Overexpression of p101 activates PI3Kγ signaling in T cells and contributes to cell survival

• Published in: Oncogene Vol. 26; no. 49; pp. 7049 - 7057
• Main Authors: JOHNSON, C, MARRIOTT, S. J, LEVY, L. S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 25.10.2007; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; Ageing, cell death; AKT protein; Apoptosis; Biological and medical sciences; Cell physiology; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes T; Malignancy; Medical sciences; Molecular and cellular biology; Molting; Stoichiometry; T-cell lymphoma; Enzyme; Transferases; retrovirus integration site; Gene overexpression; Malignant hemopathy; Carcinogenesis; Lymphoma; Survival; Cell signaling; 1-Phosphatidylinositol 3-kinase; Lymphoproliferative syndrome; T-Lymphocyte; phosphatidylinositol-3-kinase-gamma; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210504

p101, the regulatory subunit of phosphatidylinositol-3-kinase-gamma (PI3Kγ), was recently reported as a common site of retroviral insertion in T-cell lymphomas induced in mice by MoFe2-MuLV, a unique recombinant gammaretrovirus. The common interruption of p101 by retroviral integration suggests that the locus encodes an oncogene whose altered expression is related to the induction of T-cell malignancy. To examine a possible role in the malignant process, p101 was overexpressed in human T-cell lines Molt-4 and Jurkat. Transient overexpression of p101 induced apoptosis in recipient cells; however, stable expression could be established in cells that expressed moderate levels of p101. Constitutive p101 overexpression in those cells conferred significant protection against ultraviolet-induced apoptosis. Protection against apoptotic induction was attributed to p101-mediated activation of the Akt pathway. Constitutive overexpression of p101 enhanced the activity of p110γ and further sensitized it to activation upon stimulation of G protein-coupled receptor. These findings are the first to implicate altered expression of p101 in malignancy, specifically in T-cell lymphoma. The findings further provide insight into the regulation of p110γ, indicating that the stoichiometry of p110γ and p101 are important in regulating PI3Kγ signaling.