IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells.
Human telomerase activity is induced by Ag receptor ligation in T and B cells. However, it is unknown whether telomerase activity is increased in association with activation and proliferation of NK cells. We found that telomerase activity in a human NK cell line (NK-92), which requires IL-2 for proliferation, was increased within 24 h after stimulation with IL-2. Levels of human telomerase reverse transcriptase (hTERT) mRNA and protein correlated with telomerase activity. ERK1/2 and Akt kinase (Akt) were activated by IL-2 stimulation. LY294002, an inhibitor of PI3K, abolished expression of hTERT mRNA and protein expression and abolished hTERT activity, whereas PD98059, which inhibits MEK1/2 and thus ERK1/2, had no effect. In addition, radicicol, an inhibitor of heat shock protein 90 (Hsp90), and rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), blocked IL-2-induced hTERT activity and nuclear translocation of hTERT but not hTERT mRNA expression. hTERT was coimmunoprecipitated with Akt, Hsp90, mTOR, and p70 S6 kinase (S6K), suggesting that these molecules form a physical complex. Immunoprecipitates of Akt, Hsp90, mTOR, and S6K from IL-2-stimulated NK-92 cells contained telomerase activity. Furthermore, the findings that Hsp90 and mTOR immunoprecipitates from primary samples contained telomerase activity are consistent with the results from NK-92 cells. These results indicate that IL-2 stimulation induces hTERT activation and that the mechanism of IL-2-induced hTERT activation involves transcriptional or posttranslational regulation through the pathway including PI3K/Akt, Hsp90, mTOR, and S6K in NK cells.
Pubmed ID: 15843522 RIS Download
Cell Line, Transformed | Chromones | DNA-Binding Proteins | Enzyme Inhibitors | Extracellular Signal-Regulated MAP Kinases | Flavonoids | HSP90 Heat-Shock Proteins | Humans | Interleukin-2 | Killer Cells, Natural | Lactones | Leukemia, Lymphocytic, Chronic, B-Cell | Leukemia, Lymphoid | Lymphocyte Activation | Macrolides | Morpholines | Phosphatidylinositol 3-Kinases | Protein Kinases | Protein Processing, Post-Translational | Protein-Serine-Threonine Kinases | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-akt | RNA-Directed DNA Polymerase | Ribosomal Protein S6 Kinases, 70-kDa | Sirolimus | TOR Serine-Threonine Kinases | Telomerase | Transcription, Genetic