Inactivation of MAP kinase signalling in Myc Transformed Cells and Rescue by LiCl inhibition of GSK3

Osama Al-Assar,Dorothy H Crouch

doi:10.1186/1476-4598-4-13

Osama Al-Assar, Dorothy H Crouch

Open Access

https://doi.org/10.1186/1476-4598-4-13

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Abstract

c-Myc oncogene is an important regulator of cell cycle and apoptosis, and its dysregulated expression is associated with many malignancies. Myc is instrumental in directly or indirectly regulating the progression through the G1 phase and G1/S transition, and transformation by Myc results in perturbed cell cycle. Also contributory to the control of G1 is the Ras effector pathway Raf/MEK/ERK MAP kinase. Together with GSK3, ERK plays an important role in the critical hierarchical phosphorylation of S62/T58 controlling Myc protein levels. Therefore, our main aim was to examine the levels of MAPK in Myc transformed cells in light of the roles of ERK in cell cycle and control of Myc protein levels. We found that active forms of ERK were barely detectable in v-Myc (MC29) transformed cells. Furthermore, we could only detect reduced levels of activated ERK in c-Myc transformed cells compared to the non-transformed primary chick embryo fibroblast cells. The addition of LiCl inhibited GSK3 and successfully restored the levels of ERK in v-Myc and c-Myc transformed cells to those found in non-transformed cells. In addition, LiCl stabilised Myc protein in the non-transformed and c-Myc transformed cells but not in v-Myc transformed cells. These results can provide an important insight into the role of MAPK in the mechanism of Myc induced transformation and carcinogenesis.

Highlights

The c-Myc oncogene is one of the most frequently dysregulated genes in human tumours
We have found that v-Myc (MC29) transformed fibroblasts have almost non-detectable active ERK2 (Figure 1A)
The barely detectable basal levels of phosphorylated ERK2 in v-Myc transformed fibroblasts showed an increase after the addition of LiCl at the earliest time point of 20 minutes (31% of basal levels in non-transformed control chick embryo fibroblasts (CEF))

Summary

Introduction

The c-Myc oncogene is one of the most frequently dysregulated genes in human tumours. Myc was originally identified as the cellular homolog of the transforming part of the viral isolate MC29 [1]. The c-Myc oncogene is a member of the basic-helix-loop-helix-leucine-zipper transcription (bHLH-ZIP) factors, which are essential for different cellular processes [2]. C-Myc regulates the cellular processes by controlling a large number of target genes [5,6] through heterodimerization with its biological partner Max [7,8,9]. The abundance of the Myc-Max heterodimer is effectively controlled by the short lived Myc protein [10]. The Myc protein is under tight and complex control mechanisms [11]

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