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 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.
Di Cristofano
A
A
Department of Human Genetics-Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA.
Kotsi
P
P
Peng
Y F
YF
Cordon-Cardo
C
C
Elkon
K B
KB
Pandolfi
P P
PP
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D005260:Female; D006579:Heterozygote; D007074:Immunoglobulin G / Q000097:blood; D007674:Kidney Diseases / Q000276:immunology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D025521:Tumor Suppressor Proteins; D019014:fas Receptor / Q000502:physiology*
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D019014:fas Receptor