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Regulation of tumor angiogenesis by transcription factor LMO2

转录因子 LMO2 对肿瘤血管生成的调节

基本信息

批准号：
13670214
负责人：
YAMADA Yoshihiro
金额：
$ 2.62万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

项目摘要

LMO2 is activated by the chromosomal translocation associated with T cell lymphoblastic leukemia. We have studied the physiological role of LMO2 in the mouse development of hematnpoietic organ using gene targeting study. It revealed that LMO2 is necessary for the initiation of yolk sac erythropoiesis and adult hematopoiesis. This protein is also needed in the process of angiogenesis, although it is dispensable in vasculogenesis. LMO2 is composed of two tandemly repeated LIM domains which play important roles in protein-protein interactions. We think the LMO2 complex including TAL1, LDB1 and GATA1/2/3 is particularly important one in the process of fetal liver hematopoiesis and angiogenesis. LMO2 is used in the complex as the bridging molecule between TAL1, LDB1 and GATA1/2/3, in which N-terminal LIM domain (LIM1) is used in the interactions of LMO2 between TAL1 and LDB1, and C-terminal LIMdomain (LIM2) is used in those of LMO2 and GATA1/2/3.Neovascularization in the process of tumor growth in adult is considered to have the similar mechanism as embryonic angiogenesis. We observed the growth of vascular system in teratocarcinoma by injecting LMO2 null ES cells in mouse subcutaneous dorsa and compared it with the wild type ES cells. Without LMO2, mature blood vessels did not grow in the teratocarcinoma. This results suggest that LMO2 is also important in the tumor neovasuculization. We also studied the expression pattern of the transcription factors which are proved to be important in embryonic angiogenesis in human renal cell carcinoma. LMO2, TAL1, and ID1 was specifically expressed in the endothelium in the renal cell carcinoma. These factors are involved in tumor angiogenesis by up-regulating FLK1, which is the receptor of vascular endothelial growthfactor(VEGF).

LMO2被与T淋巴细胞白血病相关的染色体易位激活。我们利用基因靶向研究方法研究了LMO2在小鼠造血器官发育中的生理作用。结果表明，LMO2是卵黄囊红细胞形成和成体造血的必要条件。这种蛋白质在血管生成过程中也是必需的，尽管它在血管生成中是可有可无的。LMO2由两个串联重复的LIM结构域组成，在蛋白质-蛋白质相互作用中起重要作用。我们认为包括TAL1、LDB1和GATA1/2/3在内的LMO2复合物在胎儿肝脏造血血管生成过程中尤为重要。LMO2在配合物中作为TAL1、LDB1和GATA1/2/3之间的桥接分子，其中LMO2在TAL1和LDB1之间的相互作用中使用n端LIM结构域（LIM1）， LMO2和GATA1/2/3之间的相互作用中使用c端LIM结构域（LIM2）。成人肿瘤生长过程中的新生血管形成机制被认为与胚胎血管生成机制相似。我们在小鼠皮下背侧注射无LMO2的胚胎干细胞，观察畸胎癌血管系统的生长情况，并与野生型胚胎干细胞进行比较。在没有LMO2的情况下，畸胎癌中没有成熟血管的生长。这表明LMO2在肿瘤新生血管形成中也很重要。我们还研究了在人肾细胞癌胚胎血管生成中重要的转录因子的表达模式。LMO2、TAL1、ID1在肾细胞癌内皮中特异性表达。这些因子通过上调血管内皮生长因子（VEGF）受体FLK1参与肿瘤血管生成。