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.
A naturally occurring variant of the human androgen receptor (AR) named AR45 has been identified. It lacks the entire region encoded by exon 1 of the AR gene and is composed of the AR DNA‐binding domain, hinge region and ligand‐binding domain, preceded by a novel seven amino‐acid long N‐terminal extension. A survey of human tissues revealed that AR45 was expressed mainly in heart and skeletal muscle. In cotransfection experiments, AR45 inhibited AR function, an effect necessitating intact DNA‐ and ligand‐binding properties. Overexpression of AR45 reduced the proliferation rate of the androgen‐dependent LNCaP cells, in line with the repressive effects of AR45 on AR growth‐promoting function. AR45 interacted with the AR N‐terminal domain in two‐hybrid assays, suggesting that AR inhibition was due to the formation of AR–AR45 heterodimers. Under conditions where the transcriptional coactivator TIF2 or the oncogene β‐catenin were overexpressed, AR45 stimulated androgen‐dependent promoters in presence of dihydrotestosterone. AR45 activity was triggered additionally by the adrenal androgen androstenedione in presence of exogenous TIF2. Altogether, the data suggest an important role of AR45 in modulating AR function and add a novel level of complexity to the mode of action of androgens.
Here, we show that ectopic expression of the catalytic subunit of mouse telomerase (mTert) confers a growth advantage to primary murine embryonic fibroblasts (MEFs), which have very long telomeres, as well as facilitates their spontaneous immortalization and increases their colony-forming capacity upon activation of oncogenes. We demonstrate that these telomere lengthindependent growth-promoting effects of mTert overexpression require catalytically active mTert, as well as the formation of mTert/Terc complexes. The gene expression profile of mTert-overexpressing MEFs indicates that telomerase enhances growth in these cells through the repression of growth-inhibiting genes of the transforming growth factor-beta (TGF-b) signaling network. We functionally validate this result by showing that mTert abrogates the growth-inhibitory effect of TGF-b in MEFs, thus demonstrating that telomerase increments the proliferative potential of primary mouse embryonic fibroblasts by targeting the TGF-b pathway.
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