This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Vaqué, J. P. Articles by León, J. PubMed PubMed Citation Articles by Vaqué, J. P. Articles by León, J.

---

Signaling and Regulation

c-Myc Inhibits Ras-Mediated Differentiation of Pheochromocytoma Cells by Blocking c-Jun Up-Regulation

¹ Grupo de Biología Molecular del Cáncer, Dpto. de Biología Molecular and Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC-IDICAN and ² Instituto de Investigaciones Biomédicas, Unidad de Biomedicina de la Universidad de Cantabria-CSIC, Universidad de Cantabria, Santander, Spain; and ³ Instituto de Biomedicina, Universidad de León, León, Spain

Requests for reprints: Javier León, Dpto. de Biología Molecular, Facultad de Medicina, Avda. Cardenal Herrera Oria s/n, 39011 Santander, Spain. Phone: 34-942-201952; Fax: 34-942-201945. E-mail: leonj{at}unican.es

Although 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. (Mol Cancer Res 2008;6(2):325–39)