Evidence for inactivation of distinct telomerase repressor genes in different types of human cancers.
Telomerase activation, a critical event in human carcinogenesis, may result from defects in telomerase-repressing mechanisms. Data from microcell-mediated chromosome transfer (MMCT) suggests the presence of telomerase repressor genes that become inactivated during carcinogenic processes. The transfer of a normal human chromosome 3 represses telomerase activity of both human renal cell carcinoma (RCC) and breast carcinoma (BC) cells. For a genetic complementation analysis of telomerase repression, 2 RCC cell lines (KC12 and RCC23) and a BC cell line (21NT) were used to make somatic cell hybrids. All of the self-hybrids (KC12 x KC12 and 21NT x 21NT) and hybrids from 2 RCC cell lines (KC12 x RCC23) expressed the telomerase activity similarly to their parental cells, excluding the possibility of a ploidy-associated change in telomerase activity and suggesting the same genetic defect shared by the 2 RCC cell lines. In contrast, the fusion of BC and RCC cells (21NT x KC12 and 21NT x RCC23) produced a significant number of telomerase-negative hybrids, suggesting that the RCC and BC cells have different defects in the telomerase repression, which are functionally corrected through genetic complementation in the hybrids. This notion was supported by the mapping of the RCC telomerase repressor gene to a 5.7-Mb region on 3p21, which is different from the candidate region for the BC telomerase repressor gene on the same chromosomal band. These findings provide direct evidence for inactivation of distinct telomerase repressor genes in different types of human cancers and may have implications in the tissue-specific regulation of telomerase during human development and carcinogenesis.
Tanaka
Hiromi
H
Department of Molecular and Cell Genetics, School of Life Sciences, Faculty of Medicine, Tottori University, Tottori, Japan. hirtanak@iupui.edu
Horikawa
Izumi
I
Barrett
J Carl
JC
Oshimura
Mitsuo
M
D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*
D012097:Repressor Proteins; D019098:Telomerase