Autocrine transforming growth factor beta suppresses telomerase activity and transcription of human telomerase reverse transcriptase in human cancer cells.
Because autocrine transforming growth factor beta (TGF-beta) can suppress carcinogenesis, which is often associated with telomerase activation, we studied whether autocrine TGF-beta inhibits telomerase activity. Restoration of autocrine TGF-beta activity in human colon carcinoma HCT116 cells after reexpression of its type II receptor (RII) led to a significant reduction of telomerase activity and the mRNA level of telomerase reverse transcriptase (hTERT), whereas suppression of the autocrine TGF-beta activity with a dominant negative RII without the cytoplasmic domain (deltaRII) in human breast cancer MCF-7 cells led to a significant increase of telomerase activity and hTERT mRNA level. This appears to be due to repression of hTERT mRNA transcription because exogenous TGF-beta treatment of MCF-7 cells transiently transfected with a hTERT promoter-reporter construct significantly repressed the hTERT promoter activity in a dose-dependent manner. Furthermore, the hTERT promoter activity was significantly decreased in HCT116 RII cells and increased in MCF-7 deltaRII cells when compared with their respective controls. Therefore, autocrine TGF-beta appears to target hTERT promoter to inhibit telomerase activity.
Department of Surgery, University of Texas Health Science Center at San Antonio, 78229-3900, USA.
H
H
Yang
S
S
Kyo
M
M
Takatura
L
L
Sun
D019898:Autocrine Communication / Q000502:physiology*; D001943:Breast Neoplasms / Q000503:physiopathology*; D003110:Colonic Neoplasms / Q000503:physiopathology*; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D012313:RNA; D012333:RNA, Messenger / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase