Macdonald N, Barrow K, Tonge R, Davison M, Roberts R A, Chevalier S
Cancer Biology Group, Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom.
Biochem Biophys Res Commun. 2000 Nov 2;277(3):699-704. doi: 10.1006/bbrc.2000.3741.
The adverse effects of the peroxisome proliferators (PPs), a class of rodent nongenotoxic hepatocarcinogens, include suppression of apoptosis, induction of hepatocyte proliferation, and liver enlargement which eventually leads to tumours. The response to PPs is mediated by the peroxisome proliferator activated receptor alpha (PPARalpha). We carried out proteomic analyses of PP-treated hepatocytes from wild-type and PPARalpha-null mice to identify the molecular pathways underlying the adverse effects of PPs. We have identified eighteen protein spots exhibiting differential expression in PP-treated wild-type mouse hepatocytes. Several proteins involved in lipid metabolism pathways, but also ATP synthase beta subunit, which are regulated by PPs were identified. In addition, both 2D silver-stained gels and Western blotting analysis indicated that the anti-apoptotic glucose-regulated protein 94 (GRP94) is consistently overexpressed upon stimulation with PPs, providing us with novel insights into the anti-apoptotic mechanism activated by PPs.
过氧化物酶体增殖剂（PPs）是一类啮齿动物非基因毒性肝癌致癌物，其不良反应包括抑制细胞凋亡、诱导肝细胞增殖以及肝脏肿大，最终导致肿瘤。对PPs的反应由过氧化物酶体增殖物激活受体α（PPARα）介导。我们对野生型和PPARα基因敲除小鼠经PP处理的肝细胞进行了蛋白质组学分析，以确定PPs不良反应背后的分子途径。我们在经PP处理的野生型小鼠肝细胞中鉴定出18个表现出差异表达的蛋白质斑点。鉴定出了几种参与脂质代谢途径的蛋白质，还有受PPs调控的ATP合酶β亚基。此外，二维银染凝胶和蛋白质印迹分析均表明，抗凋亡的葡萄糖调节蛋白94（GRP94）在受到PPs刺激后持续过度表达，这为我们深入了解PPs激活的抗凋亡机制提供了新的线索。
