IFN‐γ/IRF‐1‐induced p27^kip1 down‐regulates telomerase activity and human telomerase reverse transcriptase expression in human cervical cancer

Abstract

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-c (IFN-c) 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 p27 Kip1 inhibits hTERT mRNA expression and telomerase activity through post-transcriptional up-regulation by IFN-c/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 (p27À/À MEFs) was significantly higher than that of wild-type MEFs. Overexpression of p27 suppressed hTERT promoter activity and telomerase activity of p27À/À 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.

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

“…IFNg inhibits cell proliferation via cell type-specific pathways that involve CKIs, such as p21Cip1 (29,30) and p27Kip1 (31,32). It has been shown that STAT1 interacts directly with cyclin D1/ Cdk4 and mediates the cell-cycle arrest of human U3A cells (33).…”

“…Mice transgenic for the pmel-1-TCR, which recognizes the H-2D b -restricted epitope EGSRNQDWL from gp100 (gp100 [25][26][27][28][29][30][31][32][33] ), were obtained from The Jackson Laboratory. All mice were housed in a pathogen-free environment, and all animal procedures were conducted in accordance with institutional guidelines.…”

“…All animal experiments were approved by the University of Tokyo Ethics Committee for Animal Experiments (10-P-127). The H-2D brestricted peptide human gp100 (hgp100 [25][26][27][28][29][30][31][32][33] , KVPRNQDWL) was purchased from GenScript Japan at a purity of >90%, with free amino and carboxyl terminals. B16F10, FBL3, and 3LL cell lines were maintained in culture medium consisting of DMEM with 10% FCS, 100 U/mL penicillin, and 100 mg/mL streptomycin.…”

Anti-proliferation Effects of Interferon-gamma on Gastric Cancer Cells

“…IFN-γ may directly or indirectly affect apoptosis of some cancer cells (Wagner et al, 1997;Tu et al, 2011;Ni et al, 2013), such as glioma cells (Rajiv et al, 2008), multiple myeloma cells and cervical cancer cells (Lee et al, 2005;Lindkvist et al, 2006). It can also induce aging of human endothelial cells, thus leading to cell cycle change (Kim et al, 2009), and 1 * affect the expression of genes such as Secretoglobin 3A1 (SCGB3A1) (Yamada et al, 2009), osteopontin (OPN) (Xinfang et al, 2003), CXCR3 binding chemokine IP-10 (CXCL10) (Yeruva et al, 2008), and the phosphorylation of signal transducer and activator of transcription (STAT1), for example (Mitchell et al, 2004).…”

MicroRNA-222 promotes the proliferation and migration of cervical cancer cells

“…Mice de cient in p27 exhibit increased susceptibility to tumor progression, and tumorigenecity is accelerated in Rb +/-p27 -/-and p18INK4c -/-p27 -/-mice [22], suggesting that p27 Kip1 is a rate-limiting factor for tumorigenesis. Lee et al found the direct evidence related to the e ect of p27 on hTERT expression in both human CC cells and primary MEFs de cient in p27 [23]. In the present study, the HeLa and SiHa cells were independently transfected with miR-222 to interfere with the miR-222 expression.…”