Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation. Mol Cell 2003 Nov;12(5):1287-300
Date
11/26/2003Pubmed ID
14636585DOI
10.1016/s1097-2765(03)00390-3Scopus ID
2-s2.0-10744225575 (requires institutional sign-in at Scopus site) 148 CitationsAbstract
The transcription factor NF-kappaB regulates genes involved in innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Proinflammatory cytokines induce the activation of NF-kappaB in both transient and persistent phases. We investigated the mechanism for this biphasic NF-kappaB activation. Our results show that MEKK3 is essential in the regulation of rapid activation of NF-kappaB, whereas MEKK2 is important in controlling the delayed activation of NF-kappaB in response to stimulation with the cytokines TNF-alpha and IL-1alpha. MEKK3 is involved in the formation of the IkappaBalpha:NF-kappaB/IKK complex, whereas MEKK2 participates in assembling the IkappaBbeta:NF-kappaB/IKK complex; these two distinct complexes regulate the proinflammatory cytokine-induced biphasic NF-kappaB activation. Thus, our study reveals a novel mechanism in which different MAP3K and IkappaB isoforms are involved in specific complex formation with IKK and NF-kappaB for regulating the biphasic NF-kappaB activation. These findings provide further insight into the regulation of cytokine-induced specific and temporal gene expression.
Author List
Schmidt C, Peng B, Li Z, Sclabas GM, Fujioka S, Niu J, Schmidt-Supprian M, Evans DB, Abbruzzese JL, Chiao PJAuthor
Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBinding Sites
Cells, Cultured
Fibroblasts
Gene Expression Regulation
Humans
I-kappa B Proteins
Interleukin-1
Isoenzymes
MAP Kinase Kinase Kinase 2
MAP Kinase Kinase Kinase 3
MAP Kinase Kinase Kinases
Mice
Multienzyme Complexes
NF-KappaB Inhibitor alpha
NF-kappa B
Phosphorylation
Protein Structure, Tertiary
RNA, Small Interfering
Signal Transduction
Tumor Necrosis Factor-alpha
