Essential role of mouse telomerase in highly proliferative organs

Abstract

We have investigated the role of the enzyme telomerase in highly proliferative organs in successive generations of mice lacking telomerase RNA. Late-generation animals exhibited defective spermatogenesis, with increased programmed cell death (apoptosis) and decreased proliferation in the testis. The proliferative capacity of haematopoietic cells in the bone marrow and spleen was also compromised. These progressively adverse effects coincided with substantial erosion of telomeres (the termini of eukaryotic chromosomes) and fusion and loss of chromosomes. These findings indicate an essential role for telomerase, and hence telomeres, in the maintenance of genomic integrity and in the long-term viability of high-renewal organ systems.

Aging by epigenetics—A consequence of chromatin damage?

“…Specifically, senescent cells and/or molecular markers of the senescent phenotype have been reported to increase in some aging tissues [40,41,[64][65][66][67][68][69], and are linked to some age-associated tissue pathologies, such as osteoarthritis, atherosclerosis and liver cirrhosis [70][71][72]. Moreover, manipulation of the cell signals that initiate senescence, such as telomere length and expression of the proliferation inhibitor p16INK4a [66][67][68]70,[73][74][75][76][77][78][79][80], can modulate some aspects of organismal aging [70][71][72]. In addition to a likely role in tissue aging, cellular senescence is also a well-established tumor suppression process, by virtue of its ability to arrest proliferation and neoplastic progression of cells harboring oncogenic lesions [81][82][83][84][85][86][87].…”

TGF-β and cancer: Is Smad3 a repressor of hTERT gene?

“…Expression of hTERT stimulates cell proliferation toward immortality [12][13][14][15][16] and contributes to tumor formation [17,18]. In contrast, inhibition of telomerase results in erosion of telomeres, compromise of growth capacity and apoptosis of highly proliferative cells [19][20][21][22][23][24]. Thus, hTERT is essentially a key element in telomerase activation, telomere maintenance and tumor development, and is proposed as a promising target for anticancer therapy.…”

Fibroblast growth factor 2 up regulates telomerase activity in neural precursor cells

“…Its precise role in normal cells has not yet been fully explored. Telomerase maintenance of telomeres has been proposed to play a critical role in preserving genomic stability and long term viability of highly proliferative organ systems (Lee et al, 1998). Recent works have shown that after successive generation mice genetically de®cient for the telomerase RNA (mTER null mice) present defects in germ cell growth, uterine and intestinal villus atrophy, impaired lymphocyte mitogenesis, diminished hematopoietic reserves, ulcerative dermatitis and alteration of nervous system development (Blasco et al, 1997;Herrera et al, 1999a,b).…”