L17

Question 1

what are the types of NF-kB signaling pathways

Answer 1

canonical (classical)

Non-canonical (alternative)

Question 2

describe the canonical pathway of NF-kB signaling

Answer 2

receptor is triggered by TNFRs, TLRs, and other stress signals

activated receptor interacts with the IKK complex (IKK alpha, IKK beta, and IKK gamma)

only active catalytical kinase is IKK beta

IkBa keeps transcription factor dimer (p50 and p65) inactive

IKK beta phosphorylates IkBa triggering its ubiquitination

IkBa is degraded by proteosome and transcription factor is activated

Question 3

what are the catalytical subunits of the IKK complex

Answer 3

IKK alpha and beta

Question 4

what is the regulatory subunit of the IKK complex

Answer 4

IKK gamma

Question 5

describe what happens in the non-canonical pathway of NF-kB

Answer 5

receptor is triggered by LTbetaR and BAFF-R

NIK is activated which phosphorylate IKK alpha

IKK alpha phosphorylates p100 that is binding to RelB

p100 is processed to p52 and p52 binds to RelB

Question 6

which IKK subunit is active in the non canonical pathway

Answer 6

IKK alpha

Question 7

what is RelA

Answer 7

p65

Question 8

what does The Rel Homology Domain (RHD) do

Answer 8

encodes the DNA binding and dimerisation functions of NF-kB

Question 9

which protein produces p50

Answer 9

p105

Question 10

which protein produces p52

Answer 10

p100

Question 11

what is special about p100 and p105

Answer 11

they contain ankyrin repeats in their C-termini that allow them to function as IkB inhibitors

Question 12

what are the non conserved transcriptional activation domains in NF-kB proteins

Answer 12

TA1/TA2, TAD, SD1, SDII

Question 13

NF-kB contributes in cancer markers

Answer 13

True

Question 14

Tumors that Express Aberrantly Active NF-κB/Have Altered NF-κB/IκB proteins

Answer 14

True

Question 15

why cant we inhibit NF-kB

Answer 15

causes irregulation of the NF-kB

interrupts activation of the immune system, apoptosis, and homeostasis.

Question 16

check slide 16 for extra reading

Answer 16

CHECK IT FOR THE ESSAY

Question 17

which proteins have regulatory functions in NF-kB signaling

Answer 17

IKB-alpha

IKK-gamma (NEMO)

Question 18

p53 is activated by similar triggers as NF-kB

Answer 18

true

Question 19

how is p53 different to NF-kB

Answer 19

p53 triggers cell death if damage can not be repaired (promotes tumor suppression)

NF-kB promotes cell survival (promotes tumor promoting)

Question 20

describe the p53 signaling pathway

Answer 20

p53 is kept inactive by MDM2 or its isoform MDMX. these proteins ubiquitinate p53 leading to its degradation by proteosomes

stress conditions activate ATM and ATR which modify p53 structure

p53 separates from MDM2 and MDM2 is degraded

p53 regulates genes in the nucleus

Question 21

what genes does p53 regulate

Answer 21

p21

BAX

GADD45/PCNA

Question 22

what does p21 do

Answer 22

produced by p53

acts on ciclin and CDK complexes

also acts on pRB and E2F pathways

leads to cell cycle arrest (G1/S)

Question 23

what does BAX do

Answer 23

triggers apoptosis

Question 24

what do GADD45/PCNA do

Answer 24

promote DNA repair

Question 25

what are the domains of the p53 protein

Answer 25

N-terminal domain The core domain The c-terminal domain

Question 26

describe the N-terminal domain

Answer 26

residues (1-99) contain a sub-transactivation domain and a proline rich domain which may be involved in regulation of apoptosis

Question 27

describe the core domain

Answer 27

residues (100-300) bind to specific DNA sequences

Question 28

describe the c-terminal domain

Answer 28

residues (323-393) domain contains the tetramerization domain and another DNA binding site within the regulatory region associated with ssDNA, insertion, deletion DNA mismatches or damaged DNA

Question 29

p53 forms tetramers

Answer 29

True

Question 30

what happens in cancer regarding NF-kB and p53

Answer 30

NF-kB antagonizes the functions of p53

Question 31

how does canonical NF-kB signaling lead to RA in dendritic cells

Answer 31

canonical NF-kB signaling drives the production of IL-15 and IL-18 allowing for further recruitment of dendritic cells

Question 32

how does non canonical NF-kB signaling lead to RA in dendritic cells

Answer 32

it produces IL-12, IL-17, IL-23, and IL-27 which activate T cells

Question 33

how does NF-kB pathway affect RA

Answer 33

C-Rel and NIK drive differentiation in Th-1 cells. Th-1 cells produce INF-gamma causing inflammation C-Rel, Rel-A, and NIK differentiate Th-17 cells. Th-17 cells produce IL-17 which causes inflammation

Question 34

how does the non canonical pathway in B cells affect RA

Answer 34

NIK and IKK alpha activate the B cells

Question 35

what are the steps of activating the B cells that driven by NF-kB

Answer 35

germinal center formation B cell proliferation auto-antibody production

Question 36

how does NF-kB affect T reg cells in RA

Answer 36

increased TNF-alpha expression in RA symptoms increases NF-kB activity Foxp3 is transcription factor that causes development of T reg cells RelA and C-Rel positively regulate Foxp3 promoting T reg formation NIK downregulates Foxp3 and impairs T reg responses effect is debatable

Question 37

how does NF-kB activation affect Fibroblasts-like Synoviocytes (FLS)

Answer 37

decreases FLS apoptosis proliferates FLS causes ECM destruction maintains chronic inflammation, angiogenesis, migration and invasion.

Question 38

how does NF-kB activation cause FLS proliferation

Answer 38

p50 and Rel A drive the production of CycD1 over proliferation causes hyperplasia and pannus formation

Question 39

what causes decreased FLS apoptosis

Answer 39

NF-kB activation releases cytokines which express antiapoptotic genes it can also phosphorylate Ser 536 which inhibits p53

Question 40

what causes destruction of ECM by NF-kB pathway

Answer 40

IKK epsilon activates MMP1, MMP3, and MMP9 causing destruction of ECM RelA causes the production of RANKL which causes ECM destruction

Question 41

how does p53 can control the homeostasis of DCs immune cells

Answer 41

down regulation of p53 in DCs leads to hyperactivation of NF-kB and MAPK pathway this leads to enhance antigen presentation, maturation and activation of DCs

Question 42

less p53 means less CD4 T cells differentiation

Answer 42

True

Question 43

what does the lack of p53 do to T cells

Answer 43

more production of Th17, increasing IL-17 Wip-1 is reduce resulting in impaired development, increasing DNT cells reduced FOXP3. Treg cells are reduced

Question 44

what does down regulation of p53 do to MQ

Answer 44

increase in M1 aggressive macrophages compared to M2

Question 45

p53 suppresses angiogenesis

Answer 45

True

Question 46

what does defective p53 do in RA-FLS

Answer 46

promotes apoptosis resistance and hyper-proliferation. more direct activation of NF-kB leads to more activation reduced MiR-22 production increases Cyr-61 activity. Cyr-61 produces more IL-6 driving the activation of NF-kB defective p53 produces more VEGF which promotes angiogenesis

Question 47

MiR-22 regulates which protein

Answer 47

Cyr-61