Tanaka H, Shimizu M, Horikawa I, Kugoh H, Yokota J, Barrett J C, Oshimura M
Department of Molecular and Cell Genetics, School of Life Sciences, Faculty of Medicine, Tottori University, Yonago, Japan.
Genes Chromosomes Cancer. 1998 Oct;23(2):123-33. doi: 10.1002/(sici)1098-2264(199810)23:2<123::aid-gcc5>3.0.co;2-4.
Telomeres, which are the repeated sequences located on both ends of chromosomes in eukaryotes, are known to shorten with each cell division, and their eventual loss is thought to result in cellular senescence. Unlike normal somatic cells, most tumor cells show activation of telomerase, a ribonucleoprotein enzyme that stably maintains telomere length by addition of the sequences of TTAGGG repeats to telomeres. The KC12 cell line derived from a renal cell carcinoma in a patient with von Hippel-Lindau disease showed telomerase activity and loss of heterozygosity on the short arm of chromosome 3. Introduction of a normal human chromosome 3 into KC12 cells by microcell fusion induced cellular senescence, accompanied by suppression of telomerase activity and shortening of telomere length. Microcell hybrids that escaped from cellular senescence maintained telomere length and telomerase activity similar to those of the parental KC12 cells. We previously showed a similar suppression of telomerase activity by introduction of chromosome 3 into another renal cell carcinoma cell line, RCC23. The putative telomerase repressor gene was mapped to chromosome region 3p14.2-p21.1 by deletion mapping of KC12 + chromosome 3 revertants that escaped from cellular senescence and by transfer of subchromosomal fragments of chromosome 3 into RCC23 cells.
端粒是真核生物染色体两端的重复序列，已知其会随着细胞每次分裂而缩短，并且其最终缺失被认为会导致细胞衰老。与正常体细胞不同，大多数肿瘤细胞表现出端粒酶的激活，端粒酶是一种核糖核蛋白酶，通过向端粒添加TTAGGG重复序列来稳定维持端粒长度。源自一名患有冯·希佩尔-林道病患者的肾细胞癌的KC12细胞系表现出端粒酶活性以及3号染色体短臂上的杂合性缺失。通过微细胞融合将一条正常人类3号染色体导入KC12细胞可诱导细胞衰老，同时伴随着端粒酶活性的抑制和端粒长度的缩短。逃脱细胞衰老的微细胞杂种维持着与亲本KC12细胞相似的端粒长度和端粒酶活性。我们之前表明，将3号染色体导入另一个肾细胞癌细胞系RCC23也会对端粒酶活性产生类似的抑制作用。通过对逃脱细胞衰老的KC12 + 3号染色体回复体进行缺失作图，并将3号染色体的亚染色体片段转移到RCC23细胞中，将假定的端粒酶抑制基因定位到染色体区域3p14.2 - p21.1。
