The participation of p53 independent pathway in the process of oral carcinogenesis

用致癌物处理p53缺陷型小鼠（p53^<-/->）和野生型小鼠（WT），并对它们的舌组织进行组织学检查。此外，细胞周期调节因子的mRNA和蛋白质的表达的变化和Rb的磷酸化进行了研究。本研究还探讨了ATM、p53和MDM 2蛋白表达与口腔白斑上皮异型增生的关系。在p53^<-/->和WT小鼠中，致癌物处理均诱导上皮发育异常，如上皮层增厚和基底细胞极性丧失，并且这些变化随着时间的推移而变得占主导地位.在WT小鼠中，致癌物处理增加了p21 mRNA及其蛋白的表达，而在p53^<-/->小鼠中，致癌物处理没有增加p21的表达。WT小鼠在致癌物处理后1周p53蛋白表达增加，而在处理后3周p53蛋白表达降低.在用致癌物处理的WT小鼠中发现Rb蛋白的磷酸化，尽管Rb蛋白的量没有改变。E2 F的表达也无明显变化. p53在口腔粘膜白斑中的表达随上皮异型增生程度的增加而增强，而在口腔癌中的表达随上皮异型增生程度的增加而减弱。未发现ATM与上皮异常增生之间的相关性。MDM 2在口腔黏膜白斑中的表达与上皮异型增生程度有关，在口腔癌中表达增强。提示p53依赖性通路可能参与了口腔癌的早期发生，p53非依赖性通路可能参与了口腔癌的晚期发生。

p53 deficient mice (p53^<-/->) and wild type mice (WT) were treated with carcinogens, and their tongue tissues were examined histologically. Further, changes in the expression of mRNAs and protein of cell-cycle regulators and the phosphorylation of Rb were investigated. The correlation between the expression of ATM, p53 and MDM2 and epithelial dysplasia was also studied in human oral leukoplakia.The results obtained were as follows :1. Both in p53^<-/-> and WT mice, epithelial dysplasia such as thickening of the epithelial layer and loss of basal cell polarity were induced by the treatment of carcinogens and these changes become dominant with time.2. In WT mice, the expression of p21 mRNA and its protein was increased by the treatment of carcinogens, whereas the expression of p21 was not increased by the treatment of carcinogens in p53^<-/-> mice. The expression of p53 in WT mice was increased 1 week after the treatment of carcinogens, but its expression was decreased 3 weeks after the treatment.3. Phosphorylation of Rb protein was found in WT mice treated with carcinogens, though the amount of Rb protein was not changed. The expression of E2F was not also changed.4. In oral leukoplakia, the expression of p53 becomes strong with the grade of epithelial dysplasia, but its expression in oral cancer become weaker. The correlation between ATM and epithelial dysplasia was not seen. The expression of MDM2 in oral leukoplakia was correlated with the grade of epithelial dysplasia, and its expression become stronger in oral cancer..These results indicate that p53 dependent pathway may be concerned in the early stage of oral carcinogenesis and p53 independent pathway may participate in late stage of oral carcinogenesis.