c-myc Internal Ribosome Entry Site Activity Is Developmentally Controlled and Subjected to a Strong Translational Repression in Adult Transgenic Mice

Abstract

The expression of c-myc proto-oncogene, a key regulator of cell proliferation and apoptosis, is controlled at different transcriptional and posttranscriptional levels. In particular, the c-myc mRNA contains an internal ribosome entry site (IRES) able to promote translation initiation independently from the classical cap-dependent mechanism. We analyzed the variations of c-myc IRES activity ex vivo in different proliferating cell types, and in vivo in transgenic mice expressing a bicistronic dual luciferase construct. c-myc IRES efficiency was compared to that of encephalomyocarditis virus (EMCV) IRES under the same conditions. The c-myc IRES was active but with variable efficiency in all transiently transfected cell types; it was also active in the 11-day- old (E11) embryo and in some tissues of the E16 embryo. Strikingly, its activity was undetected or very low in all adult organs tested. In contrast, EMCV IRES was very active in most cell types ex vivo, as well as in embryonic and adult tissues. These data suggest a crucial role of IRES in the control of c-mycgene expression throughout development, either during embryogenesis where its activity might participate in cell proliferation or later on, where its silencing could contribute to the downregulation of c-myc expression, whose deregulation leads to tumor formation.

ACKNOWLEDGMENTS

We are grateful to J. Auriol for technical assistance and to D. Warwick for English proofreading. We thank Abderahim Mahfoudi, Cécile Orsini, and Hervé Prats for helpful discussions.

This work was supported by grants from the Association pour la Recherche contre le Cancer, the Ligue Nationale contre le Cancer, the Conseil Régional Midi-Pyrénées, the European Commission BIOTECH program (contract 94199-181), and Rhone-Poulenc-Rorer (now Aventis). L. Créancier was financed first by the European Commission BIOTECH program and then by Retina France.