MKK3 as oncotarget

Abstract

The mitogen-activated protein kinase kinase 3 (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-offunction (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, MDAMB468, MDA-MB231, SKBR3). The effects were not mutp53 cell-context dependent since observed also p53null (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 nottransformed 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 depleEditorial

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Cite this paper

@inproceedings{Bossi2016MKK3AO, title={MKK3 as oncotarget}, author={Gianluca Bossi}, booktitle={Aging}, year={2016} }