Inactivation of MAP kinase signalling in Myc transformed cells and rescue by LiCl inhibition of GSK3.
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.
Al-Assar
Osama
O
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. o.al-assar@sheffield.ac.uk
Crouch
Dorothy H
DH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005347:Fibroblasts; D016259:Genes, myc / Q000235:genetics / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D018021:Lithium Chloride / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D016895:Culture Media, Serum-Free; D016274:Oncogene Protein p55(v-myc); D019950:Mitogen-Activated Protein Kinase 1; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride