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: 10.43). 07/2001; 20(11):2619-30. DOI: 10.1093/emboj/20.11.2619
Source: PubMed


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.

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Available from: Juana M Flores, Oct 04, 2015
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    • "2) TERT overexpression promotes tumor development without further telomere elongation.15 "
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    ABSTRACT: Telomerase reverse transcriptase (TERT) is the protein component of telomerase and combined with an RNA molecule, telomerase RNA component, forms the telomerase enzyme responsible for telomere elongation. Telomerase is essential for maintaining telomere length from replicative attrition and thus contributes to the preservation of genome integrity. Although diverse mouse models have been developed and studied to prove the physiological roles of telomerase as a telomere- elongating enzyme, recent studies have revealed non-canonical TERT activities beyond telomeres. To gain insights into the physiological impact of extra-telomeric roles, this review revisits the strategies and phenotypes of telomerase mouse models in terms of the extra-telomeric functions of telomerase.
    Yonsei medical journal 01/2014; 55(1):1-8. DOI:10.3349/ymj.2014.55.1.1 · 1.29 Impact Factor
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    • "Histopathology was performed as described [59]. Briefly, tissues and organs from sacrificed or natural death mice were fixed for 24 h in a 10% neutral-buffered formalin solution at room temperature, dehydrated through graded alcohols and xylene, and embedded in paraffin. "
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    ABSTRACT: Caloric restriction (CR), a reduction of food intake while avoiding malnutrition, can delay the onset of cancer and age-related diseases in several species, including mice. In addition, depending of the genetic background, CR can also increase or decrease mouse longevity. This has highlighted the importance of identifying the molecular pathways that interplay with CR in modulating longevity. Significant lifespan extension in mice has been recently achieved through over-expression of the catalytic subunit of mouse telomerase (mTERT) in a cancer protective background. Given the CR cancer-protective effects in rodents, we set to address here whether CR impacts on telomere length and synergizes with mTERT to extend mouse longevity. CR significantly decreased tumor incidence in TERT transgenic (TgTERT) mice and extended their lifespan compared to wild-type (WT) controls under the same diet, indicating a synergy between TgTERT and CR in increasing mouse longevity. In addition, longitudinal telomere length measurements in peripheral blood leukocytes from individual mice showed that CR resulted in maintenance and/or elongation telomeres in a percentage of WT mice, a situation that mimics telomere dynamics in TgTERT cohorts. These results demonstrate that CR attenuates telomere erosion associated to aging and that synergizes with TERT over-expression in increasing "health span" and extending mouse longevity.
    PLoS ONE 01/2013; 8(1):e53760. DOI:10.1371/journal.pone.0053760 · 3.23 Impact Factor
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    • "A recent study showed that overexpression of hTERC and hTERT together in vitro greatly induced telomerase activity and telomere length elongation, while stable overexpression of either hTERC or hTERT alone induced telomerase activity and telomere length elongation to a lesser extent [21]. Consistent with this study, several studies also highlighted the fact that both telomerase components restrict telomerase activity and telomere length in vitro, suggesting that the tumorigenic effects of hTERT overexpression are reliant on hTERC expression and in fact hTERT overexpression in an hTERC deficient background has anti-tumourigenic effects [22-24]. Our data showed that in cervical intraepithelial lesions, levels of hTERC amplification were correlated with telomerase activity and hTERT expression. "
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    ABSTRACT: BackgroundHuman papillomavirus (HPV) infection plays an etiological role in the development of cervical dysplasia and cancer. Amplification of human telomerase gene (hTERC) and over expression of telomerase were found to be associated with cervical tumorigenesis. This study was performed to analyze genomic amplification of hTERC gene, telomerase activity in association with HPV infection in different stages of cervical intraepithelial neoplasia (CIN) and cervical cancer. We were studying the role of hTERC in the progression of uterine cervical dysplasia to invasive cancer, and proposed an adjunct method for cervical cancer screening.MethodsExfoliated cervical cells were collected from 114 patients with non neoplastic lesion (NNL, n=27), cervical intraepithelial neoplasia (CIN1, n=26, CIN2, n=16, CIN3, n=24) and cervical carcinoma (CA, n=21), and analyzed for amplification of hTERC with two-color fluorescence in situ hybridization (FISH) probe and HPV-DNA with Hybrid Capture 2.From these patients, 53 were taken biopsy to analyze telomerase activity by telomeric repeat amplification protocol (TRAP) and expression of human telomerase reverse transcriptase (hTERT), with immunohistochemistry (IHC). All biopsies were clinically confirmed by phathologists.ResultsAmplification of hTERC was significantly associated with the histologic diagnoses (p<0.05). The positive correlation was found between the level of hTERC amplification and histologic grading of dysplasia (CIN2/3 from CIN1 or normal, P=0.03). A profounding increase in the accumulation of HPV and hTERC positive cases was observed in the CIN3 subgroup compared with the CIN2 group, 25% versus 62.96%, respectively (p=0.007).ConclusionshTERC ampliffication can be detected with FISH technique on exfoliated cervical cells. Amplification of hTERC and HPV infection are associated with more progressive CIN3 and CA. The testing of hTERC amplification might be a supplementary to cytology screening and HPV test, especially high-risk patients.Virtual slidesThe virtual slide(s) for this article can be found here:
    Diagnostic Pathology 10/2012; 7(1):147. DOI:10.1186/1746-1596-7-147 · 2.60 Impact Factor
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