Molecular Medicine of Neurodegenerative Disease and Malignant Tumor

神经退行性疾病和恶性肿瘤的分子医学

• 批准号: 10CE2006
• 负责人: TAKAHASHI Masahide
• 金额: $ 712.83万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for COE Research
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10CE2006/
• 关键词: Neurodegenerative disease; Malignant tumor; RET gene; Midkine; Dorfin gene; Ganglioside; Cancer invasion; Transgenic mouse; 糖鎖合成酵素遺伝子; Src遺伝子; 浸潤・転移; ノックアウトマウス; 癌転移; 神経栄養因子

1. To investigate the role of tyrosine 1062 in RET in neuronal differentiation, we produced knock-in mice in which tyrosine 1062 was replaced with phenylalanine. Differentiation of enteric neurons in the whole intestinal tract was severely impaired in mice, indicating that the intracellular signaling via tyrosine 1062 plays an important role in the development of the enteric nervous system.2. The midkine (MK) receptor is thought to be a molecular complex of protepglycans including protein tyrosine phosphatase ζ (PTPζ) and syndecan. MK binds to the chondroitin sulfate portion of PTPζ, especially to the E unit that has 4,6-disulfated N-acetylgalactosamine, with high affinity. The binding of MK to syodecan was mediated by the trisulfated structure of N- and 6-O-sulfated glucosamine and 2-sulfated uronic acid.3. Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well a … More s sporadic ALS. Dorphin physiologically bound and ubiquitylated various SOD1 mutants derived from familial ALS patients and enhanced their degradation. The overexpression of Dorfin protected against the toxic effects of mutant SOD1 on neural cells and reduced SOD1 inclusions.4. Double knock-out mice lacking the GM2/GD2 and the GD3 synthase gene were generated by mating single gene mutants. We observed a refractory skin lesion that appeared on the face of mutant mice at 25 weeks after birth or later. Characteristic proliferation of nerve fibers was found in the epidermis and subepidermis at the injured sites, probably a result of continuous skin injury. Peripheral nerve degeneration was observed in young mutant mice, suggesting that reduced sensory function induced over-scratching.5. Treatment of QG90 human lung cancer cells with hyaluronan (HA) strongly activated MMP-2 secretion and expression of antisense CD44s in QG90 cells inhibited the HA-dependent secretion of MMP-2. We found that HA-CD44 signaling plays a key role in the HA-dependent secretion of MMP-2 and, hence, in the invasiveness of QG90 cells. Less

1.为了研究RET中酪氨酸1062在神经元分化中的作用，我们建立了用苯丙氨酸取代酪氨酸1062的敲入小鼠。结论：1.小鼠全肠道肠道神经元分化严重受损，提示酪氨酸1062的细胞内信号转导在肠道神经系统发育中起重要作用。中期因子(MK)受体被认为是蛋白多糖的分子复合体，包括蛋白酪氨酸磷酸酶ζ(PtP)、ζ和Syndecan。MK与PTPζ的硫酸软骨素部分结合，特别是与含有4，6-二硫化N-乙酰半乳糖胺的E单元结合，亲和力高。N-和6-O-磺化氨基葡萄糖和2-磺化糖醛酸的三硫化结构介导了MK与降糖多糖的结合。Dorfin是一种环指型E3泛素连接酶，主要定位于铜/锌超氧化物歧化酶突变和…突变的家族性肌萎缩侧索硬化症的包涵体中S多为散发性肌萎缩侧索硬化症。多芬生理结合和泛素化来自家族性肌萎缩侧索硬化症患者的各种SOD1突变体，并促进它们的降解。Dorfin的过表达对突变型SOD1对神经细胞的毒性效应具有保护作用，并减少了SOD1的包涵体。GM2/GD2和GD3合酶基因缺失的双基因敲除小鼠是通过单基因突变体交配获得的。我们观察到在突变小鼠出生后25周或更晚的时候，面部出现了一种顽固性皮肤损害。损伤部位的表皮和真皮下可见特征性的神经纤维增殖，可能是皮肤持续损伤的结果。在年轻的突变小鼠中观察到周围神经变性，这表明感觉功能降低导致过度抓挠。透明质酸(HA)强烈刺激QG90细胞分泌基质金属蛋白酶-2，反义CD44s的表达抑制依赖透明质酸的基质金属蛋白酶-2的分泌。我们发现，HA-CD44信号在HA依赖的基质金属蛋白酶-2的分泌中起关键作用，从而在QG90细胞的侵袭性中起关键作用。较少

项目成果

Masashi Kato et al.: "Transgenic mouse model for skin malignant melanoma"Oncogene. 17. 1885-1888 (1998)

Masashi Kato 等人：“皮肤恶性黑色素瘤转基因小鼠模型”Oncogene。

Fukumoto, S et al: "GD3 synthase gene expression in PC12 cells results in the continuous activation of TrkA and ERK1/2 and enhanced proliferation."J.Biol. Chem.. 275. 5832-5838 (2000)

Fukumoto, S 等人：“PC12 细胞中 GD3 合酶基因的表达导致 TrkA 和 ERK1/2 的持续激活并增强增殖。”J.Biol。

Chunlin Ye: "Expression of midkine in the early stage of carcinogenesis in human colorectal cancer."Brit.J.Cancer. 79. 179-184 (1999)

叶春林：“中期因子在人类结直肠癌癌变早期的表达。”Brit.J.Cancer。

Nobuaki Maeda: "A receptor-like protein tyrosine phosphatase (PTPζ/RPTP β) binds a heparin binding growth factor midkine : Involvement of arginine 78 of midkine in the high affinity binding to PTP ζ."J.Biol.Chem.. 274. 12474-79 (1999)

Nobuaki Maeda：“受体样蛋白酪氨酸磷酸酶 (PTP z/RPTP β) 与肝素结合生长因子 midkine 结合：midkine 的精氨酸 78 参与与 PTP z 的高亲和力结合。”J.Biol.Chem.. 274。 12474-79 (1999)

Aye Aye Thant: "Ras pathway is required for the activation of MMP-2 and for the invasion of src-transformed 3Y1."Oncogene. 18. 6555-6563 (1999)

Aye Aye Thant：“Ras 途径是 MMP-2 激活和 src 转化的 3Y1 入侵所必需的。”癌基因。