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

Lorenzo Stramucci,Angelina Pranteda,Gianluca Bossi

doi:10.3390/cancers10050131

Lorenzo Stramucci, Angelina Pranteda + Show 1 more

Open Access

https://doi.org/10.3390/cancers10050131

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Journal: Cancers	Publication Date: May 3, 2018
Citations: 80	License type: CC BY 4.0

Affiliation: Expert System (Italy)

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.

Highlights

Mitogen activated protein kinases (MAPKs) are activated in response to a variety of stimuli, and mediate a plethora of cell processes to respond and adapt
The mutp53 gain-of-function transcriptional target and p38 mitogen activated protein kinase (p38MAPK) upstream MAP2K, MKK3 has been recently proposed as a target for tumor therapy [12,13,14]
The amount of contradictive data obtained about an unequivocal role of p38MAPK signaling in cancer, highlights how cell specific phenomena are able to skew the biological outcome of the activation of this specific pathway

Summary

Introduction

Mitogen activated protein kinases (MAPKs) are activated in response to a variety of stimuli, and mediate a plethora of cell processes to respond and adapt . As for other MAPKs, p38MAPK activation orchestrates cellular response by modulating a wide variety of targets, such as protein kinases, phosphatases, cell-cycle regulators and transcription factors, including p53 [1,2,3,4]. A precise characterization of the different players involved in its signaling cascade could shed light onto the mechanisms underlying the different reported outcomes of p38MAPK activation, and identify potential therapeutic targets. In this context, the mutp gain-of-function transcriptional target and p38MAPK upstream MAP2K, MKK3 has been recently proposed as a target for tumor therapy [12,13,14]. We summarize the current knowledge on MKK3/6-p38MAPK pathway and its delicate interaction with p53, revealing an intricate balance that could be shifted according to cell-type and —context

TP53: Apoptosis and More

Two Pathways Intersect

Findings

Concluding Remarks