Genetic Analysis of Myc and Telomerase Interactions In Vivo

Abstract

Myc is a transcription factor with pleiotropic effects on tumorigenesis which are likely to be mediated by its target genes. A known Myc transcriptional target is the catalytic subunit of telomerase, Tert. However, the contribution of Tert activation to Myc-induced tumorigenesis in vivo remains unknown. In this study, we addressed the role of telomerase in Myc-induced skin papillomatosis by using compound mice with a switchable Myc gene, Inv-MycER^TAM mice, in combination with either telomerase deficiency (Terc^−/−) or telomerase overexpression (K5-mTert) in the skin. We first demonstrated that Myc activates telomerase in the skin. With Inv-MycER^TAM × Terc^−/− mice, we further showed that this telomerase activation is partially required to elicit a full hyperplastic Myc-induced response. The presence of critically short telomeres in late-generation Inv-MycER^TAM × Terc^−/− mice further reduced the skin lesion induced by Myc. On the other hand, telomerase overexpression in the skin of K5-mTert mice augments Myc-induced hyperplasia in the absence of changes in telomere length, suggesting a direct role of telomerase in the Myc protumorigenic response. Taken together, these results highlight telomerase as a mediator of Myc-induced papillomatosis and suggest telomerase as a putative therapeutic target for Myc-dependent lesions.

I.F. is a Franco-Peral postdoctoral fellow of the Spanish Association Against Cancer (AECC). Research in the laboratory of M.A.B. is funded by the MCYT (SAF2001-1869, GEN2001-4856-C13-08), by the Regional Government of Madrid, CAM (08.1/0054/01), by the European Union (TELOSENS FIGH-CT.2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD F16R-CT-2003-508842), and by the Josef Steiner Cancer Award 2003.

We do not have any conflicts of interest.