L17 Flashcards
what are the types of NF-kB signaling pathways
canonical (classical)
Non-canonical (alternative)
describe the canonical pathway of NF-kB signaling
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
what are the catalytical subunits of the IKK complex
IKK alpha and beta
what is the regulatory subunit of the IKK complex
IKK gamma
describe what happens in the non-canonical pathway of NF-kB
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
which IKK subunit is active in the non canonical pathway
IKK alpha
what is RelA
p65
what does The Rel Homology Domain (RHD) do
encodes the DNA binding and dimerisation functions of NF-kB
which protein produces p50
p105
which protein produces p52
p100
what is special about p100 and p105
they contain ankyrin repeats in their C-termini that allow them to function as IkB inhibitors
what are the non conserved transcriptional activation domains in NF-kB proteins
TA1/TA2, TAD, SD1, SDII
NF-kB contributes in cancer markers
True
Tumors that Express Aberrantly Active NF-κB/Have Altered NF-κB/IκB proteins
True
why cant we inhibit NF-kB
causes irregulation of the NF-kB
interrupts activation of the immune system, apoptosis, and homeostasis.
check slide 16 for extra reading
CHECK IT FOR THE ESSAY
which proteins have regulatory functions in NF-kB signaling
IKB-alpha
IKK-gamma (NEMO)
p53 is activated by similar triggers as NF-kB
true
how is p53 different to NF-kB
p53 triggers cell death if damage can not be repaired (promotes tumor suppression)
NF-kB promotes cell survival (promotes tumor promoting)
describe the p53 signaling pathway
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
what genes does p53 regulate
p21
BAX
GADD45/PCNA
what does p21 do
produced by p53
acts on ciclin and CDK complexes
also acts on pRB and E2F pathways
leads to cell cycle arrest (G1/S)
what does BAX do
triggers apoptosis
what do GADD45/PCNA do
promote DNA repair
what are the domains of the p53 protein
N-terminal domain
The core domain
The c-terminal domain
describe the N-terminal domain
residues (1-99)
contain a sub-transactivation domain and a proline rich domain which may be involved in regulation of apoptosis
describe the core domain
residues (100-300)
bind to specific DNA sequences
describe the c-terminal domain
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
p53 forms tetramers
True
what happens in cancer regarding NF-kB and p53
NF-kB antagonizes the functions of p53
how does canonical NF-kB signaling lead to RA in dendritic cells
canonical NF-kB signaling drives the production of IL-15 and IL-18 allowing for further recruitment of dendritic cells
how does non canonical NF-kB signaling lead to RA in dendritic cells
it produces IL-12, IL-17, IL-23, and IL-27 which activate T cells
how does NF-kB pathway affect RA
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
how does the non canonical pathway in B cells affect RA
NIK and IKK alpha activate the B cells
what are the steps of activating the B cells that driven by NF-kB
germinal center formation
B cell proliferation
auto-antibody production
how does NF-kB affect T reg cells in RA
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
how does NF-kB activation affect Fibroblasts-like Synoviocytes (FLS)
decreases FLS apoptosis
proliferates FLS
causes ECM destruction
maintains chronic inflammation, angiogenesis, migration and invasion.
how does NF-kB activation cause FLS proliferation
p50 and Rel A drive the production of CycD1
over proliferation causes hyperplasia and pannus formation
what causes decreased FLS apoptosis
NF-kB activation releases cytokines which express antiapoptotic genes
it can also phosphorylate Ser 536 which inhibits p53
what causes destruction of ECM by NF-kB pathway
IKK epsilon activates MMP1, MMP3, and MMP9 causing destruction of ECM
RelA causes the production of RANKL which causes ECM destruction
how does p53 can control the homeostasis of DCs immune cells
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
less p53 means less CD4 T cells differentiation
True
what does the lack of p53 do to T cells
more production of Th17, increasing IL-17
Wip-1 is reduce resulting in impaired development, increasing DNT cells
reduced FOXP3. Treg cells are reduced
what does down regulation of p53 do to MQ
increase in M1 aggressive macrophages compared to M2
p53 suppresses angiogenesis
True
what does defective p53 do in RA-FLS
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
MiR-22 regulates which protein
Cyr-61
