Abstract
Inactivating mutations in the PTEN tumor suppressor gene, encoding a phosphatase, occur in three related human autosomal dominant disorders characterized by tumor susceptibility. Here it is shown that Pten heterozygous (Pten+/-) mutants develop a lethal polyclonal autoimmune disorder with features reminiscent of those observed in Fas-deficient mutants. Fas-mediated apoptosis was impaired in Pten+/- mice, and T lymphocytes from these mice show reduced activation-induced cell death and increased proliferation upon activation. Phosphatidylinositol (PI) 3-kinase inhibitors restored Fas responsiveness in Pten+/- cells. These results indicate that Pten is an essential mediator of the Fas response and a repressor of autoimmunity and thus implicate the PI 3-kinase/Akt pathway in Fas-mediated apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Antinuclear / blood
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Apoptosis*
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / pathology
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Female
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Heterozygote
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Immunoglobulin G / blood
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Kidney Diseases / immunology*
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Kidney Diseases / pathology
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Kidney Glomerulus / immunology
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Kidney Glomerulus / pathology
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred C57BL
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology*
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
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Tumor Suppressor Proteins*
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fas Receptor / physiology*
Substances
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Antibodies, Antinuclear
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Immunoglobulin G
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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fas Receptor
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase