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Neurotrophic interrelation between neuron and glia Molecular mechanism of a new glia-derived neurotrophic factor, gliostatin

神经元和神经胶质细胞之间的神经营养相互关系新型胶质细胞源性神经营养因子胶质抑素的分子机制

基本信息

批准号：
06454702
负责人：
KATO Taiji
金额：
$ 4.48万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Gliostatin is an scidic protein purified from human neurofibroma as glial growth inhibitory factor by Asai and Kato. Lately, we have demonstrated that its nucleotide sequence is completely identical to that of platelet-derived endothelial cell growth factor (PD-ECGF), which was purified from human platelets. Gliostatin/PD-ECGF is polypeptides of Mr=100,000 with a homodimeric structure comprising two 50-kDa subunits, one of which contains 482 amino acids but not carbohydrate moiety. The amino terminus has no signal sequence which is necessary for a protein to be secreted out of cells [5]. However, it has been confirmed that gliostatin/PD-ECGF has varied biological actions, but lacked the secretory signal sequence, such as 1) chemotactic activity for endothelial cells in vitro, 2) angiogenic activity in vivo, 3) glial differentiative and neurotrophic activities including neuronal surviving activity and neuritogenic activity in vitro, and 4) arthritogenic activity in vivo.Apart from much … More information of the molecular mechanism of its functions, little is known about the regulation of gene expression as well as the human tissue distribution and content of gliostatin/PD-ECGF in detail. And it is also not clear yet whether gliostatin/PD-ECGF lacking a signal sequence is extracellularly secreted in physiological conditions or not. Therefore, we have currently investigate the tissue-specific distribution of gliostatin/PD-ECGF by sensitive enzyme immunoassay (EIA), and the induction of its protein synthesis and gene expression with relevance to its secretion, using human tumor cell lines. Gliostatin/PD-ECGF was found to distribute in rather ubiquitous than specific human tissues and organs, with a relatively high levels in the tissues of digestive system (esophagus and rectum), brain, spleen, bladder and lung, but not in gall bladder, aorta, muscle, fat and kidney. Certain tumor cells (A431 and MKN74) appeared to release it into the conditioned medium. Expression of gliostation/PD-ECGF in epidermoid carcinoma cell (A431) and stomach cancer cell (MKN45) was induced by dibutyryl cyclic AMP and phorbol ester, and uniquely in MKN45 by hydrocortisone. In particular, this hydrocortisone specifically saused an increase of the apparent secretion of MKN74 without its cytotoxic effects, suggesting a possible secretion of gliostatin/PD-ECGF in the restricted but not universal cell line. Less

Gliostatin是Asai和Kato等从人神经纤维瘤中分离纯化的胶质细胞生长抑制因子。最近，我们已经证明，它的核苷酸序列是完全相同的血小板衍生的内皮细胞生长因子（PD-ECGF），这是从人血小板纯化。Gliostatin/PD-ECGF是Mr= 100，000的多肽，具有包含两个50-kDa亚基的同源二聚体结构，其中一个含有482个氨基酸但不含碳水化合物部分。氨基末端没有蛋白质分泌出细胞所必需的信号序列[5]。然而，已经证实gliostatin/PD-ECGF具有多种生物学作用，但缺乏分泌信号序列，例如1）体外对内皮细胞的趋化活性，2）体内血管生成活性，3）体外胶质分化和神经营养活性，包括神经元存活活性和神经突生成活性，以及4）体内关节炎活性。 ...更多信息由于其功能的分子机制尚不清楚，关于Gliostatin/PD-ECGF的基因表达调控以及人体组织中Gliostatin/PD-ECGF的分布和含量的详细信息知之甚少。缺乏信号序列的gliostatin/PD-ECGF在生理条件下是否分泌到细胞外尚不清楚。因此，我们目前已经调查的组织特异性分布的胶质细胞生长抑制素/PD-ECGF的敏感酶免疫测定法（EIA），和诱导其蛋白质合成和基因表达与其分泌相关，使用人类肿瘤细胞系。Gliostatin/PD-ECGF在人体组织器官中分布广泛，在消化系统（食管和直肠）、脑、脾、膀胱和肺组织中含量较高，而在胆囊、主动脉、肌肉、脂肪和肾脏组织中含量不高。某些肿瘤细胞（A431和MKN 74）似乎将其释放到条件培养基中。Gliostation/PD-ECGF在表皮样癌细胞（A431）和胃癌细胞（MKN 45）中的表达受二丁酰环磷酸腺苷（cAMP）和佛波酯（phorbol ester）的诱导，而在MKN 45中仅受氢化可的松的诱导。特别是，这种氢化可的松特异性地使MKN 74的表观分泌增加而没有其细胞毒性作用，表明在限制性但非通用的细胞系中可能分泌胶质细胞抑制素/PD-ECGF。少