(b) Western blot and analysis of p-MKK3/6, MKK3
Ifedigbo et al., "MKK3
mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury," American Journal of Pathology, vol.
Others have reported that p53 GOF mutants R175H, R273H, and R280K aberrantly induce p38 activation via transcriptional activation of MKK3
(an upstream kinase of p38), thereby maintaining the G2/M checkpoint .
The expression plasmids, for constitutively active (CA) forms of MKK3
(MKK3b (E)) and MKK6 (MKK6b (E)) and dominant-negative mutant forms of p38[alpha] (fp38[alpha] (AF)) and p38[beta] (fp38[beta]2 (AF)), have been described previously .
Nuclear factor-(NF-) [kappa]B and activator protein- (AP-) 1 are two main transcription factors that initiate inflammation by activation of a series of intracellular signals composed of inhibitor of [kappa]B kinase (IKK[alpha]/[beta]), AKT (protein kinase B), Src, and Syk for NF-[kappa]B and extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK), interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, transforming growth factor beta-kinase 1 (TAK1), mitogen-activated protein kinase kinase 3 (MKK3
), and MKK6 for AP-1 [5-8].
Furthermore, miR-20a, another component of the miR-17-92 cluster, acts in a feedback loop to repress the expression of MKK3
and to negatively regulate p38 pathway-mediated VEGF-induced ECs migration and angiogenesis .
(4-10) The MKK4 and MKK7 MAPKKs have been shown to activate JNK, and the MKK3
and MKK6 MAPKKs serve as the major activators of the p38 MAPK.
p38[delta] MAPK is unique as it can be activated by four separate MKKs: the p38 MAPK specific MKK3
and MKK6 and also the JNK MKKs-4 and -7 [7-9, 18].
The p38 MAPK participates in macrophage and neutrophil functional responses including respiratory burst activity, chemotaxis, granular exocytosis, adherence, and apoptosis, as well as mediates T cell differentiation and apoptosis by regulating the production of IFN-7.37 In addition, p38 MAPKs can be activated by MAPKKs, MKK3
Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3
This implies that MKK3
enhances the activity of the MEF2 transcription factor.
MKK6 activates all four p38 isoforms, while MKK3
can activate p38[alpha], [beta], and [delta], but not p38[gamma] , and MKK4 activates p38[alpha] and [delta] .