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

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]. Paradoxically, c-Myc promotes both cell cycle progression and apoptosis under low serum condition [3,4]. c-Myc regulates the cellular processes by controlling a large number of target genes [5,6] through heterodimerization with its biological partner Max [7-9]. 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].Critical phosphorylation events determining the protein half life occur in Myc homology box I (aa45-aa65) [10]. These detrimental events involve the hierarchical phosphorylation of S62 and T58 by ERK1/2 MAPK and GSK3β, respectively [12]. It is widely accepted that these kinases are involved in the phosphorylation events at these residues although other reports question the role of MAPK [13]. These two kinases are part of two different Ras effector pathways. The presence of different Ras isoforms provides for selective activation of specific Ras effector pathway, although this can only be shown in vivo [14]. It has been reported that PI-3 kinase is most effectively activated by M-Ras and R-Ras and to a less extent by H-Ras [15,16]. On the other hand, Raf-1 is most effectively activated by K-Ras [17,18]. This selective activation of different Ras effector pathways has opposing effects on Myc controlled functions. Whereas the activation of Raf fails to suppress Myc induced apoptosis, the activation of PI-3 Kinase can effectively suppress it [19]. A key component of the PI3-kinase/Akt (PKB) pro-survival pathway is GSK3 [20], whereas the active phosphorylated form of ERK1/2 MAPK is a downs