MKK3 as oncotarget

(MAP2K3, MKK3) is a member of the dual-specificity protein kinase group (MKK) that belongs to the mitogen-activated protein kinase (MAPK) signaling pathway. Following different forms of stressful stimuli and inflammatory cytokines, MKK3 is activated through phosphorylation on serine and threonine residues at sites Ser189 and Thr193 by MKKK proteins (MEKK 1-4) [1]. Activated MKK3 phosphorylates specifically p38MAPK, an important kinase involved in a plethora of cellular programs, including cell differentiation, motility, division, and death. Consistent literature identified MKK3 as relevant player involved in tumor invasion and progression in gliomas and breast tumors. We previously identified MKK3 in a gene expression profile array performed with p53-null H1299 cells ectopically expressing mutant p53-R175H gain-of-function (GOF), one of the most frequent alteration revealed in human cancer [2]. Studies of validation performed with a panel of cancer cell lines harbouring different p53 mutants (R273H, R280K) showed the generalized effect since other p53 mutants were able to upregulated MKK3 gene expression. By contrast, normal wild type (wt) p53 protein does not affect the MKK3 expression [3]. Mechanistically, we demonstrate that mutp53 is physically recruited on MKK3 promoter and that through the involvement of specific transcriptional co-factors (NF-κB and NF-Y) sustains MKK3 expression [3]. To explore whether MKK3 might contribute in mutp53 GOF activities, functional studies were performed by silencing the endogenous MKK3 protein by using inducible RNA interference (RNAi) system. We demonstrated the MKK3 depletion impairs at different extent the cell proliferation and cell survival of tested mutp53 cancer cells (HT29, MDA-MB468, MDA-MB231, SKBR3). The effects were not mutp53 cell-context dependent since observed also p53-null (H1299) human cancer cells predicting that MKK3 might represent a generally required factor [3]. We further extended our studies also in other cell lines in wtp53 cell-context with transformed and not-transformed phenotype. Interestingly, results beside confirming MKK3 as generally required factor further suggested MKK3 as tumor-specific required factor. Indeed, similarly to mutp53 cancer cells, MKK3 deple-Editorial tion affects cell proliferation and cell survival also in wtp53 carrying cancer cells (MCF7, HCT116) but not in primary no-transformed cells (FB1329, MCF10A) [4]. Under microscope examination MKK3 depletion induces large cytoplasmic vacuoles in cancer but not normal cells. Accordingly, we investigated whether MKK3 silencing might induce autophagic degeneration. Through biochemical analyses we found that MKK3 depletion induces accumulation of LC3-II levels and SQSTM1/p62 degradation in both wt and mutp53 carrying cancer cells. Moreover, MKK3 depletion raises wtp53 protein level correlated to endoplasmic reticulum …