Sharma H W, Sokoloski J A, Perez J R, Maltese J Y, Sartorelli A C, Stein C A, Nichols G, Khaled Z, Telang N T, Narayanan R
Division of Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12343-6. doi: 10.1073/pnas.92.26.12343.
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, down-regulation 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.
端粒酶是一种核糖核酸 - 蛋白质复合物，它将5'-TTAGGG-3'的六聚体重复序列添加到哺乳动物染色体DNA（端粒）的末端，以补偿连续几轮DNA复制过程中发生的渐进性损失。虽然体细胞不表达端粒酶，但生殖细胞和永生化细胞，包括肿瘤细胞，都表达这种活性。为了确定永生化细胞的表型分化是否与端粒酶活性的调节有关，通过多种试剂诱导白血病细胞系发生终末分化。分化状态导致端粒酶活性明显下调。分化诱导剂并未直接抑制端粒酶活性，这表明端粒酶活性的抑制是对分化诱导的反应。端粒酶活性的丧失并非由于产生了抑制剂，因为分化细胞的提取物并未导致端粒酶活性受到抑制。通过使用包括上皮细胞和胚胎干细胞在内的其他细胞谱系，发现端粒酶活性的下调是对分化诱导的普遍反应。这些发现首次提供了端粒酶活性与终末分化之间的直接联系，并可能为研究端粒酶活性的调节提供一个模型。
