Biomedical Engineering Reference
In-Depth Information
unique pathway from DNA damage to activation of the IKK complex, involving
sumoylation and ubiquitinylation of NEMO. Here we will expand upon this discus-
sion and include signaling pathways induced by other genotoxic stressors (Figure
4.4). However, it is difficult to draw general conclusions at this stage due to dis-
crepancies between the stresses and cellular systems used by different laboratories.
As discussed in
Chapter 3
, DNA damage has recently been shown to induce a
unique signaling pathway that relies on ubiquitin and ubiquitin-like modifications.
Activation of NF-
B following exposure of cells to topoisomerase inhibitors, which
cause DNA damage, is dependent on NEMO [53]. The zinc finger domain of NEMO,
κ
UV
?
p38
Ub
CK2
α
Caspase-2
PIDD
RAIDD
Ub
NEMO
Su
NEMO
AT M
AT M
Nucleus
Cytoplasm
DNA strand break
FIGURE 4.4
Stress-induced NF-
κ
B signaling pathways. Schematic diagram showing proteins
involved in NF-
B activation by UV irradiation and DNA damaging agents. UV has been
reported to activate NF-
κ
B via both IKK-dependent and -independent pathways. Only the IKK-
independent CK2 pathway is shown, since the proteins involved in the IKK-dependent pathway
have not been fully characterized. p38 acts as an allosteric activator of CK2, which phosphorylates
(P) the C-terminal protein, glutamic acid, serine, and threonine (PEST) region of I
κ
κ
Ba on multiple
serine residues following UV irradiation. This triggers I
Ba polyubiquitination by an unknown
E3 ligase and degradation by the proteasome. DNA damage induces nuclear translocation and
sumoylation of NEMO. Following desumoylation, NEMO is phosphorylated by the ATM kinase.
This triggers NEMO polyubiquitination and subsequent translocation back to the cytoplasm,
where it associates with and activates the IKK complex. RIP is essential for activation of NF-
κ
B
by DNA damaging agents, which induce it to form a complex with IKK. The complex of caspase-
2/PIDD/RAIDD, termed the p53 induced protein with a death domain (PIDD)osome, is required
for induction of NEMO sumoylation following genotoxic shock. Polyubiquitinated (Ub) and
sumoylated (S) proteins are indicated. Abbreviations are defined in the text.
κ
