Central role of PI3K in transcriptional activation of hTERT in HTLV-I-infected cells.
The persistence of human T-cell leukemia/lymphoma virus-I (HTLV-I)-infected cells is dependent upon clonal expansion and up-regulation of telomerase (hTERT). We have previously found that in interleukin (IL)-2-independent transformed HTLV-I cells, Tax strongly activates the hTERT promoter through nuclear factor-kappaB (NF-kappaB)-mediated Sp1 and c-Myc activation. In IL-2-dependent cells and adult T-cell leukemia/lymphoma (ATLL) patient samples, however, Tax expression is very low to undetectable, yet these cells retain strong telomerase activity. This suggests the existence of compensatory mechanisms in IL-2-dependent cells and ATLL patients. In this study, we demonstrate that telomerase activity is significantly decreased upon IL-2 withdrawal in immortalized HTLV-I cell lines. Inhibition of PI3K or AKT signaling pathways reduced telomerase activity in HTLV-I cells. We found that IL-2/IL-2R signaling was associated with a PI3K-dependent/AKT-independent transcriptional up-regulation of the endogenous hTERT promoter. We found that activation of the PI3K pathway mediated cytoplasmic retention of the Wilms tumor (WTI) protein, which strongly suppressed the hTERT promoter. The importance of this regulatory pathway for telomerase expression is underscored by findings that the PI3K pathway is commonly found activated in cancer cells.
Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, Kansas City, USA.
Marcia
M
Bellon
Christophe
C
Nicot
D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D015490:HTLV-I Infections / Q000201:enzymology* / Q000235:genetics*; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019098:Telomerase / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D025721:WT1 Proteins / Q000378:metabolism
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D025721:WT1 Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase