DIFFERENTIATION OF IMMORTAL CELLS INHIBITS TELOMERASE ACTIVITY

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 rou nds of DNA replication. Although somatic cells do not express telomera se, germ cells and immortalized cells, including neoplastic cells, exp ress this activity. To determine whether the phenotypic differentiatio n of immortalized cells is linked to the regulation of telomerase acti vity, terminal differentiation was induced in leukemic cell lines by d iverse agents. A pronounced downregulation of telomerase activity was produced as a consequence of the differentiated status. The differenti ation-inducing agents did not directly inhibit telomerase activity, su ggesting 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 differentia ted cells did not cause inhibition of telomerase activity, By using ad ditional cell lineages including epithelial and embryonal stem cells, down-regulation of telomerase activity was found to be a general respo nse to the induction of differentiation. These findings provide the fi rst direct link between telomerase activity and terminal differentiati on and may provide a model to study regulation of telomerase activity.