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

Abstract

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.

Transcriptional Activation of hTERT, the Human Telomerase Reverse Transcriptase, by Nuclear Factor of Activated T Cells

“…Regardless of the dose, wortmannin produced the weakest inhibition of hTERT mRNA expression, although telomerase activity was sharply decreased. This decrease in telomerase activity may be due to the inhibition of Akt, which inhibits hTERT phosphorylation and thus its activity (19). The calcineurin inhibitor FK506 inhibited hTERT expression the most (ϳ50%) (Fig.…”

“…Phosphorylation of hTERT and the resulting effects on its nuclear translocation and telomerase activity have been well described (17, 18). These post-translational modifications may explain the discrepancies between hTERT expression (19) and the reduction of telomerase activity in response to several inhibitors of cell proliferation, such as rapamycin or wortmannin (17,19,20). In normal and malignant human cells, however, a positive correlation is consistently observed between telomerase activity and hTERT mRNA expression (6, 21-23), thereby highlighting the importance of the transcriptional regulation of hTERT.…”

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

“…In addition, several other proteins have been implicated in playing direct and indirect roles regulating human telomerase activity (reviewed by Smogorzewska and de Lange [64]). These proteins include heat-shock proteins p23 and Hsp90, PinX1 and p53, with p23 and Hsp90 being implicated in facilitating hTERT folding and telomerase holoenzyme assembly [65][66][67][68]. PinX1 as a telomere-binding protein associates with hTERT/hTERC complex in vitro and inhibits telomerase activity [69][70][71].…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…IL-2 has been demonstrated to increase telomerase activity in NK cells indicated by an increase in levels of human telomerase reverse transcriptase (hTERT) mRNA, a catalytic component of telomerase. 121 IL-21 has also been demonstrated to increase NK cell longevity by maintaining telomere length, suggesting telomerase activity is taking place. 122 Considering CD8 C T cells, IL-15 has been shown to increase CD8 C memory T cell longevity by inducing telomerase activity through JAK3 and PI3K signaling pathways.…”

“…In order to do this, one must also consider the artificial 121 Decrease apoptosis 133 Reversal of anergy 138 Decrease apoptosis 134 Reversal of anergy 138,139 …”