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GENE THERAPY OF GLOMERULONEPHRITIS BY GENE TRANSFER OF CELL CYCLE-RELATED GENES.

通过细胞周期相关基因的基因转移进行肾小球肾炎的基因治疗。

基本信息

批准号：
09557090
负责人：
TERADA Yoshio
金额：
$ 7.55万
依托单位：
TOKYO MEDICAL AND DENTAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

Recent studies have revealed that mitogen-actiated protein kinase(MAPK)consists of at least three subfamilies, namely include classical MAPK(also known as ERK), stress-activated protein kinase/c-Jun N-terminal kinase(JNK), and p38 kinase. TGF-b-activating kinase(TAK)-1 is a novel MAPKKK which is reported to stimulate p38K and/or JNK pathway. To elucidate functional roles of the TAK1 pathway, we transfected its constitutive active form(TAKdN)and negative form(TAKK63W)to LLCPK1 cells. TAKdN inhibited 3H-thymidine uptake, and reduced the percentages of S and G2/M phases. TAKK63W ameliorated inhibition of 3H-thymidine uptake and the percentages of S and G2/M phases by TGF-b. Western blot analysis demonstrates that the cyclin D1 protein level was negatively regulated by overexpression of TAKdN.Moreover, overexpression of TAKdN inhibited cyclin D1 promoter activity. In contract, constitutive active MKK1, the classical p42/44 MAPK-activator, increased cyclin D1 promoter activity and protein level. Overexpression of the active form of MKK1 increased 3H-thymidine uptake, while the inactive form decreased the uptake.In conclusion, cyclin D1 promoter activity and cell cycle progression are negatively regulated by the TAK1-MKK6-p38K pathway and positively regulated by the MKK1-p42/44 MAPK pathway.

近年来的研究发现，丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）至少由三个亚家族组成，即经典MAPK（又称ERK）、应激活化蛋白激酶/c-Jun N-末端激酶（stress-activated protein kinase/c-Jun N-terminal kinase，JNK）和p38激酶。TGF-b-activating kinase（TAK）-1是一种新的MAPKKK，据报道其刺激p38 K和/或JNK通路。为了阐明TAK 1通路的功能作用，我们将其组成型活性形式（TAKdN）和阴性形式（TAKK 63 W）转染到LLCPK 1细胞中。TAKdN抑制~ 3 H-胸腺嘧啶核苷的摄取，并减少S期和G2/M期细胞的百分比。TAKK 63 W可改善TGF-β对~ 3 H-胸腺嘧啶核苷摄取的抑制及S期和G2/M期细胞比例的影响。Western blot分析表明，TAKdN的过表达对cyclin D1蛋白表达水平有负调控作用，并且抑制cyclin D1启动子活性。相反，组成型活性MKK 1，经典的p42/44 MAPK激活剂，增加细胞周期蛋白D1启动子活性和蛋白水平。结论：细胞周期蛋白D1启动子活性和细胞周期进程受TAK 1-MKK 6-p38 K通路负调控，而受MKK 1-p42/44 MAPK通路正调控。