Telomerase contributes to tumorigenesis by a telomere length-independent mechanism.
Once immortalized, human cells are susceptible to transformation by introduction of an oncogene such as ras. Several lines of evidence now suggest that the maintenance of telomere length is a major determinant of replicative lifespan in human cells and thus of the immortalized state. The majority of human tumor cells acquire immortality through expression of the catalytic subunit of telomerase (hTERT), whereas others activate an alternative mechanism of telomere maintenance (ALT) that does not depend on the actions of telomerase. We have examined whether ALT could substitute for telomerase in the processes of transformation in vitro and tumorigenesis in vivo. Expression of oncogenic H-Ras in the immortal ALT cell line GM847 did not result in their transformation. However, subsequent ectopic expression of hTERT in these cells imparted a tumorigenic phenotype. Indeed, this outcome was also observed after introduction of a mutant hTERT that retained catalytic activity but was incapable of maintaining telomere length. These studies indicate that hTERT confers an additional function that is required for tumorigenesis but does not depend on its ability to maintain telomeres.
Stewart
Sheila A
SA
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Hahn
William C
WC
O'Connor
Benjamin F
BF
Banner
Elisa N
EN
Lundberg
Ante S
AS
Modha
Poonam
P
Mizuno
Hana
H
Brooks
Mary W
MW
Fleming
Mark
M
Zimonjic
Drazen B
DB
Popescu
Nicholas C
NC
Weinberg
Robert A
RA
D015153:Blotting, Western; D002384:Catalysis; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D007621:Karyotyping; D007700:Kinetics; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D019098:Telomerase / Q000502:physiology*; D016615:Telomere / Q000201:enzymology / Q000502:physiology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D019098:Telomerase; D005947:Glucose; D010100:Oxygen