Lecture 7 Flashcards

1
Q

what is an intrinsic defense mechanism by the host in response to microbial infection?

A

cell death and infection

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2
Q

why do pathogens suppress cell death?

A

to allow for replication and promote the cell for dissemination

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3
Q

what are the examples of cell death mechanisms?

A

apoptosis, necrosis, pyroptosis

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4
Q

what is apoptosis?

A

cells own molecules cause death, important for achieving balance between cell death and cell growth

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5
Q

what is necrosis?

A

cell is a victim of molecules synthesized by other cells

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6
Q

what is pyroptosis?

A

highly inflammatory response to intracellular pathogens or non infectious stimuli. it is caspase-1 dependent process that releases cytokines IL-18 and IL-1B

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7
Q

what are the two steps in necrosis?

A

from normal cell, it goes to:

  1. irregular chromatin clumping, mitochondria swells
  2. cellular components disintegrate, membrane rupture
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8
Q

what are the steps in apoptosis?

A

from normal cell it goes to:

  1. compaction and segregation of chromatin, convolution of nuclear outline
  2. nucleus fragments, cytoplasm condenses, cell surface protusion, membrane bound apoptopic bodies,
  3. phagocytosis of apoptopic bodies,
  4. degradation by lysosomal enzymes
  5. digestion within lysosomes
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9
Q

what was apoptosis originally described as?

A

characteristic EM appearance

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10
Q

what organism was used as a genetic model for determining apoptopic pathways?

A

C. elegans (the worm)

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11
Q

how do tumor suppressor genes keep cell number down?

A
  1. inhibiting progress through the cell cycle resulting in prevention of cell birth
  2. promoting programmed cell death (apoptosis)
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12
Q

what is an example of tumor suppressor gene?

A

p53 gene, inhibits cyclin dependent kinases and is inactivated in many different tumors

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13
Q

what do oncogenes stimulate?

A

appropriate cell growth under normal conditions as required for the continued turnover and replenishment of the skin, GI, and blood

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14
Q

what are examples of mutant oncogenes?

A

Ras in pancreatic and colon cancer and Bcl-2 activated in lymphoid tumors

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15
Q

what is BcL-xL?

A

a BCL-2 family member present in the mitochondria, serves as a pro survival function by preventing the release of mitochondrial contents such as cytochrome c that would lead to caspase activation

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16
Q

what is the importance of the Bcl-2: Bax ratio?

A

determines susceptibility to death

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17
Q

what is the main function of BCL-2/BCL-xL?

A

to repress many but not all apoptopic pathways

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18
Q

what is important about BH3?

A

BH3 only proteins bind and regulate the anti-apoptopic BCL-2 proteins to promote apoptosis

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19
Q

what are some features of p53?

A

mutated/inactivated in a majority of human cancers, integrates numerous signals that control cell survival and death, common denominator in human cancer

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20
Q

what in p53 interacts directly with DNA?

A

the central core domain

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21
Q

what are the “hot spots” of tumor derived p53 mutations?

A

the amino acid residues in the core domain that are critical for DNA binding

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22
Q

what are the two ways p53 induces apoptosis?

A
  1. through transcriptional activation of pro-apoptic genes (such as Puma, Noxa, Bax, Apaf-1)
  2. localization to mitochondria via interaction with Bcl-2 family protein Bcl-xL and facilitating Bax oligomerization
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23
Q

what are some features of caspases?

A
  1. constitute 14 members of a protein family
  2. there are two classes of them, initiators and effectors
  3. initiation of them are regulated by caspase inhibitors
  4. all have similar domain structure
  5. not all mammalian caspase participate in apoptosis
24
Q

what are caspase initiators?

A

they initiate the caspase cascade by cleaving the inactive forms of the effector caspases which activates them

25
what are caspase effectors?
once they are activated they cleave other protein substrates to advance the apoptopic process
26
what does the pro domain of the initiator pro caspase do?
recruit other pro caspases to dimerize
27
what do both pro caspases in the dimer undergo?
autocatalysis, where both the pro domain and the linker region between the small and large subunit are cleaved, leading to formation of an active heterotramer
28
what do initiator caspases do to effector caspases?
they cleave effector caspases at sites, resulting in production of small and large subunits of the effector caspase
29
what do effector caspase function in?
function in the breakdown of cell structures through cleavage of specific substrates
30
what are the cell structures that effector caspases break down?
actin cytoskeleton, lamins, golgi, and translation apparatus
31
what are IAP's?
they inhibit apoptosis, specifically through binding and inhibiting caspases
32
what is BIR?
baculoviral IAP repeat, essential for anti-apoptopic activity, blocks caspases or activation of caspases
33
true or false: not all BIRP's are IAP's
TRUE!!!!
34
what are the ways bacterial toxins cause apoptosis?
1. pore forming toxins 2. superantigens 3. toxins that interfere with host signaling (AB toxins) 4. type 3 secretion apparatus to deliver effector proteins into host cytosol
35
what are ways that microorganisms cause induction of apoptosis?
1. activation of host cell receptors that signal for apoptosis 2. induction of second messengers 3. regulation of caspase activity 4. inhibition of protein synthesis 5. disruption of cytoplasmic membrane
36
what are the two pathways of apoptosis?
intrinsic and extrinsic
37
what happens if ced-9/Bcl-2 lose function?
too many cells die
38
what happens if ced3,ced4, or caspases lose function?
too many cells live, cancer
39
what does MDM2 do?
it is a type of oncogene that inhibits p53
40
what are the proteins in pro-survival?
Bcl-2 and Bcl-X
41
what are the proteins in pro-apoptosis?
Bax and Noxa
42
what consist of the p53 binding sites?
four copies of the pentamer consensus sequenceq
43
what are the oncogenes that regulate p53?
E1A, Myc, and Ras promote p53
44
what kinases from DNA damage regulate p53?
ATM and Chk2 promote p53
45
what acetylases from DNA damage regulate p53?
PCAF and p300 promote p53
46
what kinases from DNA damage stresses regulate p53?
ATR and casein kinase II promote p53
47
how many member are part of the caspase family?
14
48
what are the two classes of caspases?
initiators and effectors
49
what regulates the initiation of the cascade reaction of caspases?
caspase inhibitors
50
true or false: all caspases have slightly different domain structures
FALSE!!!! they all have similar domain structures
51
True or false: not all mammalian caspases participate in apoptosis
TRUE
52
what proteins inhibit Bcl-2 and Bcl-xL?
Noxa
53
what proteins inhibit apaf-1?
Bcl-2 and Bcl-xL
54
what proteins promote Apaf-1?
Bax
55
what does Apaf-1 promote?
Caspase 9 and 3