IFN-gamma/IRF-1-induced p27kip1 down-regulates telomerase activity and human telomerase reverse transcriptase expression in human cervical cancer.
Telomerase activation is regulated by the expression of human telomerase reverse transcriptase (hTERT) and 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. The p27 tumor suppressor protein inhibits the formation of tumors through the induction of cell cycle arrest and/or apoptosis. We demonstrate here that p27Kip1 inhibits hTERT mRNA expression and telomerase activity through post-transcriptional up-regulation by IFN-gamma/IRF-1 signaling. The ectopic expression of p27 suppressed hTERT expression and telomerase activity in human cervical cancer cell lines, HeLa and HT3. Furthermore, hTERT promoter activity of mouse embryonic fibroblasts (MEFs) deficient in p27 (p27-/- MEFs) was significantly higher than that of wild-type MEFs. Overexpression of p27 suppressed hTERT promoter activity and telomerase activity of p27-/- MEFs. In addition p27 down-regulated E7 protein expression and in transiently transfected HeLa cells, E7 increased hTERT promoter activity. In conclusion, we propose that inhibition of the hTERT expression and telomerase activity may be a novel tumor suppressor function of p27.
Lee
Seung-Hoon
SH
Molecular Therapy Research Center, School of Medicine, Sungkyunkwan University, Samsung Medical Center Annex 8F, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea.
Kim
Jung-Whan
JW
Oh
Sun-Hee
SH
Kim
Yong-Jin
YJ
Rho
Seung-Bae
SB
Park
Kyungsook
K
Park
Kui-Lea
KL
Lee
Je-Ho
JH
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007371:Interferon-gamma; D019098:Telomerase