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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten+/- mice
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grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten+/- mice

机译：grb2杂合性可挽救pten +/-小鼠的胚胎致死性，但不能挽救其​​肿瘤发生

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摘要

PTEN is a tumor suppressor gene implicated in both sporadic cancers and inherited tumor-prone syndromes. Here we show that pten+/- mice display a partially penetrant embryonic lethality. This lethality is associated with defects in both neural and placental development. Notably, this lethality is completely rescued by grb2 haploinsufficiency. In contrast, grb2 heterozygosity did not alter tumorigenesis in either pten+/- or T cell-specific pten-/- mice. grb2-/hypomorph murine embryonic fibroblasts (MEFs) show decreased activation of both PKB and Erk upon stimulation with epidermal growth factor, whereas grb2-/hypomorph; pten+/- MEFs activate PKB but not Erk normally. Similarly, grb2-/hypomorph fibroblasts die in low serum, and this phenotype is rescued by pten haploinsufficiency. Activation of both PKB and Erk as well as survival in low serum-containing media are all rescued by reexpression of Grb2 containing mutations within the N-terminal Src homology 3 (SH3) domain, but not by C-terminal SH3 domain mutants. The N-terminal SH3 domain mutants fail to bind to Sos, whereas the C-terminal SH3 domain mutants fail to bind to Gab1, suggesting that Erk and PKB activation in fibroblasts in response to epidermal growth factor depends on Gab1 or other C-terminal SH3 domain-interacting proteins, but not on Sos. Thus, PTEN/phosphatidylinositol 3' kinase signaling requires Grb2 during both embryonic development and fibroblast survival, but Grb2 heterozygosity does not effect tumorigenesis in pten-deficient mice. In fibroblasts, survival signals emanating from the epidermal growth factor receptor appear to be PKB-dependent, and this activation depends on the C-terminal SH3 domain of Grb2, likely through the interaction of Grb2 with Gab1.
机译：PTEN是一种肿瘤抑制基因，与散发性癌症和遗传易感综合症有关。在这里，我们显示pten +/-小鼠显示出部分渗透的胚胎致死性。这种致死性与神经和胎盘发育的缺陷有关。值得注意的是，grb2单倍剂量不足可以完全挽救这种致命性。相反，在pten +/-或T细胞特异性pten-/-小鼠中，grb2杂合性不会改变肿瘤发生。 grb2- / hypomorph鼠胚胎成纤维细胞（MEF）在表皮生长因子刺激下显示PKB和Erk的激活均降低，而grb2- / hypomorph pten +/- MEF正常激活PKB，但不能激活Erk。同样，grb2- /亚同型成纤维细胞在低血清中死亡，这种表型可以通过pten单倍体不足来挽救。 PKB和Erk的激活以及在低血清含量培养基中的存活都可以通过在N端Src同源性3（SH3）域内重新表达含有Grb2的突变而得以挽救，而在C端SH3结构域突变体中则无法挽回。 N末端SH3结构域突变体无法与Sos结合，而C末端SH3结构域突变体无法与Gab1结合，表明成纤维细胞对表皮生长因子的响应Erk和PKB激活取决于Gab1或其他C末端SH3结构域相互作用蛋白，而不是在Sos上。因此，PTEN /磷脂酰肌醇3'激酶信号传导在胚胎发育和成纤维细胞存活期间都需要Grb2，但是Grb2杂合性不会影响pten缺陷小鼠的肿瘤发生。在成纤维细胞中，从表皮生长因子受体发出的存活信号似乎是PKB依赖性的，这种激活取决于Grb2的C末端SH3结构域，可能是通过Grb2与Gab1的相互作用引起的。

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