Impaired Fas Response and Autoimmunity in Pten$^{+/-}$ Mice

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 featu...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 1999-09, Vol.285 (5436), p.2122-2125
Main Authors: Di Cristofano, Antonio, Kotsi, Paraskevi, Peng, Yu Feng, Cordon-Cardo, Carlos, Elkon, Keith B., Pandolfi, Pier Paolo
Format: Article
Language:English
Subjects:
Ageing, cell death
Animals
Antibodies
Antibodies, Antinuclear - blood
Apoptosis
Autoimmune Diseases - immunology
Autoimmune Diseases - pathology
B lymphocytes
B-Lymphocytes - immunology
B-Lymphocytes - pathology
Biological and medical sciences
Cell death
Cell physiology
fas Receptor - physiology
Female
Female animals
Fundamental and applied biological sciences. Psychology
Heterozygote
Immunoglobulin G - blood
Kidney Diseases - immunology
Kidney Diseases - pathology
Kidney Glomerulus - immunology
Kidney Glomerulus - pathology
Lymph nodes
Lymphocyte Activation
Male
Mice
Mice, Inbred C57BL
Molecular and cellular biology
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Phosphoric Monoester Hydrolases - genetics
Phosphoric Monoester Hydrolases - physiology
Phosphorylation
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
Spleen
Spleen cells
Splenocytes
T lymphocytes
T-Lymphocytes - immunology
T-Lymphocytes - pathology
Tumor Suppressor Proteins
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Description
Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.285.5436.2122