Two intracellular traffics of a growth factor

生长因子的两种细胞内运输

• 批准号: 16590223
• 负责人: KADOMATSU Kenji
• 金额: $ 2.24万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590223/
• 关键词: endocytosis; growth factor; nuclear transfer; midkine; intracellular traffic; nephritis; cisplatin; diabetes mellitus; プロテアゾーム

This study addressed two traffics of the growth factor midkine (MK), namely degradation and nuclear targeting. MK is implicated in cancer development, neuronal survival and differentiation, and inflammation. LDL receptor-related protein (LRP) is one of the receptors for MK. We previously found that MK is endocytosed via LRP, and is further translocated to the nucleus, this being important for the anti-apoptotic activity of MK. In the present study, we found that MK goes into the lysosomal as well as proteasomal degradation pathways after endocytosis. Inhibitors for the lysosome and proteasome suppressed MK degradation after endocytosis. The intranuclear degradation of MK was only inhibited by a proteasomal inhibitor, i.e., not lysosomal inhibitors. The N-terminal half of MK is degraded via the proteasome faster than the C-terminal half. The C-terminal half was responsible for the nuclear targeting of MK. Our findings support the idea that endocytosed MK enters both the two degradation pathways, and at least a part of endocytosed MK is translocated to the cytoplasm from the endosome, and is further transferred to the nucleus. We report additional findings that MK is involved in the pathogenesis of interstitial nephritis, cisplatin-induced nephritis and diabetic nephropathy.

本研究探讨了生长因子中期因子（MK）的两种运输方式，即降解和核靶向。MK与癌症发展、神经元存活和分化以及炎症有关。LDL受体相关蛋白（LRP）是MK的受体之一。我们以前发现，MK是通过LRP内吞，并进一步易位到细胞核，这是重要的MK的抗凋亡活性。在本研究中，我们发现MK在内吞作用后进入溶酶体以及蛋白酶体降解途径。溶酶体和蛋白酶体抑制剂抑制MK降解后的内吞作用。MK的核内降解仅被蛋白酶体抑制剂抑制，即，而不是溶酶体抑制剂。MK的N-末端的一半通过蛋白酶体降解的速度比C-末端的一半快。C端的一半负责MK的核靶向。我们的研究结果支持这样的想法，即内吞MK进入两个降解途径，至少有一部分内吞MK从内体易位到细胞质，并进一步转移到细胞核。我们报告了其他发现，MK参与间质性肾炎，顺铂诱导的肾炎和糖尿病肾病的发病机制。

项目成果

Postischemic gene transfer of midkine, a neurotrophic factor, protects against focal brain ischemia.

中期因子（一种神经营养因子）的缺血后基因转移可防止局灶性脑缺血。

• 发表时间: 2005
• 期刊: Gene Ther., 12
• 作者: Takada;J.;et al.
• 通讯作者: et al.

N-Acetylglucosamine-6-O-sulfotransferase-1 and -2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules

N-乙酰葡萄糖胺-6-O-磺基转移酶-1和-2通过高内皮小静脉中L-选择素配体生物合成协同控制淋巴细胞归巢

• 发表时间: 2005
• 期刊: Nat Immunot., 6
• 作者: Kawashima;H.;et al.
• 通讯作者: et al.

Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury

• DOI: 10.1152/ajpheart.00555.2004
• 发表时间: 2005-05-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
• 影响因子: 4.8
• 作者: Hayashi, K;Banno, H;Muramatsu, T
• 通讯作者: Muramatsu, T

Morpholino antisense oligomer targeting human midikine : its application for cancer therapy.

靶向人 midikine 的吗啉代反义寡聚物：其在癌症治疗中的应用。

• 发表时间: 2005
• 期刊: Int J.Cancer, 114
• 作者: Takei;Y.;et al.
• 通讯作者: et al.

Lack of the growth factor midkine enhances survival against cisplatin-induced renal damage

• DOI: 10.1016/s0002-9440(10)63417-7
• 发表时间: 2004-11-01
• 期刊: AMERICAN JOURNAL OF PATHOLOGY
• 影响因子: 6
• 作者: Kawai, H;Sato, W;Muramatsu, T
• 通讯作者: Muramatsu, T