Abstract
The aim of the present study was to investigate the effect of transforming growth factor-beta1 (TGF-beta1) on telomerase activity in a panel of human anaplastic thyroid carcinoma (ATC) cell lines. Addition of TGF-beta1 decreased the telomerase activity in HTh 74 and KTC-1 cells, while in C 643 and HTh 7 an increased activity was observed. The decreased telomerase activity appeared to be due to transcriptional repression of the hTERT promoter. Addition of a PI-3 kinase inhibitor (LY294002) abrogated the stimulatory effect of TGF-beta1 on the telomerase activity, indicating the possible involvement of hTERT activation via phosphorylation. Furthermore, the MEK-inhibitor U0126 had similar effects suggesting dual regulatory mechanisms. Interestingly, the cell lines differed genetically in that ATC cell lines responding with increased telomerase activity harbored a p53 mutation. In conclusion, TGF-beta1 exerts opposing effects on telomerase activity in ATC cell lines, possibly reflecting deregulation of TGF-beta1 signaling in a more malignant genotype.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Down-Regulation / drug effects
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Genotype
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Humans
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mutation / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Promoter Regions, Genetic / genetics
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-myc / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Telomerase / genetics
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Telomerase / metabolism*
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Thyroid Neoplasms / enzymology*
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / metabolism
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
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Tumor Suppressor Protein p53 / genetics
Substances
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MYC protein, human
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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TGFB1 protein, human
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Suppressor Protein p53
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Mitogen-Activated Protein Kinase Kinases
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Telomerase