Loss of atm radiosensitizes multiple p53 null tissues.
Loss of atm radiosensitizes multiple p53 null tissues.
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发表时间：
1998-12
期刊：
影响因子：
11.2
通讯作者：
Christoph H. Westphal;Katherine P Hoyes;C. Canman;Xin Huang;Michael B. Kastan;J. H. Hendry;Philip Leder
中科院分区：
文献类型：
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作者：
Christoph H. Westphal;Katherine P Hoyes;C. Canman;Xin Huang;Michael B. Kastan;J. H. Hendry;Philip Leder
一个不寻常的临床发现，在共济失调毛细血管扩张，一种人类疾病引起的突变的atm，是精致的敏感性辐射。相比之下，p53的纯合缺失在某些组织区室中表现为耐辐射。先前的研究（A. J. Levine, Cell, 88: 323-331, 1997）表明，在体外，p53缺陷的骨髓细胞对γ辐射具有抗性。此外，最近有研究表明，由于atm的丢失而引起的胃肠道放射致敏（C. H. Westphal等，Nat. Genet）。基因工程学报，16:397- 401,1997)。在先前工作的基础上，我们研究了p53缺陷小鼠的体内骨髓耐药性。我们的研究结果表明，由于骨髓抵抗，近交系FVB株p53缺失小鼠能够存活致死剂量的辐照。此外，atm的缺失甚至使p53零骨髓和小鼠胚胎成纤维细胞放射增敏。这里提出的结果表明，atm的损失以p53不依赖的方式使多个组织放射致敏。因此，在p53零型和p53野生型人类肿瘤中，atm的功能性抑制可能是基于γ照射的抗肿瘤治疗的有用辅助手段。
An unusual clinical finding in ataxia-telangiectasia, a human disorder caused by mutations in atm, is exquisite sensitivity to gamma irradiation. By contrast, homozygous deletion of p53 is marked by radiation resistance in certain tissue compartments. Previous studies (A. J. Levine, Cell, 88: 323-331, 1997) have shown that, in vitro, p53-deficient bone marrow cells are resistant to gamma irradiation. Furthermore, the gastrointestinal radiosensitization engendered by the loss of atm has recently been shown (C. H. Westphal et al., Nat. Genet., 16: 397-401, 1997) to be independent of p53. Expanding on previous work, we have looked at in vivo bone marrow resistance in p53-deficient mice. Our results indicate that inbred FVB strain p53 null mice survive lethal irradiation doses because of bone marrow resistance. Moreover, the deletion of atm radiosensitizes even p53 null bone marrow and mouse embryonic fibroblast cells. The results presented here argue that the loss of atm radiosensitizes multiple tissues in a p53-independent manner. Hence, functional inhibition of atm in p53 null and p53 wild-type human tumors may be a useful adjunct to gamma irradiation-based antitumor therapy.