Fas Is Involved in the p53-Dependent Apoptotic Response to Ionizing Radiation in Mouse Testis1

Abstract

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.

Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells

“…In BEpC and pulmonary endothelial cells, we found that bleomycin increased the ex- pression of several TNF ligand and TNF receptor family genes. Expression of DRs, such as FAS, DR4, and DR5, has been shown to be activated by p53 in response to DNA damage (8), and bleomycin has been shown to regulate expression of DNA damage-inducible proteins, including p53, that are associated with acute injury in the lung (21). The exact mechanism by which bleomycin regulates TNF-receptor expression, that triggers apoptosis, is currently under investigation in our laboratory.…”

Involvement of p53 and Fas/CD95 in murine neural progenitor cell response to ionizing irradiation

“…Reap et al (1997) have demonstrated a major implication of Fas/FasL interactions in radiationinduced apoptosis in splenic T and B cells both in vivo and in vitro. Furthermore, Embree-Ku et al (2002) have reported that lpr mice, having a nonfunctional Fas receptor, exhibited a reduced number of apoptotic seminiferous tubules 12 h following a 5 Gy irradiation compared to wild-type mice. In contrast, mice deficient for FasL had the same response than wild-type mice.…”

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

“…Activation of nuclear factor-nB1 (NFnB1) has been implicated in promoting tumor growth as well as antiapoptotic and proangiogenic effects (21,22). Tumor necrosis factor (ligand) superfamily member 6 (TNFSF6) is a FAS (cell surface receptor) ligand that activates apoptosis signal through caspases (23).…”