Constitutive activation of the telomerase is a key step in the development of human cancers. Interferon-γ (IFN-γ) signaling induces growth arrest in many tumors through multiple regulatory mechanisms. In this study, we show that IFN-γ 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-γ-induced attenuation of telomerase activity and hTERT expression.
Bibliographical noteFunding Information:
We thank Dr Takashi Fujita (Tokyo Metropolitan Institute of Medical Science, Japan) for the IRF-1 DNA and Dr Seon-Woo Kim (Biostatistics Unit in Samsung Biomedical Center, Korea) for statistical analysis. This work was supported by SRC and G7 funds from the Korea Science and Engineering Foundation.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cancer Research