Novel interaction of ornithine decarboxylase with sepiapterin reductase regulates neuroblastoma cell proliferation.
Novel interaction of ornithine decarboxylase with sepiapterin reductase regulates neuroblastoma cell proliferation.
复制标题
DOI：
10.1016/j.jmb.2013.09.037
复制
发表时间：
2014-01-23
影响因子：
5.6
通讯作者：
Bachmann, Andre S.
中科院分区：
文献类型：
--
作者：
Lange, Ingo;Geerts, Dirk;Feith, David J.;Mocz, Gabor;Koster, Jan;Bachmann, Andre S.
关键词：
鸟氨酸脱羧酶(ODC)是多胺生物合成的前哨酶。ODC和多胺都调节细胞分裂、增殖和凋亡。Sepiapterin Reductase(SPR)催化四氢生物蝶呤(BH4)生物合成的最后一步，BH4是一氧化氮合酶(NOS)的重要辅助因子，与神经系统疾病有关，但尚未与癌症有关。在这项研究中，我们提出了令人信服的证据，证明了天然ODC和SPR在物理上相互作用，并使用电子蛋白质-蛋白质对接模拟定义了这两种酶所涉及的单个氨基酸残基。由此得到的杂化络合物是一种令人惊讶的紧凑结构，在单体和二聚体构象中都具有两种能量和结构等价的结合模式。通过在神经母细胞瘤(NB)细胞中的免疫共沉淀和共定位，证实了ODC和SPR蛋白在生理条件下的新的相互作用。重要的是，我们发现siRNA介导的SPR表达下调显著降低了NB细胞内源性ODC酶的活性，从而证明了ODC-SPR相互作用的生物学相关性。最后，在88例人鼻咽癌的队列中，我们发现SPR基因的高表达与不良的生存预后显著相关(logrank检验P=5·10−4)，提示SPR在鼻咽癌的发生中起致癌作用。总之，我们发现ODC结合了SPR，从而提出了一个新的概念，即通过两种酶的相互作用，两条特征良好的生化途径会聚在一起。我们认为SPR是一种新的ODC酶活性调节因子，并基于临床证据提出了SPR驱动ODC介导的NB恶性进展的模型。
Ornithine decarboxylase (ODC) is the sentinel enzyme in polyamine biosynthesis. Both ODC and polyamines regulate cell division, proliferation, and apoptosis. Sepiapterin reductase (SPR) catalyzes the last step in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), and has been implicated in neurological diseases but not yet in cancer. In this study, we present compelling evidence that native ODC and SPR physically interact, and we defined the individual amino acid residues involved in both enzymes using in silico protein-protein docking simulations. The resulting heterocomplex is a surprisingly compact structure, featuring two energetically and structurally equivalent binding modes both in monomer and dimer conformations. The novel interaction between ODC and SPR proteins was confirmed under physiological conditions by co-immunoprecipitation and co-localization in neuroblastoma (NB) cells. Importantly, we showed that siRNA-mediated knock-down of SPR expression significantly reduced endogenous ODC enzyme activity in NB cells, thus demonstrating the biological relevance of the ODC-SPR interaction. Finally, in a cohort of 88 human NB tumors we found that high SPR mRNA expression correlated significantly with poor survival prognosis using a Kaplan-Meier analysis (Logrank test P = 5 • 10−4), suggesting an oncogenic role for SPR in NB tumorigenesis. In conclusion, we showed that ODC binds SPR and thus propose a new concept in which two well-characterized biochemical pathways converge via the interaction of two enzymes. We identified SPR as a novel regulator of ODC enzyme activity, and based on clinical evidence present a model in which SPR drives ODC-mediated malignant progression in NB.
登录
查看更多内容
DOI：
10.1186/cc2955
发表时间：
2004-10
期刊：
Critical care (London, England)
影响因子：
--
作者：
Bewick V;Cheek L;Ball J
通讯作者：
Ball J
DOI：
10.1158/1078-0432.ccr-08-3213
发表时间：
2009-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Evageliou NF;Hogarty MD
通讯作者：
Hogarty MD
影响因子：
11.2
作者：
Friedman, Jennifer;Roze, Emmanuel;Blau, Nenad
通讯作者：
Blau, Nenad
影响因子：
64.8
作者：
AUVINEN, M;PAASINEN, A;HOLTTA, E
通讯作者：
HOLTTA, E
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Rudnev D;Evangelista C;Kim IF;Soboleva A;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Edgar R
通讯作者：
Edgar R