Impaired Fas response and autoimmunity in Pten+/- mice

Science. 1999 Sep 24;285(5436):2122-5. doi: 10.1126/science.285.5436.2122.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Antinuclear / blood
  • Apoptosis*
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • Female
  • Heterozygote
  • Immunoglobulin G / blood
  • Kidney Diseases / immunology*
  • Kidney Diseases / pathology
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / physiology*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Tumor Suppressor Proteins*
  • fas Receptor / physiology*

Substances

  • Antibodies, Antinuclear
  • Immunoglobulin G
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • fas Receptor
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase