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.
Kawauchi
Kiyotaka
K
Department of Medicine, Daini Hospital, Tokyo Women's Medical University, Arakawa-ku, Tokyo, Japan.
Ihjima
Kimiko
K
Yamada
Osamu
O
D002461:Cell Line, Transformed; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology; D007945:Leukemia, Lymphoid / Q000201:enzymology; D008213:Lymphocyte Activation / Q000276:immunology; D018942:Macrolides; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000276:immunology*
D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D018841:HSP90 Heat-Shock Proteins; D007376:Interleukin-2; D007783:Lactones; D018942:Macrolides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012194:RNA-Directed DNA Polymerase; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human; C494918:AKT1 protein, human; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; C035359:monorden; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one