A new role for the von Hippel-Lindau tumor suppressor protein:: stimulation of mitochondrial oxidative phosphorylation complex biogenesis
A new role for the von Hippel-Lindau tumor suppressor protein:: stimulation of mitochondrial oxidative phosphorylation complex biogenesis
复制标题
DOI：
10.1093/carcin/bgi001
复制
发表时间：
2005-03-01
期刊：
影响因子：
4.7
通讯作者：
Godinot, C
中科院分区：
文献类型：
--
作者：
Hervouet, E;Demont, J;Godinot, C
尽管Warburg在许多年前就描述了癌症中的线粒体缺陷，但这种损伤的机制仍然是未知的。许多类型的癌细胞都受到关注，特别是透明细胞肾癌（CCRC）。在这种癌症中，肿瘤抑制基因VHL （von Hippel-Lindau因子）失效。先前的研究表明，将源自ccrc的VHL缺陷细胞转染VHL基因后，将其注射到裸鼠体内，可以抑制其形成肿瘤的能力。然而，在这些癌细胞中观察到各种额外的遗传改变。为了探究VHL失活是否与线粒体损伤有关，我们研究了野生型VHL转染VHL缺陷786-0或RCC10细胞对其氧化磷酸化（OXPHOS）亚基含量和功能的影响。我们发现野生型VHL蛋白（pVHL）的存在增加了线粒体DNA和呼吸链蛋白的含量，并允许细胞在没有葡萄糖的情况下依靠线粒体ATP的产生来生长。western blot分析显示，在mtDNA升高的同时，pVHL的存在也上调了线粒体转录因子A。综上所述，在ccrc中，pVHL缺乏是导致OXPHOS复合物生物发生下调的因素之一。
Although mitochondrial deficiency in cancer has been described by Warburg, many years ago, the mechanisms underlying this impairment remain essentially unknown. Many types of cancer cells are concerned and, in particular, clear cell renal carcinoma (CCRC). In this cancer, the tumor suppressor gene, VHL (von Hippel-Lindau factor) is invalidated. Previous studies have shown that the transfection of the VHL gene in VHL-deficient cells originating from CCRCs could suppress their ability to form tumors when they were injected into nude mice. However, various additional genetic alterations are observed in such cancer cells. In order to investigate whether VHL invalidation was related to the mitochondrial impairment, we have studied the effects of wild-type VHL transfection into VHL-deficient 786-0 or RCC10 cells on their oxidative phosphorylation (OXPHOS) subunit contents and functions. We show that the presence of wild-type VHL protein (pVHL) increased mitochondrial DNA and respiratory chain protein contents and permitted the cells to rely on their mitochondrial ATP production to grow in the absence of glucose. In parallel to mtDNA increase, the presence of pVHL up regulated the mitochondrial transcription factor A, as shown by western blot analysis. In conclusion, in CCRCs, pVHL deficiency is one of the factors responsible for down-regulation of the biogenesis of OXPHOS complexes.