Isoangustone A, a novel licorice compound, inhibits cell proliferation by targeting PI3K, MKK4, and MKK7
in human melanoma.
While mice deficient in JNK1/2 were shown to be resistant to I/Rinduced apoptosis, cardiac-specific transgenic mice expressing MKK7
, the MAPKK for JNK kinases, were also protected from I/R injury .
(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.
The dose-dependant inhibition of BxPC-3 pancreatic cancer cells by alpinetin (6) was also reported (Du et al., 2012); At high concentrations (with an effective dose of 60 [micro]g/ml or 222.22 [micro]M) of alpinetin inhibited the proliferation of HepG2 cell lines with cells cycle arrest in the G0/G1 phase by up-regulating the expression levels of Mitogen-activated protein kinase kinase-7 (MKK7
) (Tang et al., 2012).
Kotsinas, P Papanagnou, P Galanos et al., "MKK7
and ARF: new players in the DNA damage response scenery," Cell Cycle, vol.
is reported to be responsible for the activation of p38[delta] MAPK in 293T cells under peroxide stress, mediated by the scaffolding action of islet brain-2 .
Additionally, exposure of islets to stress from the islet isolation process activates JNK and p38 via MKK7
In the neurons, the MLK family of kinases serves as the major MAPKKS and phosphorylates MKK4 & MKK7
, which in turn phosphorylate the JNKS.
JNKs can be activated by the upstream MKK4 and MKK7
kinases [186, 187].
TNF-[alpha] can also activate cellular proliferation through activation of another transcription factor, activator protein-1 (AP-1) , which is activated by TNF-[alpha] through sequential recruitment of TNFR1, TRADD, TRAF2, MAP/ERK kinase kinase-1 (MEKK1), MAP kinase kinase-7 (MKK7
), and JNK.
HEK 293 cells were transfected with GAL4-CBP and either empty vector or vectors overexpressing constitutively active MKK1, MKK5, MKK6, or MKK7
mutants that selectively activate ERK1/2, ERK5, p38[alpha], and JNK (respectively).