Heaney Jason D, Michelson Megan V, Youngren Kirsten K, Lam Man-Yee J, Nadeau Joseph H
Department of Genetics, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44120, USA.
Hum Mol Genet. 2009 Apr 15;18(8):1395-404. doi: 10.1093/hmg/ddp045. Epub 2009 Jan 23.
The agouti-yellow (A(y)) deletion is the only genetic modifier known to suppress testicular germ cell tumor (TGCT) susceptibility in mice or humans. The A(y) mutation deletes Raly and Eif2s2, and induces the ectopic expression of agouti, all of which are potential TGCT-modifying mutations. Here we report that the reduced TGCT incidence of heterozygous A(y) males and the recessive embryonic lethality of A(y) are caused by the deletion of Eif2s2, the beta subunit of translation initiation factor eIF2. We found that the incidence of affected males was reduced 2-fold in mice that were partially deficient for Eif2s2 and that embryonic lethality occurred near the time of implantation in mice that were fully deficient for Eif2s2. In contrast, neither reduced expression of Raly in gene-trap mice nor ectopic expression of agouti in transgenic or viable-yellow (A(vy)) mutants affected TGCT incidence or embryonic viability. In addition, we provide evidence that partial deficiency of Eif2s2 attenuated germ cell proliferation and differentiation, both of which are important to TGCT formation. These results show that germ cell development and TGCT pathogenesis are sensitive to the availability of the eIF2 translation initiation complex and to changes in the rate of translation.
刺豚鼠黄色（A(y)）缺失是已知的唯一能抑制小鼠或人类睾丸生殖细胞肿瘤（TGCT）易感性的基因修饰因子。A(y)突变删除了Raly和Eif2s2，并诱导刺豚鼠信号蛋白的异位表达，所有这些都是潜在的TGCT修饰突变。在此我们报告，杂合子A(y)雄性小鼠TGCT发病率降低以及A(y)的隐性胚胎致死性是由翻译起始因子eIF2的β亚基Eif2s2缺失所致。我们发现，Eif2s2部分缺陷的小鼠中受影响雄性的发病率降低了2倍，而Eif2s2完全缺陷的小鼠在着床时出现胚胎致死性。相比之下，基因陷阱小鼠中Raly表达降低以及转基因或存活黄色（A(vy)）突变体中刺豚鼠信号蛋白异位表达均未影响TGCT发病率或胚胎活力。此外，我们提供证据表明，Eif2s2部分缺陷会减弱生殖细胞增殖和分化，而这两者对TGCT形成都很重要。这些结果表明，生殖细胞发育和TGCT发病机制对eIF2翻译起始复合物的可用性以及翻译速率的变化敏感。
