Forced cytochrome B gene mutation expression induces mitochondrial proliferation and prevents apoptosis in human uroepithelial SV-HUC-1 cells.
Forced cytochrome B gene mutation expression induces mitochondrial proliferation and prevents apoptosis in human uroepithelial SV-HUC-1 cells.
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DOI：
10.1002/ijc.24701
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发表时间：
2009-12-15
影响因子：
6.4
通讯作者：
Sidransky, David
中科院分区：
文献类型：
--
作者：
Dasgupta, Santanu;Hoque, Mohammad Obaidul;Upadhyay, Sunil;Sidransky, David
线粒体编码的细胞色素B（CYTB）基因突变在不同解剖起源的肿瘤中均有报道，但这些突变的功能意义尚未得到充分研究。早些时候，我们在一位原发性膀胱癌患者的CYTB基因中发现了一个7-氨基酸缺失突变。在本研究中，我们在SV-40转化的人尿路上皮HUC-1细胞中过表达CYTB基因的7个氨基酸缺失突变。将核转录的线粒体CYTB（mtCYTB）靶向到线粒体中，并在转染的HUC-1细胞中产生线粒体和线粒体COX-I蛋白的增加的拷贝。促凋亡蛋白Bax主要局限于mtCYTB转染的HUC-1细胞的细胞质中，而不释放细胞色素C。在mtCYTB转染的细胞中，下游凋亡蛋白PARP也保持沿着未裂解，核纤层蛋白B1增加。我们的研究结果表明，在转化的人尿路上皮HUC-1细胞中强制过表达mtCYTB引发线粒体增殖和诱导有利于持续细胞生长的抗凋亡信号级联反应。编码线粒体DNA突变似乎在肿瘤进展中具有显著的功能贡献。
Mitochondria encoded Cytochrome B (CYTB) gene mutations were reported in tumors of different anatomic origin but the functional significance of these mutations are not well studied. Earlier, we found a 7-amino acid deletion mutation in the CYTB gene in a primary bladder cancer patient. In the present study, we overexpressed this 7-amino acid deletion mutation of CYTB gene in SV-40 transformed human uroepithelial HUC-1 cells. The nuclear transcribed mitochondrial CYTB (mtCYTB) was targeted into the mitochondria and generated increased copies of mitochondria and mitochondrial COX-I protein in the transfected HUC-1 cells. The pro-apoptotic protein Bax largely remained confined to the cytoplasm of the mtCYTB transfected HUC-1 cells without release of Cytochrome C. The downstream apoptotic proteins PARP also remained uncleaved along with increased Lamin B1 in the mtCYTB transfected cells. Our results demonstrate that forced overexpression of mtCYTB in transformed human uroepithelial HUC-1 cells triggered mitochondrial proliferation and induction of an anti-apoptotic signaling cascade favoring sustained cellular growth. Coding mitochondrial DNA mutations appear to have significant functional contribution in tumor progression.
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