Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-gamma induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression.
Constitutive activation of the telomerase is a key step in the development of human cancers. Interferon-gamma (IFN-gamma) signaling induces growth arrest in many tumors through multiple regulatory mechanisms. In this study, we show that IFN-gamma signaling represses telomerase activity and human telomerase reverse transcriptase (hTERT) transcription, and suggest that this signaling is mediated by IRF-1. Ectopic expression of IRF-1 attenuated hTERT promoter activity. Murine embryonic fibroblasts (MEFs) genetically deficient in IRF-1 (IRF-1(-/-)) showed an elevated level (>15 times) of hTERT promoter activity as compared to the hTERT promoter activity of wild-type MEFs. The telomerase activity and hTERT expression in IRF-1(-/-) MEFs were downregulated by IRF-1 transfection. Interestingly, less extent of telomerase repression was observed in HPV E6 and E7 negative, p53 mutant HT-3 cells than in HPV 18 E6 and E7 positive HeLa cells (intact p53). These findings provide evidence that IRF-1 is a potential mediator of IFN-gamma-induced attenuation of telomerase activity and hTERT expression.
Lee
Seung-Hoon
SH
Molecular Therapy Research Center, College of Medicine, Sungkyunkwan University, Samsung Medical Center Annex 8F, Seoul, Korea.
Kim
Jung-Whan
JW
Lee
Han-Woong
HW
Cho
Yong-Suk
YS
Oh
Sun-Hee
SH
Kim
Yong-Jin
YJ
Jung
Chul-Ho
CH
Zhang
Wei
W
Lee
Je-Ho
JH
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts; D016193:G1 Phase / Q000235:genetics; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D007371:Interferon-gamma; D019098:Telomerase