Apoptosis in small intestinal epithelia from p53-null mice: Evidence for a delayed, p53-indepdendent G2/M-associated cell death after gamma-irradiation
Apoptosis in small intestinal epithelia from p53-null mice: Evidence for a delayed, p53-indepdendent G2/M-associated cell death after gamma-irradiation
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DOI：
10.1038/sj.onc.1201126
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发表时间：
1997-06-12
期刊：
影响因子：
8
通讯作者：
Hickman, JA
中科院分区：
文献类型：
--
作者：
Merritt, AJ;Allen, TD;Hickman, JA
对p53基因纯合子小鼠照射后小肠上皮细胞的死亡进行了表征和定量。在野生型p53纯合子动物中，（4.5 h）在8戈伊照射后，在隐窝的增殖区室中观察到p53蛋白的升高，在该区域中细胞通过凋亡而经历细胞死亡，我们以前曾报道过p53同源性缺失动物经γ射线照射（8戈伊）后4.5小时，小肠隐窝上皮细胞的凋亡完全受到抑制。因此，在4.5小时时，在取自轻度动物的200个半隐窝中仅观察到400个凋亡细胞，这在p53缺失动物中降至背景水平（10-30）（Merritt等，1994），并且在12小时后没有增加。然而，我们发现在8戈伊的γ-辐射后延迟启动p53非依赖性凋亡：在24小时，在200个半隐窝中观察到大约100个凋亡细胞，在1戈伊的γ-辐射后没有观察到这种晚期凋亡波。这种不依赖于p53的凋亡的形态学外观表明死亡可能是由于异常的有丝分裂而引起的。用11至17戈伊照射小鼠后3天对隐窝再生的分析表明，（P=0.135）来自p53 nub动物的克隆原细胞重新填充隐窝的潜力，这些数据支持这样的观点，即在8戈伊γ射线照射后，p53的缺失不会使这些上皮细胞在体内对8戈伊以上的剂量具有放射抗性。相反，用1GS照射不能在体内诱导p53非依赖性凋亡，这表明p53损伤“传感器”比参与p53非依赖性细胞死亡机制的传感器更敏感。
The death of small intestinal epithelial cells has been characterized and quantitated after irradiation of mice rendered homozygously null for the p53 gene, In wild-type animals homozygous for p53 a rapid (4.5 h) elevation of p53 protein was observed in the proliferative compartment of the crypts after 8 Gy of irradiation, Cells underwent cell death by apoptosis in this region, We had reported previously a total repression of apoptosis in small intestinal crypt epithelia 4.5 h after the gamma-irradiation (8 Gy) of p53 homozygously null animals, Thus, while 400 apoptotic cells mere observed in 200 half crypts taken from mild-type animals at 4.5 h, this fell to background levels (10-30) in the p53 null animals (Merritt et al., 1994) and did not increase by 12 h, However, we have nom found a delayed initiation of a p53-independent apoptosis after 8 Gy of gamma-radiation: at 24 h, approximately 100 apoptotic cells were observed in 200 half crypts, This late wave of apoptosis was not observed after 1 Gy of gamma-radiation. The morphological appearance of this p53-independent apoptosis suggested that death may have arisen as the result of aberrant mitosis, Analysis of the regeneration of crypts 3 days after irradiation of mice with between 11 and 17 Gy showed that there was no significant increase (P=0.135) in the potential of clonogenic cells from the p53 nub animals to repopulate the crypts, The data support the idea that a p53-independent apoptotic mechanism permits the engagement of apoptosis, probably by a mitotic catastrophe, after 8 Gy of gamma-irradiation in,live and that a loss of p53 does not make these epithelial cells radioresistant lit vivo to doses of 8 Gy and above, In contrast, irradiation with 1 GS failed to induce a p53-independent apoptosis in vivo, suggesting that the p53 'sensor' of damage was more sensitive than that engaging the p53-independent mechanism of cell death.