Dietary energy restriction in mice negatively regulates hepatic glucose-regulated protein 78 (GRP78) expression at the posttranscriptional level.
Dietary energy restriction in mice negatively regulates hepatic glucose-regulated protein 78 (GRP78) expression at the posttranscriptional level.
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小鼠的饮食能量限制会在转录后水平负向调节肝葡萄糖调节蛋白 78 (GRP78) 的表达。
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发表时间：
1996
期刊：
影响因子：
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通讯作者：
S. Spindler
中科院分区：
文献类型：
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作者：
J. B. Tillman;P. Mote;J. Dhahbi;R. Walford;S. Spindler
饮食能量限制延缓了与年龄相关的生理变化，延长了最长寿命，并降低了癌症发病率。我们之前的研究表明，50%的能量限制使小鼠肝脏中葡萄糖调节蛋白mRNA的表达减少了50%至80%。葡萄糖调节蛋白78 （GRP78）水平的变化可以降低或增加特定蛋白质的分泌率。因此，能量限制可能会使肝脏分泌的蛋白质谱发生全局变化。这些研究是为了探究该基因负调控的分子基础。通过转染和核运行技术，GRP78基因转录在急性极度葡萄糖剥夺的培养细胞中的强诱导已经被很好地表征。然而，能量限制对GRP78基因在体内表达的负调控作用尚不清楚。在我们的研究中，使用Western blotting测定的GRP78蛋白水平的降低与Northern blotting和dot blotting测定的肝脏GRP78 mRNA的降低密切相关。在每种情况下，这些变化在统计学上都是显著的。这种密切的对应关系表明，能量限制并不影响GRP78蛋白的翻译速率或稳定性。通过使用转录运行试验，在能量受限小鼠中检测到该基因的转录率没有统计学意义上的差异。这些结果强烈表明，能量限制会导致GRP78 mRNA的不稳定，从而抑制该基因在肝脏的表达。
Dietary energy restriction delays age-related physiologic changes, increases maximum life span, and reduces cancer incidence. We showed previously that 50% energy restriction in mice reduces hepatic expression of glucose-regulated protein mRNA by 50 to 80%. Changes in glucose-regulated protein 78 (GRP78) levels can either decrease or increase the rate of secretion of specific proteins. Therefore, energy restriction probably produces a global change in the spectrum of proteins secreted by the liver. These studies were initiated to investigate the molecular basis for the negative regulation of the gene. By use of transfection and nuclear run-on techniques, the strong induction of GRP78 gene transcription in cultured cells subjected to acute, extreme glucose deprivation has been well characterized. However, negative regulation of GRP78 gene expression in vivo by energy restriction is not as well understood. In our studies, a reduction in GRP78 protein levels determined using Western blotting closely paralleled a reduction in hepatic GRP78 mRNA measured by Northern and dot blotting. In each case the changes were statistically significant. This close correspondence indicates that energy restriction does not influence the translation rate or the stability of GRP78 protein. No statistically significant difference in the rate of transcription of the gene was detected in energy-restricted mice by use of transcription run-on assays. These results strongly suggest that energy restriction results in destabilization of GRP78 mRNA, thereby repressing hepatic expression of the gene.