Gonzalez-Suarez EES, Ramirez A, Flores JM, Martin-Caballero J, Jorcano JL, Blasco MAIncreased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J 20:2619-2630

Department of Immunology and Oncology, National Centre of Biotechnology, E-28049 Madrid.
The EMBO Journal (Impact Factor: 10.75). 07/2001; 20(11):2619-30. DOI: 10.1093/emboj/20.11.2619
Source: PubMed

ABSTRACT Telomerase transgenics are an important tool to assess the role of telomerase in cancer, as well as to evaluate the potential use of telomerase for gene therapy of age-associated diseases. Here, we have targeted the expression of the catalytic component of mouse telomerase, mTERT, to basal keratinocytes using the bovine keratin 5 promoter. These telomerase-transgenic mice are viable and show histologically normal stratified epithelia with high levels of telomerase activity and normal telomere length. Interestingly, the epidermis of these mice is highly responsive to the mitogenic effects of phorbol esters, and it is more susceptible than that of wild-type littermates to the development skin tumors upon chemical carcinogenesis. The epidermis of telomerase-transgenic mice also shows an increased wound-healing rate compared with wild-type littermates. These results suggest that, contrary to the general assumption, telomerase actively promotes proliferation in cells that have sufficiently long telomeres and unravel potential risks of gene therapy for age-associated diseases based on telomerase upregulation.

Download full-text


Available from: Juana M Flores, Aug 25, 2015
  • Source
    • "Next, we used our wild-type mouse aging metabolomic signature to predict the ages of transgenic mice overexpressing the telomerase reverse-transcriptase subunit or TERT in various stratified epithelia (K5-TERT mice). We have previously shown that K5-TERT mice have increased tissue fitness and a delayed aging (Gonzalez-Suarez et al., 2001, 2005). Serum metabolomic profiles were not significantly different when comparing "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice. In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that over-express telomerase, their metabolic score corresponded to younger ages than expected. Importantly, telomerase reactivation late in life by using a TERT based gene therapy recently described by us, significantly reverted the metabolic profile of old mice to that of younger mice, further confirming an anti-aging role for telomerase. Thus, the metabolomic signature associated to natural mouse aging accurately predicts aging produced by telomere shortening, suggesting that natural mouse aging is in part produced by presence of short telomeres. These results indicate that the metabolomic signature is associated to the biological age rather than to the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
    Aging cell 10/2012; 12(1). DOI:10.1111/acel.12025 · 5.94 Impact Factor
  • Source
    • "Histopathology was performed as previously described (Gonzá lez-Suá rez et al., 2001). Briefly, tissues and organs were fixed for 24 hr in a 10% neutral buffered formalin solution at room temperature, dehydrated through graded alcohols and xylene, and embedded in paraffin. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrantly short telomeres result in decreased longevity in both humans and mice with defective telomere maintenance. Normal populations of humans and mice present high interindividual variation in telomere length, but it is unknown whether this is associated with their lifespan potential. To address this issue, we performed a longitudinal telomere length study along the lifespan of wild-type and transgenic telomerase reverse transcriptase mice. We found that mouse telomeres shorten ∼100 times faster than human telomeres. Importantly, the rate of increase in the percentage of short telomeres, rather than the rate of telomere shortening per month, was a significant predictor of lifespan in both mouse cohorts, and those individuals who showed a higher rate of increase in the percentage of short telomeres were also the ones with a shorter lifespan. These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity.
    Cell Reports 09/2012; 2(4). DOI:10.1016/j.celrep.2012.08.023 · 8.36 Impact Factor
  • Source
    • "It is also unclear whether telomerase activity can prevent any type of DNA damage at telomeres as an overexpression of TERT could not suppress irradiation-induced cellular senescence or the persistence of telomeric DDR following irradiation, H 2 O 2 , or chemotherapy induced DNA damage (Hewitt et al, 2012). The data could provide a plausible explanation for the increased tumorigenesis in telomerase transgenic mice—a finding which is difficult to explain by telomere length dependent effects of telomerase given the long telomere reserves in mouse tissues (Gonzalez-Suarez et al, 2001). According to the findings of Suram et al (2012), anti-telomerase therapies could have immediate anti-cancer effects in tumours depending on telomerase-mediated healing of stalled replication forks at telomeres. "
    The EMBO Journal 05/2012; 31(13):2833-4. DOI:10.1038/emboj.2012.162 · 10.75 Impact Factor
Show more