way to kill cancer cells
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13
Q

How is chromatin degraded during apoptosis?

A

internucleosomal cleavage by caspase-activated deoxynuclease

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14
Q

Where is Bcl-2 located?

A

on the outer membrane of the mitochondria

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15
Q

What does active Bax do?

A

makes pores in the mitochondrial membrane to allow cytochrome C to escape into the cytoplasm where it acts as an apoptotic signal

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16
Q

What happens once cytochrome C is released into the cytoplasm?

A
  • binds Apaf-1
  • leads to activation of procaspase 9 which is activated into caspase 9 with ATP energy
  • this then cleaves and activates caspase 3 which can trigger apoptosis
17
Q

How does Bcl-2 inhibit apoptosis?

A
  • inhibits the release of cytochrome C from the mitochondria by sequestering Bax to prevent pore formation
18
Q

What is Bcl-2?

A
  • anti-apoptosis gene that can act as an oncogene
  • overexpressed in many cancers such as B cell lymphomas
19
Q

When in normal cells is Bcl-2 expressed?

A
  • in maturing cells
  • usually switched off after development unless in cancer
20
Q

What are viral Bcl2 homologs?

A
  • viral proteins that act similarly to Bcl-2 and enhance the survival of infected cells
  • can sometimes lead to tumour formation and therapy resistance
  • EBV and KSHV
21
Q

Describe the Bcl-2 family

A
  • 4 homologous domains (Bh1-4)
  • transmembrane domain
  • many alpha helix domains
22
Q

Describe the Bax familt

A
  • Bax, Bak and Box (brain)
  • BH domains 1, 2 and 3 but not 4
  • transmembrane domain
  • similar to Bcl-2s
23
Q

What is associated with high or low levels of Bax?

A
  • overexpression of Bax accelerates cell death
  • low levels are correlated with poor prognosis in breast cancer
  • relative abundance of Bcl-2 + Bax can determine whether the cell lives or dies in response to an apoptotic signal
24
Q

Where is Bax?

A
  • can sit on the mitochondrial membrane or be cytosolic
  • only translocates to the membrane when it receives an apoptotic signal
  • can be sequestered by Bcl-2 to prevent mitochondrial pore formation
25
Q

How do Bax and Bak work?

A
  • in response to an apoptotic signal they translocate to the mitochondria where they homo-oligomerise and insert into the outer membrane of the mitochondria
  • can have a Bak or a Bax pore not both at once
26
Q

What happens when mice have Bax OR Bak KOs vs when they have Bax AND Bak KOs?

A
  • when both are KO mice have enlarged splee and lymph nodes and developmental issues - cells arent killed by apoptosis but can be killed by cytochrome C injection
  • when only 1 is KO there is much less of an effect
  • shows that only 1 is needed for intrinsic apoptosis
27
Q

What happens when cytochrome C binds Apaf-1?

A

-cytochrome C binds Apaf-1 and induces a conformational change that opens it up and exposes the CARD
- Apaf-1 forms a hepatmeric structure and allows binding of pro-caspase 9 to CARD, causing its cleavage and activation

28
Q

What is the function of Apaf-1 in cancer?

A
  • can act as a TSG
  • mutations seen in gastrointestinal cancers and metastatic melanomas
29
Q

What are BH3-only proteins?

A
  • proteins that detect different death cues + act to cause apoptosis
  • transmit death signals to the mitochondria
  • e.g. bid interacts directly with Bax or Bak
  • p53 upregulates BH3s and Bax
30
Q

How do BH3 only proteins and Bax compete?

A
  • both bind Bcl2
  • BH3 proteins can sit on the same hydrophobic cleft as Bax
  • binding of BH3 can remove Bax
  • frees it it to make pores in the mitochondria
31
Q

BH3 proteins respond to many different signals. Give an example.

A
  • bad transmits signals due to survival factor depletion
  • respond to many different signals but always displace Bax or Bak from Bcl2
32
Q

What is Bcl-X?

A
  • Bcl-2 family gene
  • encodes for 3 different proteins generated by alternative RNA splicing
33
Q

What are the forms of Bcl-X?

A
  • Bcl-XL - antiapoptotic and seen mutated in colon cancer
  • Bcl-XS - proapoptotic - no BH4 domain
34
Q

What are the different tissue distributions of Bcl-X and Bcl-2?

A
  • as cells in the crypt undergo differentiation, Bcl-2 expression makes way for Bcl-XL to protect intestinal cells
  • Bcl-2 is found in proliferative cells in the base of the crypt while Bcl-XL is found in the upper regions

Cancer mechanisms and therapeutics (12 decks)

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