Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.10 (
IKK
)
4,900
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Camptothecin
(
CPT
) and derivatives are topoisomerase I poisons currently used as anticancer drugs. Their cytotoxicity is maximal for cells in S phase. Using asynchronous and S phase-synchronized HeLa cells, we showed that both the nuclear factor-kappaB (NF-kappaB) activation and its transcriptional activity, induced by
CPT
treatment, are enhanced in S phase cells. After
CPT
treatment, NF-kappaB activation reached a maximum within 2-3 hr and was still detectable after 24 hr. The nature of the complex evolved with time, forming mostly p50/p65 after 2 hr to almost exclusively p52 after 24 hr. In HeLa cells, the different steps of the induction were readily observable in S phase synchronized cells, whereas they were barely noticeable in a randomly growing cell population. The signal progressed through the activation of the
IKK
complex, the phosphorylation of IkappaBalpha, and the degradation of phosphorylated-IkappaBalpha and -IkappaBbeta. The stable expression of wild-type HA-tagged-IkappaBalpha or mutated HA-tagged-IkappaBalpha (S32,36A) allowed us to confirm the essential role of Ser32 and Ser36. NF-kappaB-activating kinase (NIK) could play a role upstream of the
IKK
complex, as the transient expression of a kinase inactive mutant NIK(K429,430A) abolished the activation of NF-kappaB by
CPT
. A kinase inactive mutant of mitogen-activated protein/ERK kinase kinase 1 (MEKK1), another kinase susceptible of acting upstream of the signalsome, did not. Cytotoxicity studies with clonal populations expressing different amounts of wild-type or mutated IkappaBalpha revealed that the overexpression of wild-type IkappaBa in large amount increases the sensitivity of HeLa cells to
CPT
more efficiently than a lower level of expression of non-phosphorylable IkappaBalpha.
...
PMID:S phase dependence and involvement of NF-kappaB activating kinase to NF-kappaB activation by camptothecin. 1158 57
