Cell transformation by v-Jun deactivates ERK MAP kinase signalling.
Previous studies have shown that v-Jun accelerates G1 progression and enables cells to sustain S phase entry in the absence of serum growth factors. Since growth factor-dependent ERK MAP kinase signalling plays an important role in regulating the G1/S transition, we investigated whether aberrant ERK regulation might contribute to cell cycle deregulation by v-Jun. Contrary to expectation, we find that cells transformed by v-Jun exhibit a profound reduction in the basal level of active, dual-phosphorylated ERK. In addition, ERK becomes refractory to stimulation by a subset of agonists including serum, LPA, and EGF, but remains partially responsive to the phorbol ester, TPA. Biochemical analysis indicates that these defects are attributable to a combination of inefficient signal propagation between Ras and Raf within the ERK pathway and increased tonic deactivation by MAP kinase phosphatases. Taken together, these results demonstrate that cell transformation by v-Jun induces alterations in cell physiology which antagonize ERK signalling at multiple levels. The potential significance of this phenotype for oncogenesis by v-Jun is discussed.
Black
Elizabeth J
EJ
Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Walker
Mark
M
Clark
William
W
MacLaren
Ann
A
Gillespie
David A F
DA
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007124:Immunoenzyme Techniques; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016759:Oncogene Protein p65(gag-jun) / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016759:Oncogene Protein p65(gag-jun); D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D013755:Tetradecanoylphorbol Acetate