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* Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Universidad Autonóma de Madrid, Cantoblanco, Madrid E-28049;
Hospital Ramón y Cajal, Carretera de Colmenar Km 9, Madrid E-28034;
Department of Animal Pathology, Veterinary School, Universidad Complutense de Madrid, Madrid E-28040; and
§ Centro de Biología Molecular/CSIC, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049, Spain
1Correspondence: Centro Nacional de Biotecnología, Carretera de Colmenar Km 16, Cantoblanco, Madrid E-28049, Spain. E-mail: acarrera{at}cnb.uam.es
Alterations in the cell division:cell death ratio induce multiple autoimmune and transformation processes. Phosphoinositide 3-kinase (PI3K) controls cell division and cell death in vitro, but its effect on the function of the cellular immune system and on tumor formation in mammals is poorly characterized. Here we show that transgenic mice expressing in T lymphocytes an active form of PI3K derived from a thymic lymphoma, p65PI3K, developed an infiltrating lymphoproliferative disorder and autoimmune renal disease with an increased number of T lymphocytes exhibiting a memory phenotype and reduced apoptosis. This pathology was strikingly similar to that described in mice exhibiting heterozygous loss of the tumor suppressor PTEN, a lipid and protein phosphatase. We show that overexpression of PTEN selectively blocks p65PI3K-induced 3T3 fibroblast transformation. Moreover, the early development of T cell lymphomas in p65PI3K Tg p53-/- mice indicated that PI3K contributes to tumor development. These observations demonstrate that constitutive activation of PI3K extends T cell survival in vivo, affects T cell homeostasis, and contributes to tumor generation, supporting a model in which selective increases in one type of PTEN substrate, the PI3K-derived lipid products, induce tumorigenesis. PI3K thus emerges as a potential target in autoimmune disease and cancer therapy.—R.-Borlado, L., Redondo, C., Alvarez, B., Jimenez, C., Criado, L. M., Flores, J., Marcos, M. A. R., Martinez-A., C., Balomenos, D., Carrera, A. C. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo.
Key Words: lymphoproliferative disease • autoimmunity • cancer • phosphoinositide 3-kinase • PTEN
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