MacCallum D E, Hupp T R, Midgley C A, Stuart D, Campbell S J, Harper A, Walsh F S, Wright E G, Balmain A, Lane D P, Hall P A
Department of Molecular and Cellular Pathology, University of Dundee, UK.
Oncogene. 1996 Dec 19;13(12):2575-87.
The induction of the p53 response to ionising radiation has been studied during murine development and in the adult animal. The response has been assessed by precise quantitative assay of p53 protein levels in tissues and by immunohistochemistry. Newly developed transgenic mice in which a lacZ transgene is driven by a p53 response element have also been used to directly assess the transcriptional activity of the induced protein. There is striking developmental control of the p53 response so that in early development all tissues accumulate high levels of p53 following radiation and indeed p53 is present at elevated levels in some unirradiated tissues. Later in development clear heterogeneity of the p53 response becomes apparent, both in terms of the responses of individual tissues and of cell populations, within those tissues. The study of lacZ transgene expression and the occurrence of apoptosis in different tissues that accumulate p53 protein point to a further level of control regulating the nature and degree of the downstream response to elevated levels of p53 in cells. These findings have important implications for the susceptibility of different tissue types to carcinogenic and other insults. The early expression of the p53 response is consistent with novel models of p53 function that suggest it may have evolved principally as a defense against teratogenic insult that permits plasticity of development.
在小鼠发育过程中和成年动物体内，对电离辐射诱导的p53反应进行了研究。通过对组织中p53蛋白水平进行精确的定量分析以及免疫组织化学方法来评估该反应。新开发的转基因小鼠（其中lacZ转基因由p53反应元件驱动）也已用于直接评估诱导蛋白的转录活性。p53反应存在显著的发育调控，因此在早期发育阶段，所有组织在辐射后都会积累高水平的p53，实际上在一些未受辐射的组织中p53水平也会升高。在发育后期，p53反应的明显异质性变得明显，这在个体组织的反应以及这些组织内的细胞群体反应方面均如此。对lacZ转基因表达以及在积累p53蛋白的不同组织中细胞凋亡发生情况的研究表明，存在进一步的调控水平，可调节细胞中p53水平升高时下游反应的性质和程度。这些发现对于不同组织类型对致癌和其他损伤的易感性具有重要意义。p53反应的早期表达与p53功能的新模型一致，该模型表明它可能主要作为一种防御致畸损伤的机制而进化，这种机制允许发育的可塑性。
