Division of Urology, Department of Surgery, University of Pennsylvania and Veterans Affairs Medical Center Philadelphia, Philadelphia, Pennsylvania 19104, USA.
J Cell Biochem. 2013 Sep;114(9):2170-87. doi: 10.1002/jcb.24567.
We originally discovered TERE1 as a potential tumor suppressor protein based upon reduced expression in bladder and prostate cancer specimens and growth inhibition of tumor cell lines/xenografts upon ectopic expression. Analysis of TERE1 (aka UBIAD1) has shown it is a prenyltransferase enzyme in the natural bio-synthetic pathways for both vitamin K-2 and COQ10 production and exhibits multiple subcellular localizations including mitochondria, endoplasmic reticulum, and golgi. Vitamin K-2 is involved in mitochondrial electron transport, SXR nuclear hormone receptor signaling and redox cycling: together these functions may form the basis for tumor suppressor function. To gain further insight into mechanisms of growth suppression and enzymatic regulation of TERE1 we isolated TERE1 associated proteins and identified the WD40 repeat, mitochondrial protein TBL2. We examined whether disease specific mutations in TERE1 affected interactions with TBL2 and the role of each protein in altering mitochondrial function, ROS/RNS production and SXR target gene regulation. Biochemical binding assays demonstrated a direct, high affinity interaction between TERE1 and TBL2 proteins; TERE1 was localized to both mitochondrial and non-mitochondrial membranes whereas TBL2 was predominantly mitochondrial; multiple independent single amino acid substitutions in TERE1 which cause a human hereditary corneal disease reduced binding to TBL2 strongly suggesting the relevance of this interaction. Ectopic TERE1 expression elevated mitochondrial trans-membrane potential, oxidative stress, NO production, and activated SXR targets. A TERE1-TBL2 complex likely functions in oxidative/nitrosative stress, lipid metabolism, and SXR signaling pathways in its role as a tumor suppressor.
我们最初发现 TERE1 是一种潜在的肿瘤抑制蛋白，其在膀胱癌和前列腺癌标本中的表达降低，并且异位表达会抑制肿瘤细胞系/异种移植物的生长。对 TERE1（又名 UBIAD1）的分析表明，它是维生素 K-2 和 COQ10 生产的天然生物合成途径中的一种prenyltransferase 酶，表现出多种亚细胞定位，包括线粒体、内质网和高尔基体。维生素 K-2 参与线粒体电子传递、SXR 核激素受体信号和氧化还原循环：这些功能一起可能构成肿瘤抑制功能的基础。为了深入了解生长抑制和 TERE1 酶促调节的机制，我们分离了 TERE1 相关蛋白，并鉴定了 WD40 重复、线粒体蛋白 TBL2。我们检查了 TERE1 中的疾病特异性突变是否影响与 TBL2 的相互作用，以及每个蛋白在改变线粒体功能、ROS/RNS 产生和 SXR 靶基因调节中的作用。生化结合测定表明 TERE1 和 TBL2 蛋白之间存在直接的、高亲和力的相互作用；TERE1 定位于线粒体和非线粒体膜，而 TBL2 主要位于线粒体；TERE1 中的多个独立的单点突变导致人类遗传性角膜疾病，与 TBL2 的结合大大降低，强烈表明这种相互作用的相关性。异位 TERE1 表达可提高线粒体跨膜电位、氧化应激、NO 产生，并激活 SXR 靶标。作为肿瘤抑制因子，TERE1-TBL2 复合物可能在氧化/硝化应激、脂质代谢和 SXR 信号通路中发挥作用。
