Abstract
Cotransfection of primary rat embryo fibroblasts (REF) with c-Jun and activated Ras leads to oncogenic transformation and this process requires the phosphorylation of the N-terminal domain of c-Jun. Ras augments this phosphorylation and, consequently activates the c-Jun transactivation property of TRE (TPA Responsive Element)-dependent promoters. To analyse the role of the c-Jun C-terminal phosphorylation site in oncogenic cooperation we tested the activities of N-terminal c-Jun Ala63/73 (named Nt), C-terminal c-Jun Ala234/242/246/252 (named Ct) and (Nt+Ct)–with both mutations–non-phosphorylatable c-Jun mutants. In cooperation with Ras, the Ct mutant and wt c-Jun display similar oncogenic properties whereas the Nt form was defective in transforming REF cells. Unexpectedly, the Nt+Ct mutant exhibited identical oncogenic properties to wt c-Jun, demonstrating that the Ct mutation rescues in cis the Nt mutation. The transcriptional activity and the capacity to bind the c-Jun coactivator CREB Binding Protein (CBP) were enhanced by Ras for the wt and Ct proteins but not for the Nt mutant. Interestingly, the Nt+Ct mutant presents identical transactivation and CBP binding activities to wt c-Jun. Therefore the rescue in cis of the defective Nt mutation by the Ct mutation seems to be due to the recovery of CBP binding. Our results revealed that the process of oncogenic cooperation can occur between Ras and the Nt+Ct non-phosphorylatable c-Jun protein.
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Acknowledgements
This work was supported by grants from the Association pour la Recherche sue le Cancer and Fondation pour la Recherche Médicale (to B Binétruy and M Castellazzi). L Caron was supported by a co-fellowship from INSERM and Région PACA and E Vial was supported by Fondation pour la Recherche Médicale. We are indebted to Yannick Le Marchand-Brustel for her help and to Peter Angel for providing us with mutants of human c-Jun cDNA.
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Bost, F., Caron, L., Vial, E. et al. The defective transforming phenotype of c-Jun Ala63/73 is rescued by mutation of the C-terminal phosphorylation site. Oncogene 20, 7425–7429 (2001). https://doi.org/10.1038/sj.onc.1204924
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DOI: https://doi.org/10.1038/sj.onc.1204924
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