Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer

Abstract

TP53 is universally recognized as a pivotal protein in cell-cycle fate and apoptotic induction and, unsurprisingly, it is one of the most commonly hijacked control mechanisms in cancer. Recently, the kinase MKK3 emerged as a potential therapeutic target in different types of solid tumor being linked to mutant p53 gain-of-function. In this review, we summarize the delicate relationship among p53 mutational status, MKK3/MKK6 and the downstream activated master kinase p38MAPK, dissecting a finely-tuned crosstalk, in a potentially cell-context dependent scenario that urges towards a deeper characterization of the different molecular players involved in this signaling cascade and their interactions.

Keywords: MKK3/MKK6; mutations; p38MAPK; p53.

Figure 1

p53 and potential outcomes of p38MAPK activation. Both pro-apoptotic or survival stimuli can be transduced by p38MAPK pathway. A wide array of MAP3Ks stimuli that converge to MAP2Ks (MKK3 and MKK6) which, in turn, mediate the activation of different p38MAPK isoforms. Preferential activation of specific nodes and isoforms according to the type and/or duration of the stimulus are fundamental in the final biological outcome. In addition, cell-context and integration with other signaling pathways are able to skew the final outcome. In the wtp53 cell-context (left) activated p38MAPK alpha phosphorylates directly wtp53, contributing to its activation, and stabilize p21 mRNA orchestrating growth arrest or apoptosis. Conversely, activated wtp53 induces Wip1 phosphatase expression mediating a negative regulatory feedback on p38MAPK-p53 signaling. Conversely, in a mutant p53 cell-context (right), the increased MKK3 gene expression by mutated protein, through NF-Y and NF-κB transcription factors, could contribute in sustaining and/or enhancing the p38MAPK signaling in a positive regulatory feedback, which potentially supporting further mutant p53 gain-of-function activities and thus cancer cell proliferation, survival or chemoresistance.