Komarova Elena A, Kondratov Roman V, Wang Kaihua, Christov Konstantin, Golovkina Tatiana V, Goldblum John R, Gudkov Andrei V
Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Oncogene. 2004 Apr 22;23(19):3265-71. doi: 10.1038/sj.onc.1207494.
Ionizing radiation (IR) induces p53-dependent apoptosis in radiosensitive tissues, suggesting that p53 is a determinant of radiation syndromes. In fact, p53-deficient mice survive doses of IR that cause lethal hematopoietic syndrome in wild-type animals. Surprisingly, p53 deficiency results in sensitization of mice to higher doses of IR, causing lethal gastro-intestinal (GI) syndrome. While cells in the crypts of p53-wild-type epithelium undergo prolonged growth arrest after irradiation, continuous cell proliferation ongoing in p53-deficient epithelium correlates with accelerated death of damaged cells followed by rapid destruction of villi and accelerated lethality. p21-deficient mice are also characterized by increased sensitivity to GI syndrome-inducing doses of IR. We conclude that p53/p21-mediated growth arrest plays a protective role in the epithelium of small intestine after severe doses of IR. Pharmacological inhibition of p53 by a small molecule that can rescue from lethal hematopoietic syndrome has no effect on the lethality from gastro-intestinal syndrome, presumably because of a temporary and reversible nature of its action.
电离辐射（IR）在放射敏感组织中诱导p53依赖性凋亡，这表明p53是辐射综合征的一个决定因素。事实上，p53基因缺陷的小鼠能够在足以导致野生型动物发生致死性造血综合征的辐射剂量下存活。令人惊讶的是，p53基因缺陷会导致小鼠对更高剂量的IR敏感，从而引发致死性胃肠道（GI）综合征。在p53野生型上皮隐窝中的细胞在照射后会经历长时间的生长停滞，而p53基因缺陷的上皮中持续的细胞增殖与受损细胞的加速死亡相关，随后绒毛迅速破坏并加速致死。p21基因缺陷的小鼠也表现出对诱导GI综合征剂量的IR敏感性增加。我们得出结论，p53/p21介导的生长停滞在高剂量IR照射后对小肠上皮起到保护作用。一种能够挽救致死性造血综合征的小分子对p53的药理抑制作用对胃肠道综合征的致死性没有影响，这可能是由于其作用具有暂时和可逆的性质。
