UBIAD1调控Ras信号的机制研究

UBIAD1是维生素K2和非线粒体辅酶Q10合酶，参与心血管变性、帕金森病、泌尿系肿瘤和SCCD发生，但UBIAD1抑制肿瘤机制不明。UBIAD1缺失、Ras突变、eNOS功能异常促进黑素瘤、膀胱癌发展。前期发现UBIAD1与H-Ras结合使H-Ras滞留至高尔基体，改变Ras区域化信号，抑制细胞增殖；抑制eNOS破坏UBIAD1对H-Ras的功能且UBIAD1/eNOS/H-Ras相互作用；抑制NOS导致果蝇产生类Heix突变表型。推测高尔基体UBIAD1通过eNOS调控H-Ras亚硝基化及激活，抑制H-Ras高尔基体-胞膜循环，调节Ras区域化信号和细胞增殖。通过细胞及果蝇研究eNOS表达、活性、偶联情况及产物NO对UBIAD1/H-Ras复合体功能的作用，探究eNOS为桥梁调节UBIAD1/H-Ras功能的机制。结果可揭示UBIAD1抑癌机制，更为靶向Ras转运药物开发提供理论基础。

UBIAD1, one of the UbiA superfamily of intramembrane prenyltransferases, is the vitamin K2 and non-mitochondrial CoQ10 synthase. Dysfunctional UBIAD1 has been linked to cardiovascular degeneration, Parkinson’s disease, urologic cancers and Schnyder crystalline corneal dystrophy. However the mechanism between UBIAD1 and tumorigenesis is still not clear. The deletion of UBIAD1, Ras mutation and abnormal function of eNOS promote the development of melanoma and bladder cancer. It was previously found that UBIAD1 interacted H-Ras in Golgi apparatus, influenced Ras regionalized signal and inhibited Ras tumorigenicity. eNOS dysfunction decreased the inhibition of UBIAD1 to Ras. UBIAD1, eNOS, H-Ras formed a complex in Golgi apparatus. We investigate UBIAD1 regulates eNOS on H-Ras nitrosylation in Golgi apparatus and activates H-Ras, inhibiting Golgi-plasma membrane cycling of H-Ras，regulates Ras regionalized signal and cell proliferation. Inhibition of NOS induces the Heix mutant phenotype in wild-type Drosophila. To research the mechanism of eNOS as a bridge regulates the function of UBIAD1/eNOS/H-Ras complex, we study the effect of eNOS expression, activity, coupling status and the production of NO on the function of UBIAD1/H-Ras complex in cells and Drosophila. The results not only shed light on mechanism of the inhibition of UBIAD1 in cancer, but also provide theoretical basis for the development of Ras targeted drugs.