Differentiation of immortal cells inhibits telomerase activity.

Abstract

Telomerase, a ribonucleic acid-protein complex, adds hexameric repeats of 5'-TTAGGG-3' to the ends of mammalian chromosomal DNA (telomeres) to compensate for the progressive loss that occurs with successive rounds of DNA replication. Although somatic cells do not express telomerase, germ cells and immortalized cells, including neoplastic cells, express this activity. To determine whether the phenotypic differentiation of immortalized cells is linked to the regulation of telomerase activity, terminal differentiation was induced in leukemic cell lines by diverse agents. A pronounced downregulation of telomerase activity was produced as a consequence of the differentiated status. The differentiation-inducing agents did not directly inhibit telomerase activity, suggesting that the inhibition of telomerase activity is in response to induction of differentiation. The loss of telomerase activity was not due to the production of an inhibitor, since extracts from differentiated cells did not cause inhibition of telomerase activity. By using additional cell lineages including epithelial and embryonal stem cells, downregulation of telomerase activity was found to be a general response to the induction of differentiation. These findings provide the first direct link between telomerase activity and terminal differentiation and may provide a model to study regulation of telomerase activity.The ends of eukaryotic chromosomes, called telomeres, consist of an array of tandem repeats of the hexanucleotide 5'-TTAGGG-3'. It is currently assumed that telomeres were evolved to protect the ends of chromosomes against exonucleases and ligases, to prevent the activation of DNA-damage checkpoints, and to counter the loss of terminal DNA segments that occurs when linear DNA is replicated (for a review, see refs.

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

“…Indeed, although some variations of their expression could occur (Reichman et al, 1997), mRNAs encoding the other known enzymatic subunits are nearly ubiquitously expressed in telomerase negative cells Takakura et al, 1998). Down-regulation of telomerase activity has been found to be a frequent response to the induction of di erentiation of immortalized cell lines and generally linked to a decrease of mRNA encoding the catalytic subunit of the enzyme, TERT (Holt et al, 1996;Kruk et al, 1996;Sharma et al, 1995;Xu et al, 1999). We also found that downregulation of telomerase activity both in vivo, in mouse cortices, and in vitro, during NPC di erentiation, was directly linked to the down regulation of mTERT mRNA synthesis.…”

Telomerase activity in a specific cell subset co-expressing integrinβ1/EGFR but not p75NGFR/bcl2/integrin β4 in normal human epithelial cells

“…Recent studies argue that telomerase activity is regulated in the cell cycle, because the activity is linked to the proliferative potential and declines when the cells exit the cell cycle in the process of di erentiation (Sharma et al, 1995;Holt et al, 1996;Albannell et al, 1996;Bestilny et al, 1996). By using a synchronized cell population, it was also shown that telomerase activity was regulated in the cell cycle (Zhu et al, 1996).…”

“…One of underlying questions is whether telomerase activity could be regulated during the course of cell growth and di erentiation. Recently, it was shown that telomerase activity was downregulated when cell growth was inhibited by cell cycle inhibitors (Zhu et al, 1996) or the cells became quiescent in vitro (Sharma et al, 1995;Albannell et al, 1996;Bestilny et al, 1996;Holt et al, 1996). These previous studies suggest that telomerase activity is regulated in the process of cell growth and differentiation.…”

Regulation of telomerase activity by the p53 family member p73

“…In the absence of telomerase activity and hTERT expressiona state reported for the majority of somatic cellstelomeric DNA erodes progressively with each round of cell division and eventually leads cells into senescence or into crisis, which results in cell death (Harley et al, 1990). In contrast, undifferentiated progenitor cells in many different self-renewing tissues express telomerase, supporting the hypothesis that differentiating cells turn off telomerase, which may contribute to limiting their replicative potential (Sharma et al, 1995). An unlimited replicative potential is one hallmark of cancer cells (Hanahan and Weinberg, 2000).…”

“…Here, we have shown that induction of TAp73 expression by E2F1 triggers hTERT repression in H1299 cells. Furthermore, hTERT expression is known to be downregulated both by cellular stress and during the terminal differentiation of progenitor cells when TAp73 expression is induced, suggesting that TAp73 might also play a causal role in hTERT regulation under these conditions (Sharma et al, 1995;Xu et al, 1996). Considering that p73 loss predisposes mice to various types of cancer (Flores et al, 2005), it is intriguing to speculate that p73 haploinsufficiency might result in elevated levels of mTERT, thus selecting for cells that have acquired the proper genetic hits to become cancerous.…”