Constitutive Expression of Tert in Thymocytes Leads to Increased Incidence and Dissemination of T-Cell Lymphoma in Lck-Tert Mice

Canela, Andrés; Juan, Manel; Flores, Juana M.; Blasco, Marı́a A.

doi:10.1128/mcb.24.10.4275-4293.2004

Cited by 84 publications

(60 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…K5-mTert mice also show an increased susceptibility to both induced and spontaneous tumorigenesis when compared to wild-type mice (GonzalezSuarez et al, 2001(GonzalezSuarez et al, , 2002. Similarly, two independent telomerase transgenic mouse models, Lck-mTert mice (Tert is overexpressed in thymocytes) and b-actin-mTert mice (Tert is ubiquitously expressed) also showed increased tumors with age (Artandi et al, 2002;Canela et al, 2004). All together, these findings suggest that telomerase has a role in promoting tumorigenesis at the same time that it may prevent or delay some pathologies associated with aging by increasing tissue fitness.…”

Section: Discussionmentioning

confidence: 64%

Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice

et al. 2005

View full text Add to dashboard Cite

Many degenerative diseases that occur with aging, as well as premature aging syndromes, are characterized by presenting cells with critically short telomeres. Telomerase reintroduction is envisioned as a putative therapy for diseases characterized by telomere exhaustion. K5-mTert transgenic mice overexpress telomerase in a wide spectrum of tissues. These mice have a higher incidence of both induced and spontaneous tumors, resulting in increased mortality during the first year of life. Here, we show that in spite of this elevated tumor incidence and the initial lower survival, K5-mTert mice show an extension of the maximum lifespan from 1.5 to 3 months, depending on the transgenic line, which represents up to a 10% increase in the mean lifespan compared to wild-type littermates. This longer lifespan is coincidental with a lower incidence of certain age-related degenerative diseases, mainly those related to kidney function and germline integrity. Importantly, these effects of telomerase overexpression cannot be attributed to dramatic differences in telomere length in aged K5-Tert mice compared to wild-type mice, as shown by quantitative telomeric FISH. These findings indicate that telomerase overexpression extends the maximum lifespan of mice.

show abstract

Section: Discussionmentioning

confidence: 64%

Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice

et al. 2005

View full text Add to dashboard Cite

show abstract

“…An in vivo experiment also showed that p53 mutant transgenic mice expressing mTERT had high tumor incidence on exposure to chemical carcinogenesis, which was also a tumorigenic process independent of telomere elongation (20). Moreover, it was reported that high levels of telomerase expression in mouse T cells may lead to spontaneous T-cell lymphoma, without telomere lengthening (21). All these evidences support the hypothesis that expression of telomerase may affect cancer-related genes and biological pathways and consequently initiate and promote tumorigenesis.…”

Section: Discussionmentioning

confidence: 96%

Differential Induction in Telomerase Activity among Bladder Cancer Patients and Controls on γ-Radiation

Xing

Zhu

Zhao³

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Expression of telomerase is one of the hallmarks of tumor cells and has been used as a diagnostic biomarker and a therapeutic target in cancer. Novel findings have shown that telomerase activation in normal human epithelial cells may affect expression of several cancer-related genes, such as growth-related genes and c-myc gene, suggesting a possible role of telomerase in tumor initiation. Therefore, we hypothesized that individuals who are sensitive to mutagen challenge in terms of induced telomerase activity might have increased cancer risk. We tested this hypothesis in a bladder cancer case-control study (51 cases and 51 matched controls) by measuring baseline and ;-radiation -induced telomerase activities in peripheral blood lymphocytes. We found a significantly higher ;-radiation -induced telomerase activity in bladder cancer cases compared with the controls (1.34 versus 1.23; P = 0.044). A similar finding was also observed using the normalized telomerase activity (ratio of ;-radiation induced versus baseline; 1.49 versus 1.19; P < 0.001). In further categorizing the telomerase activity using 75% of the normalized value in the controls as a cutoff point, we found a significantly increased risk for bladder cancer associated with higher induced telomerase activity (adjusted odds ratio, 3.62; 95% confidence interval, 1.38-9.51). In quartile analysis, a dose-response association was noted between the induced telomerase activity and increased bladder cancer risk (P trend = 0.005). Our findings provide the first evidence linking the mutagen-induced telomerase activity in peripheral blood lymphocytes to the risk of bladder cancer, which warrants further investigation in large-sized studies and other cancer types. (Cancer Epidemiol Biomarkers Prev 2007;16(3):606 -9)

show abstract

“…In some multicellular organisms, including humans, telomerase is repressed in normal somatic tissues but activated in cancer cells, and is believed to promote tumor growth (15). Although the two core components of telomerase are generally assumed to act in concert to replenish telomeres, there is increasing evidence that the TERT protein can have physiologic effects that are independent of telomere length and telomerase RNA (16)(17)(18)(19). For instance, in mice, TERT overexpression in the absence of telomerase RNA was reported to have an inhibitory effect on tumorigenesis and wound healing (20).…”

mentioning

confidence: 99%

Telomerase can act as a template- and RNA-independent terminal transferase

Lue

Bosoy

Moriarty

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Telomerase is a special reverse transcriptase that extends one strand of the telomere repeat by using a template embedded in an RNA subunit. Like other polymerases, telomerase is believed to use a pair of divalent metal ions (coordinated by a triad of aspartic acid residues) for catalyzing nucleotide addition. Here we show that, in the presence of manganese, both yeast and human telomerase can switch to a template-and RNA-independent mode of DNA synthesis, acting in effect as a terminal transferase. Even as a terminal transferase, yeast telomerase retains a species-dependent preference for GT-rich, telomere-like DNA on the 5 end of the substrate. The terminal transferase activity of telomerase may account for some of the hitherto unexplained effects of telomerase overexpression on cell physiology.reverse transcriptase ͉ telomere ͉ divalent metal ion T elomerase is a ribonucleoprotein responsible for the synthesis of one strand of the telomere terminal repeat. The catalytic core of telomerase consists minimally of two components: an RNA in which the template is embedded (named TLC1 in the budding yeast Saccharomyces cerevisiae), and a reverse transcriptase (RT)-like protein that mediates catalysis (named TERT in general and Est2p in yeast) (1-4). Telomerase RNAs from different organisms are divergent in sequence but share conserved secondary structural elements (5, 6). Many mutations in nontemplate regions of telomerase RNA reduced enzyme activity, suggesting that these regions contribute important catalytic functions [although the precise nature of the contribution(s) is not clear] (7-9). Other RNA structures act to define the boundary of the template segment that supports reverse transcription (10, 11). Thus, the RNA subunit serves multiple essential roles in the course of a normal telomerase reaction. The TERT protein is well conserved in evolution and comprises a central RT domain that is flanked on both the N-and C-terminal side by telomerase-specific motifs (4, 12, 13). Mutational analysis indicates that these motifs are likely to mediate binding to telomeric DNA and telomerase RNA. Direct recognition of telomeric DNA by TERT is believed to be sequence-dependent and to allow telomerase to catalyze the addition of multiple repeats without dissociation from the DNA (13,14).In unicellular organisms, telomerase is constitutively active and required for the long-term proliferation of cells. In some multicellular organisms, including humans, telomerase is repressed in normal somatic tissues but activated in cancer cells, and is believed to promote tumor growth (15). Although the two core components of telomerase are generally assumed to act in concert to replenish telomeres, there is increasing evidence that the TERT protein can have physiologic effects that are independent of telomere length and telomerase . For instance, in mice, TERT overexpression in the absence of telomerase RNA was reported to have an inhibitory effect on tumorigenesis and wound healing (20). The mechanisms for such effects are currently no...

show abstract

Constitutive Expression of Tert in Thymocytes Leads to Increased Incidence and Dissemination of T-Cell Lymphoma in Lck-Tert Mice

Cited by 84 publications

References 32 publications

Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice

Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice

Differential Induction in Telomerase Activity among Bladder Cancer Patients and Controls on γ-Radiation

Telomerase can act as a template- and RNA-independent terminal transferase

Contact Info

Product

Resources

About