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c-Myc inhibits ras-mediated differentiation of pheochromocytoma cells by blocking c-Jun up-regulation

AutorVaqué, José P.; Fernández-García, Belén; García-Sanz, Pablo; Ferrándiz, Nuria ; Bretones, Gabriel ; Calvo, Fernando; Crespo, Piero ; Marín, M. Carmen; León, Javier
Fecha de publicación2008
EditorAmerican Association for Cancer Research
CitaciónMolecular Cancer Research 6(2): 325-339 (2008)
ResumenAlthough mutant Ras proteins were originally described as transforming oncoproteins, they induce growth arrest, senescence, and/or differentiation in many cell types. c-Myc is an oncogenic transcription factor that cooperates with Ras in cellular transformation and oncogenesis. However, the Myc-Ras relationship in cellular differentiation is largely unknown. Here, we have analyzed the effects of c-Myc on PC12-derived cells (UR61 cell line), harboring an inducible N-Ras oncogene. In these cells, Ras activation induces neuronal-like differentiation by a process involving c-Jun activation. We found that c-Myc inhibited Ras-mediated differentiation by a mechanism that involves the blockade of c-Jun induction in response to Ras signal. Accordingly, ectopically expressed c-Jun could bypass c-Myc impediment of Ras-induced differentiation and activator protein 1 activation. Interestingly, it did not rescue the proliferative arrest elicited by Ras and did not enhance the differentiation-associated apoptosis. The blockade of Ras-mediated induction of c-Jun takes place at the level of c-Jun proximal promoter. Mutational analysis revealed that c-Myc regions involved in DNA binding and transactivation are required to block differentiation and c-Jun induction. c-Myc does not seem to require Miz-1 to inhibit differentiation and block c-Jun induction. Furthermore, Max is not required for c-Myc activity, as UR61 cells lack a functional Max gene. c-Myc-inhibitory effect on the Ras/c-Jun connection is not restricted to UR61 cells as it can occur in other cell types as K562 or HEK293. In conclusion, we describe a novel interplay between c-Myc and c-Jun that controls the ability of Ras to trigger the differentiation program of pheochromocytoma cells. Copyright © 2008 American Association for Cancer Research.
URIhttp://hdl.handle.net/10261/81101
DOI10.1158/1541-7786.MCR-07-0180
Identificadoresdoi: 10.1158/1541-7786.MCR-07-0180
issn: 1541-7786
e-issn: 1557-3125
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