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 (Pl) 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 Pl 3-kinase/Akt pathway in Fas-mediated apoptosis.
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