Impaired Fas response and autoimmunity in Pten+/- mice
Impaired Fas response and autoimmunity in Pten+/- mice
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DOI：
10.1126/science.285.5436.2122
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发表时间：
1999-09-24
期刊：
影响因子：
56.9
通讯作者：
Pandolfi, PP
中科院分区：
文献类型：
--
作者：
Di Cristofano, A;Kotsi, P;Pandolfi, PP
编码磷酸酶的PTEN肿瘤抑制基因的失活突变发生在三种以肿瘤易感性为特征的相关人类常染色体显性遗传病中。研究表明，Pten杂合子(Pten(+/-))突变体发生致死性多克隆自身免疫性疾病，其特征与Fas缺陷突变体的特征相似。在Pten(+/-)小鼠中，Fas介导的细胞凋亡受到损害，这些小鼠的T淋巴细胞表现出激活诱导的细胞死亡减少和激活后的增殖增加。磷脂酰肌醇(PI)3-激酶抑制剂可恢复Pten(+/-)细胞的Fas反应性。这些结果表明，Pten是Fas反应的重要介质和自身免疫的抑制因子，从而参与了PI3K/Akt通路在Fas介导的细胞凋亡中的作用。
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.