Role of peroxisome proliferator-activated receptor α in altered cell cycle regulation in mouse liver
Role of peroxisome proliferator-activated receptor α in altered cell cycle regulation in mouse liver
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DOI：
10.1093/carcin/19.11.1989
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发表时间：
1998-11-01
期刊：
影响因子：
4.7
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Peters, JM;Aoyama, T;Gonzalez, FJ
过氧化物酶体增殖物诱导的肝癌发生的潜在机制尚不清楚，但由过氧化物酶体增殖物激活受体α（PPARalpha）介导。为了确定PPARalpha在肝癌发生机制中的作用，评价了Wy-14，643对酰基CoA氧化酶（ACO）和PPARalpha缺失小鼠中参与细胞增殖的蛋白质的表达模式的影响。与对照组相比，野生型小鼠喂食Wy-14，643 5周或11个月后，AGO、CDK-1、CDK-2、CDK-4、PCNA和c-myc蛋白均显著增加。在Wy-14，643处理的PPARa缺失小鼠中未观察到该效应。细胞周期蛋白B1，细胞周期蛋白D，细胞周期蛋白E和p53的表达模式在任何组中没有差异。编码CDK-1、CDK-4、细胞周期蛋白D1和c-myc的mRNA在喂食Wy-14，643的野生型小鼠中也增加，但在PPARa缺失小鼠中没有增加。这些结果表明，CDK-1，CDK-4和c-myc的增加可能是由PPAR α直接或间接介导的转录增加引起的。因此，过氧化物酶体增殖物诱导的细胞周期调节蛋白的PPAR α依赖性改变可能有助于过氧化物酶体增殖物的肝癌性。
The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are unclear but are mediated by the peroxisome proliferator-activated receptor a (PPAR alpha), To determine the role of PPAR alpha in the mechanisms of hepatocarcinogenesis, the effect of Wy-14,643 on expression patterns of acyl CoA oxidase (ACO) and proteins involved in cell proliferation in the PPAR alpha-null mouse were evaluated. AGO, CDK-1, CDK-2, CDK-4, PCNA and c-myc proteins were significantly increased in wild-type mice fed Wy-14,643 for 5 weeks or 11 months, as compared with controls. This effect was not observed in Wy-14,643-treated PPARa-null mice. Expression patterns of cyclin B1, cyclin D, cyclin E and p53 were not different in any of the groups. mRNAs encoding CDK-1, CDK-4, cyclin D1 and c-myc were also increased in wild-type mice fed Wy-14,643 but not in PPARa-null mice. These results indicate that the increase in CDK-1, CDK-4 and c-myc may be caused by an increase in transcription that is mediated directly or indirectly by PPAR alpha. Thus PPAR alpha-dependent alterations in cell cycle regulatory proteins induced by peroxisome proliferators are likely to contribute to the hepatocarcinogenicity of peroxisome proliferators.