Genetic analysis of myc and telomerase interactions in vivo.
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-MycERTAM 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-MycERTAM 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-MycERTAM 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.
Flores
Ignacio
I
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Evan
Gerard
G
Blasco
María A
MA
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism
D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D019098:Telomerase; C509187:Tert protein, mouse