Moxl as a Molecular Target for Cancer Drug Discovery

Moxl 作为癌症药物发现的分子靶点

• 批准号: 6333832
• 负责人: John David Lambeth
• 金额: $ 22.9万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-05 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6333832
• 关键词: angiogenesis; apoptosis; athymic mouse; biological signal transduction; catalase; cell biology; cell growth regulation; enzyme activity; fibroblast growth factor; free radical oxygen; mitogen activated protein kinase; phospholipase D; prostaglandin endoperoxide synthase; protein localization; protooncogene; respiratory burst oxidase; superoxide dismutase; tissue /cell culture; vascular endothelial growth factors

Reactive oxygen species (ROS) are implicated as intracellular signals and may affect cell growth and tissue hypertrophy by affecting mitogenesis, apoptosis and perhaps angiogenesis. Increased levels of ROS are seen in a variety of actively growing cells including Ras-transformed cells, a variety of cancers and cells treated with growth factors such as EGF and PDGF. Vascular smooth muscle generates ROS in response to agonists, and this has been linked to cell growth and hypertrophy which is implicated in atherosclerosis and hypertension. The origin of ROS in these cells is controversial and both mitochondrial and non-mitochondrial sources have been proposed. Phagocytes generate high levels of ROS by activating the superoxide-generating respiratory burst oxidase (a.k.a. NADPH oxidase), and it has been speculated that either this oxidase or a similar enzyme accounts for ROS generation in non-phagocytic cells. We have molecularly cloned the cDNA for p65mox1, the first member of a family of novel oxidases which are related to the catalytic flavocytochrome subunit of the respiratory burst oxidase. The mox1 message shows a unique tissue distribution in non phagocytic cells including colon, prostate and vascular smooth muscle. NIH 3T3 cells expressing mox1 generate increased superoxide and show transformed properties (focus formation, anchorage-independent growth) and marked tumorigenicity in athymic mice. This study characterizes the basic biochemistry and cell biology of mox1. Specifically, we will carry out a molecular characterization of the enzyme activity, its cofactor/coenzyme requirements, and its subcellular location. We will investigate the downstream signaling pathways that link p65mox1 to cell growth and tumorigenicity. We will also investigate the wider spectrum of biological effects of p65mox1, which include mitogenesis, angiogenesis and perhaps inhibition of apoptosis, and interventions in this pathway which may be relevant to treatment of human hyperproliferative disorders such as cancer.

活性氧（ROS）是细胞内信号，可能通过影响有丝分裂、凋亡和血管生成来影响细胞生长和组织肥大。ROS水平的增加可见于多种活跃生长的细胞中，包括Ras转化的细胞、多种癌症和用生长因子如EGF和PDGF处理的细胞。 血管平滑肌响应于激动剂而产生ROS，并且这与细胞生长和肥大有关，这与动脉粥样硬化和高血压有关。 ROS在这些细胞中的起源是有争议的，线粒体和非线粒体来源已被提出。 吞噬细胞通过激活产生超氧化物的呼吸爆发氧化酶（又称呼吸爆发氧化酶）产生高水平的ROS。NADPH氧化酶），并且据推测，该氧化酶或类似的酶导致非吞噬细胞中的ROS产生。 我们已经分子克隆了p65 mox 1的cDNA，p65 mox 1是与呼吸爆发氧化酶的催化黄细胞色素亚基有关的新型氧化酶家族的第一个成员。 mox 1信息显示在非吞噬细胞中的独特组织分布，包括结肠、前列腺和血管平滑肌。 表达mox 1的NIH 3 T3细胞产生增加的超氧化物，并显示转化特性（病灶形成，锚定非依赖性生长）和显着的致瘤性在无胸腺小鼠。 本研究描述了mox 1的基本生物化学和细胞生物学特征。 具体来说，我们将进行酶活性的分子表征，其辅因子/辅酶的要求，和它的亚细胞位置。 我们将研究p65 mox 1与细胞生长和致瘤性之间的下游信号通路。 我们还将研究p65 mox 1的更广泛的生物学效应，包括有丝分裂，血管生成和可能抑制细胞凋亡，以及在这一途径中的干预措施，这可能与治疗人类过度增殖性疾病，如癌症有关。