Cooperation between p53 mutation and high telomerase transgenic expression in spontaneous cancer development.
Telomerase reintroduction in adult somatic tissues is envisioned as a way to extend their proliferative capacity. It is still a question, however, whether constitutive telomerase expression in adult tissues impacts the normal aging and spontaneous cancer incidence of an organism. Here, we studied the aging and spontaneous cancer incidence of mice with transgenic telomerase expression in a wide range of adult tissues, K5-Tert mice. For this, we maintained large colonies of K5-Tert mice for more than 2 years. K5-Tert mice showed a decreased life span compared to wild-type cohorts associated with a higher incidence of preneoplastic and neoplastic lesions in various tissue types. Neoplasias in K5-Tert mice were coincident with transgene expression in the affected tissues. These observations suggest that high telomerase activity may cooperate with genetic alterations that occur with age to promote tumorigenesis. Indeed, we demonstrate here that increased cancer incidence and the reduced viability of K5-Tert mice are aggravated in a p53(+/-) genetic background, indicating that telomerase cooperates with loss of p53 function in inducing tumorigenesis. Altogether, these results demonstrate that constitutive high levels of telomerase activity result in a decreased life span associated with an increased incidence of neoplasias as the organism ages.
González-Suárez
Eva
E
Department of Immunology and Oncology, National Center for Biotechnology, E-28049 Madrid, Spain.
Flores
Juana M
JM
Blasco
María A
MA
D000818:Animals; D004268:DNA-Binding Proteins; D003627:Data Interpretation, Statistical; D015870:Gene Expression; D015994:Incidence; D008221:Lymphoid Tissue; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016296:Mutagenesis; D009369:Neoplasms / Q000473:pathology*; D011230:Precancerous Conditions / Q000473:pathology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D019098:Telomerase; C509187:Tert protein, mouse