Palmer D G, Paraskeva C, Williams A C
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, UK.
Int J Cancer. 1997 Nov 27;73(5):702-6. doi: 10.1002/(sici)1097-0215(19971127)73:5<702::aid-ijc15>3.0.co;2-7.
The high incidence of colorectal cancer in Western society is believed to be strongly related to diet. Mutation of the p53 gene is a late event in colorectal carcinogenesis, and thus, the majority of pre-malignant adenomas express wild-type p53. As loss of p53 protein function is an important step in colorectal carcinogenesis, we investigated whether naturally occurring lumenal factors can modulate the expression of p53 in non-tumorigenic human colonic adenoma cell lines. Levels of p53 protein and mRNA were measured in adherent cells which had been incubated with growth-inhibitory concentrations of sodium butyrate (a by-product of dietary fibre fermentation) or sodium deoxycholate (a bile acid) for up to 48 hr. We report that both butyrate and deoxycholate can down-regulate the expression of wild-type and mutant p53. In contrast, incubation for 48 hr with the endogenous inhibitory growth factor TGFbeta1 did not alter p53 protein expression. Thus, in addition to cellular mechanisms which regulate p53 function, such as post-translational stabilisation, nuclear exclusion, negative feedback inhibition of p53 mRNA translation or binding of p53 by cellular proteins, p53 protein levels also may be regulated by changes in the level of p53 gene transcription. Furthermore, we show that lumenal factors are able to affect directly the expression of p53 protein in colonic epithelial cells.
西方社会中结直肠癌的高发病率被认为与饮食密切相关。p53基因的突变是结直肠癌发生过程中的晚期事件，因此，大多数癌前腺瘤表达野生型p53。由于p53蛋白功能的丧失是结直肠癌发生的重要步骤，我们研究了天然存在的肠腔因子是否能调节非致瘤性人结肠腺瘤细胞系中p53的表达。在用生长抑制浓度的丁酸钠（膳食纤维发酵的副产物）或脱氧胆酸钠（一种胆汁酸）孵育长达48小时的贴壁细胞中测量p53蛋白和mRNA的水平。我们报告丁酸盐和脱氧胆酸盐均可下调野生型和突变型p53的表达。相比之下，用内源性生长抑制因子TGFβ1孵育48小时不会改变p53蛋白的表达。因此，除了调节p53功能的细胞机制，如翻译后稳定、核排除、p53 mRNA翻译的负反馈抑制或细胞蛋白与p53的结合外，p53蛋白水平也可能受p53基因转录水平变化的调节。此外，我们表明肠腔因子能够直接影响结肠上皮细胞中p53蛋白的表达。
