Blesa José R, Prieto-Ruiz Jesús A, Abraham Beth A, Harrison Bridget L, Hegde Anita A, Hernández-Yago José
Fundacion Centro de Investigacion Principe Felipe, Av. Autopista del Saler 16-3, Valencia, Spain.
Biochem Cell Biol. 2008 Feb;86(1):46-56. doi: 10.1139/o07-151.
The human TOMM34 gene encodes a cytosolic protein with chaperone-like activity that helps import some preproteins to the mitochondria by keeping them in an unfolded, import-compatible state. TOMM34 was found to be upregulated frequently in colorectal tumors, suggesting that it also has a role in the growth of cancer cells. In this context, TOMM34 is a potential target for novel anticancer drugs, and it might also be used in the diagnosis of colorectal cancer. Nuclear respiratory factors (NRFs) play an important role in governing the nuclear-mitochondrial interactions implicated in mitochondrial biogenesis. Our previous studies revealed that NRFs promote the expression of the major members of the mitochondrial transport machinery, TOMM70 and TOMM20. Here we report the existence of binding sites for NRF-1, Sp1, and NRF-2 in the 5' region of the human TOMM34 gene. We determined the effects of mutations at these sites on promoter activity in HeLa S3 and A204 cells, in conjunction with chromatin immunoprecipitation experiments, electrophoretic mobility shift assays, and in vivo methylation analysis of the promoter region. We conclude that NRF-1 is the main transcription factor regulating the expression of TOMM34. Sp1 interacts with NRF-1 to stimulate the promoter's full activity.
人类TOMM34基因编码一种具有伴侣样活性的胞质蛋白，该蛋白通过使一些前体蛋白保持未折叠的、与导入兼容的状态，帮助将它们导入线粒体。研究发现TOMM34在结直肠肿瘤中经常上调，这表明它在癌细胞生长中也发挥作用。在这种情况下，TOMM34是新型抗癌药物的潜在靶点，它也可能用于结直肠癌的诊断。核呼吸因子（NRFs）在调控与线粒体生物发生相关的核-线粒体相互作用中起重要作用。我们之前的研究表明，NRFs促进线粒体转运机制的主要成员TOMM70和TOMM20的表达。在此我们报告在人类TOMM34基因的5'区域存在NRF-1、Sp1和NRF-2的结合位点。我们结合染色质免疫沉淀实验、电泳迁移率变动分析以及启动子区域的体内甲基化分析，确定了这些位点的突变对HeLa S3和A204细胞中启动子活性的影响。我们得出结论，NRF-1是调节TOMM34表达的主要转录因子。Sp1与NRF-1相互作用以刺激启动子的全部活性。
