Lecture 10: NFkb Flashcards
Five NFkB members
RelA (p65) RelB c-Rel p50/p105 (NFkB1) p52/p100 (NFkB2)
N terminal Rel-homology domain (RHD)
mediates DNA binding and dimerization of NFkB
RelA, RelB, c-Rel contain unrelated c terminal transcriptional activation domains
p105 and p100
ubiquitin-dependent proteolytic processing removes C-terminal domain and result in production of mature DNA-binding proteins (p50 and p52)
Most common form of NFkB dimers
p50/p65 (NFkB1/RelA)
Rel B can only form heterodimers
kB binding site symmetry
5’-GGGRNNYYCC-3’
each dimer subunit reacts with one half site
Inhibitors of kappa B (IkBs)
IkB a
IkB b
other less studied forms are IkB gamma and BCL3
Ank domains
IkB with Ank domains can interact with RHD sequences on Nf-kB and block the ability of NfkB dimers to bind DNA and nuclear translocation
most studied member is IkBa
3 types of IkB kinase (IKK)
IKK-a
IKK-b
IKK-y (NEMO)
a and b together are catalytically active and y subunit serves as a regulatory function
How does IKK activates NFkB activation cascade
phosphorylate IkB on Ser32 and Ser36
IkB recognize by B-TRCP and SCF (E3 ubiquitin ligase)
proteasomal degradation of IkB
p50/RelA translocate into nucleus
NFkB can be activated by?
interleukin receptor (ILR) via TAK1
toll-like receptor (TLR) via TAK1
RTK and PI3K via AKT or tank binding kinase (TBK1)
Lymphocyte receptor via PKC
TNF receptor pathway activation TAK1 via RIPK1
PHOSPHORYLATES IKKy and activates its activity
Non-canonical pathway of NFkB
NIK is activated by receptor ligation
phosphorylate IKKa and IKKb
proteasomal degradation of p100
RelB binds with p52 which has DNA binding activity
regulates distinct class of genes
5 effects of NFkB transcription factors
- negative control of apoptosis (BCL2, BCLXL, CIAP1,2, XIAP survivin)
- cell proliferation (cyclin D, MYC)
- cell adhesion and motility (ICAM, VCAM, fibronectin, metalloproteinases)
- inflammation (IL-6)
- angiogenesis (VEGF, COX2)
Negative feedback for NFkB
- induction of IkB proteins IkBa and IKB gamma
- induction of A20 (encoded by TNFAIP3), a ubiquitin-editing enzyme, negatively regulates IKK activity (prevent activation)
NFkB activation in leukemia and lymphogenesis
constitutively active in response to growth factors and cytokines or viral oncoproteins
NFkB activation can lead to production of CD40 ligand which positive feedback to increase signalling
activates cyclin D1 and D2 (promote G1 to S phase)
activates inhibitor of apoptosis (BCL-XL, cIAPS and A1/BFL1)
2 pathways which contribute to induction of cyclin D1
- activation of AP1 by growth factors (GF) through MAPK
- activation of RANKL which binds to RANK and activated IKKa
promote G1 to S phase