Repression of the telomerase catalytic subunit by a gene on human chromosome 3 that induces cellular senescence.
The cellular senescence program is controlled by multiple genetic pathways, one of which involves the regulation of telomerase and telomere shortening. The introduction of a normal human chromosome 3 into the human renal cell carcinoma cell line RCC23 caused repression of telomerase activity, progressive shortening of telomeres, and restoration of the cellular senescence program. We attributed the repression of telomerase activity to the marked downregulation of the gene encoding the catalytic subunit of telomerase (hEST2/hTRT) but not another protein component (TP1/TLP1) or the RNA component of telomerase. These results suggest that a senescence-inducing gene on chromosome 3 controls hEST2/hTRT gene expression either directly or indirectly and support the notion that hEST2/hTRT is the major determinant of telomerase enzymatic activity in human cells.
Horikawa
I
I
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Oshimura
M
M
Barrett
J C
JC
D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016922:Cellular Senescence / Q000502:physiology; D002893:Chromosomes, Human, Pair 3; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012313:RNA; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011506:Proteins; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase