Embree-Ku Michelle, Venturini Deborah, Boekelheide Kim
Department of Pathology and Laboratory Medicine, Brown University, 171 Meeting Street, Providence, Rhode Island 02912, USA.
Biol Reprod. 2002 May;66(5):1456-61. doi: 10.1095/biolreprod66.5.1456.
Apoptosis induced in male germ cells following ionizing radiation is dependent on functional p53 (Trp53) being present. We sought to determine whether Fas (Tnfrsf6/CD95/APO-1), an apoptotic factor, is involved in this p53-dependent germ cell death. In p53 knock-out mice exposed to 5 Gy of x-radiation, germ cells were protected from cell death, as assessed by counting apoptotic seminiferous tubules 12 h following radiation. Similarly, spermatid head counts in p53 knock-out mice remained near normal 29 days after exposure to 0.5 Gy of radiation, whereas wild-type animals had a more than twofold reduction in spermatid head counts. Fas mRNA expression remained at pretreatment levels in p53 knock-out mice; however, Fas increased in a time-dependent manner in wild-type mice following exposure to 5 Gy of radiation, indicating that radiation-induced Fas expression is p53-dependent. The functional significance of Fas involvement was demonstrated when lpr(cg) mice, having a nonfunctional Fas receptor, were exposed to 5 Gy of radiation; the number of apoptotic seminiferous tubules 12 h following radiation was significantly reduced compared to that of wild-type mice. Additionally, lpr(cg) mice exposed to 0.5 Gy of radiation had increased spermatid head counts 29 days following radiation compared to wild-type mice. Interestingly, gld mice with a non-functional Fas ligand (Tnfsf6/FasL/CD95L) were as sensitive to radiation as wild-type animals, and levels of FasL mRNA were not affected by radiation treatment. These results indicate that apoptosis and up-regulation of Fas following radiation are both p53-dependent events. Although Fas is necessary, in part, for radiation-induced p53-dependent apoptosis, FasL is not.
电离辐射诱导的雄性生殖细胞凋亡依赖于功能性p53（Trp53）的存在。我们试图确定凋亡因子Fas（Tnfrsf6/CD95/APO-1）是否参与这种p53依赖的生殖细胞死亡。在接受5 Gy X射线照射的p53基因敲除小鼠中，通过计算辐射后12小时凋亡的生精小管数量评估发现，生殖细胞受到了细胞死亡保护。同样，p53基因敲除小鼠在接受0.5 Gy辐射后29天，精子细胞头部计数仍接近正常，而野生型动物的精子细胞头部计数减少了两倍多。Fas mRNA表达在p53基因敲除小鼠中保持在预处理水平；然而，野生型小鼠在接受5 Gy辐射后，Fas以时间依赖性方式增加，表明辐射诱导的Fas表达是p53依赖性的。当具有无功能Fas受体的lpr（cg）小鼠接受5 Gy辐射时，证明了Fas参与的功能意义；与野生型小鼠相比，辐射后12小时凋亡的生精小管数量显著减少。此外，与野生型小鼠相比，接受0.5 Gy辐射的lpr（cg）小鼠在辐射后29天精子细胞头部计数增加。有趣的是，具有无功能Fas配体（Tnfsf6/FasL/CD95L）的gld小鼠对辐射的敏感性与野生型动物相同，并且FasL mRNA水平不受辐射处理的影响。这些结果表明，辐射后的凋亡和Fas上调都是p53依赖性事件。虽然Fas部分上是辐射诱导的p53依赖性凋亡所必需的，但FasL不是。
