title: JAK-STAT and JAK-PI3K-mTORC1 pathways regulate telomerase transcriptionally and posttranslationally in ATL cells.
abstract: Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2-regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1-3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2-dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2-stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2-induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2-stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2-dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2-induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/mTORC1 pathway in IL-2-responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2-dependent ATL.
authors.affiliation: Medical Research Institute and Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan. yamadao@lab.twmu.ac.jp
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamada
authors.forename: Kohji
authors.initials: K
authors.lastname: Ozaki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akiyama
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kawauchi
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D053612:Janus Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D050791:STAT Transcription Factors; D050799:STAT5 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase