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Molecular and Cellular Biology, August 2006, p. 6130-6138, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00543-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Genetic Analysis of Myc and Telomerase Interactions In Vivo

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain,¹ Cancer Research Institute, University of California at San Francisco, San Francisco, California²

Received 28 March 2006/ Returned for modification 19 April 2006/ Accepted 7 June 2006

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 x 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 x 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.