{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T03:47:26Z","timestamp":1777088846465,"version":"3.51.4"},"reference-count":62,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,9,6]]},"abstract":"<jats:p>Interleukin (IL)-7 is essential for normal T cell development. Previously, we have shown that IL-7 increases viability and proliferation of T cell acute lymphoblastic leukemia (T-ALL) cells by up-regulating Bcl-2 and down-regulating the cyclin-dependent kinase inhibitor p27kip1. Here, we examined the signaling pathways via which IL-7 mediates these effects. We investigated mitogen-activated protein kinase (MEK)\u2013extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)\u2013Akt (protein kinase B) pathways, which have active roles in T cell expansion and have been implicated in tumorigenesis. IL-7 induced activation of the MEK\u2013Erk pathway in T-ALL cells; however, inhibition of the MEK\u2013Erk pathway by the use of the cell-permeable inhibitor PD98059, did not affect IL-7\u2013mediated viability or cell cycle progression of leukemic cells. IL-7 induced PI3K-dependent phosphorylation of Akt and its downstream targets GSK-3, FOXO1, and FOXO3a. PI3K activation was mandatory for IL-7\u2013mediated Bcl-2 up-regulation, p27kip1 down-regulation, Rb hyperphosphorylation, and consequent viability and cell cycle progression of T-ALL cells. PI3K signaling was also required for cell size increase, up-regulation of CD71, expression of the glucose transporter Glut1, uptake of glucose, and maintenance of mitochondrial integrity. Our results implicate PI3K as a major effector of IL-7\u2013induced viability, metabolic activation, growth and proliferation of T-ALL cells, and suggest that PI3K and its downstream effectors may represent molecular targets for therapeutic intervention in T-ALL.<\/jats:p>","DOI":"10.1084\/jem.20040789","type":"journal-article","created":{"date-parts":[[2004,9,8]],"date-time":"2004-09-08T01:34:56Z","timestamp":1094607296000},"page":"659-669","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":221,"title":["Activation of PI3K Is Indispensable for Interleukin 7\u2013mediated Viability, Proliferation, Glucose Use, and Growth of T Cell Acute Lymphoblastic Leukemia Cells"],"prefix":"10.1084","volume":"200","author":[{"given":"Joao T.","family":"Barata","sequence":"first","affiliation":[{"name":"1Tumor Biology Unit, Institute of Molecular Medicine, University of Lisbon Medical School, 1649-028, Lisbon, Portugal"}]},{"given":"Ana","family":"Silva","sequence":"additional","affiliation":[{"name":"1Tumor Biology Unit, Institute of Molecular Medicine, University of Lisbon Medical School, 1649-028, Lisbon, Portugal"}]},{"given":"Joana G.","family":"Brandao","sequence":"additional","affiliation":[{"name":"1Tumor Biology Unit, Institute of Molecular Medicine, University of Lisbon Medical School, 1649-028, Lisbon, Portugal"}]},{"given":"Lee M.","family":"Nadler","sequence":"additional","affiliation":[{"name":"2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"}]},{"given":"Angelo A.","family":"Cardoso","sequence":"additional","affiliation":[{"name":"2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"}]},{"given":"Vassiliki A.","family":"Boussiotis","sequence":"additional","affiliation":[{"name":"2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"}]}],"member":"291","published-online":{"date-parts":[[2004,9,7]]},"reference":[{"key":"2023072512424402600_BIB1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1074-7613(00)80517-8","volume":"7","year":"1997","journal-title":"Immunity."},{"key":"2023072512424402600_BIB2","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1182\/blood.V78.3.564.564","volume":"78","year":"1991","journal-title":"Blood."},{"key":"2023072512424402600_BIB3","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1182\/blood.V96.1.297","volume":"96","year":"2000","journal-title":"Blood."},{"key":"2023072512424402600_BIB4","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1182\/blood.V86.7.2661.2661","volume":"86","year":"1995","journal-title":"Blood."},{"key":"2023072512424402600_BIB5","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S1074-7613(00)80337-4","volume":"6","year":"1997","journal-title":"Immunity."},{"key":"2023072512424402600_BIB6","first-page":"1229","volume":"88","year":"2003","journal-title":"Haematologica."},{"key":"2023072512424402600_BIB7","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1182\/blood.V98.5.1524","volume":"98","year":"2001","journal-title":"Blood."},{"key":"2023072512424402600_BIB8","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1182\/blood-2002-12-3861","volume":"103","year":"2004","journal-title":"Blood."},{"key":"2023072512424402600_BIB9","doi-asserted-by":"crossref","first-page":"31108","DOI":"10.1074\/jbc.274.43.31108","volume":"274","year":"1999","journal-title":"J. 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