Abstract
The phosphatidylinositol phosphatase gene PTEN is a dual specific phosphatase acting on phospho amino acids but also on three phosphorylated inositol phospholipids. Present results demonstrate that PTEN is inducible by costimulatory signals in human CD4(+) T cells. PTEN expression was up-regulated on RNA and protein level in freshly isolated human CD4(+) T cells following stimulation with CD28 or CD2. In contrast, PTEN expression was high but remained CD28 and CD2 unresponsive in lymphoma cells. Intracellular staining revealed PTEN expression in CD4(+) T cell populations stimulated with anti-CD28 or anti-CD28 / anti-CD3. Stimulation with anti-CD3 alone did not induce PTEN expression. Inhibition of PTEN expression by antisense oligonucleotides in CD4(+) T cells stimulated with non-mitogenic anti-CD28 resulted in massively increased proliferation, which was sensitive to the phosphatidylinositol 3-kinase (PI3 K) inhibitor wortmannin. Although CD28 and CD2 induce PI3 K signal transduction, wortmannin did not block PTEN up-regulation by CD28 or CD2 indicating that PTEN gene expression is PI3 K independent. These results demonstrate that PTEN negatively controls costimulatory signals by antagonizing PI3 K activity in the absence of TCR engagement.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Androstadienes / pharmacology
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CD2 Antigens / physiology*
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CD28 Antigens / physiology*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / enzymology*
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Cell Cycle
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Cell Division / physiology
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Cells, Cultured / cytology
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Cells, Cultured / enzymology
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Enzyme Activation
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Humans
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Lymphocyte Activation
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / metabolism
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Lymphoma, T-Cell / pathology
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Oligodeoxyribonucleotides, Antisense / pharmacology
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / biosynthesis
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology*
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RNA, Messenger / biosynthesis
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Receptors, Antigen, T-Cell / immunology
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Signal Transduction / drug effects
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Thionucleotides / pharmacology
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / enzymology
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
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Wortmannin
Substances
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Androstadienes
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CD2 Antigens
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CD28 Antigens
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Enzyme Inhibitors
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Oligodeoxyribonucleotides, Antisense
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Thionucleotides
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Tumor Suppressor Proteins
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Wortmannin