Abstract
In addition to c-myc rearrangement, over 50% of Burkitt's lymphoma cases present clustered mutations in exon 2, where many of the functional activities of c-Myc protein are based. This report describes the functional consequences induced by tumour-derived c-myc mutations located in c-myc box II. Two mutated alleles were studied, focusing on the P138C mutation, and compared to wild-type c-myc. The c-Myc transformation, transactivation and apoptosis activities were explored based on cells over-expressing c-Myc. While the transcriptional activation activity was not affected, our experiments exploring the anchorage-independent growth capacity of c-Myc-transfected Rat1a cells showed that c-Myc box II mutants were less potent than wild-type c-Myc in promoting cell transformation. Considering the possibility that these mutations could be interfering with the ability of c-Myc to promote apoptosis, we tested c-Myc-transfected Rat1a fibroblasts under several conditions: serum deprivation-, staurosporine- and TNFα-induced cell death. Interestingly, the mutated alleles were characterized by an overall decrease in ability to mediate apoptosis. Our study indicates that point mutations located in c-Myc box II can decrease the ability of the protein to promote both transformation and apoptosis without modifying its transactivating activity.
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Acknowledgements
We thank Dr T Littlewood (ICRF, London) for providing the pBpuro MycERTM vector, Dr P Lazarovici (Hadassah, Jerusalem) for providing staurosporine, Drs P Charbord and D Fellmann (IETG, Besançon) for their constant support, Dr U Brinkmann (NCI, Bethesda) for his advice on cell proliferation analysis, A Lienart and V Mougey (EFS, Bourgogne Franche-Comté) for her help on FACS analysis and L Sorbara (NCI, Bethesda) for her help on the Western blot work. This work was supported in part by a grant from Fondation de France, Paris and Ligue Départementale contre le Cancer du Doubs. T Fest was supported during his fellowship at NIH/NCI Bethesda, MD, by an ARC Paris and Philippe Foundation, Paris–New York, post-doctoral fellowship.
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Kuttler, F., Amé, P., Clark, H. et al. c-myc box II mutations in Burkitt's lymphoma-derived alleles reduce cell-transformation activity and lower response to broad apoptotic stimuli. Oncogene 20, 6084–6094 (2001). https://doi.org/10.1038/sj.onc.1204827
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DOI: https://doi.org/10.1038/sj.onc.1204827
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