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通过与T细胞淋巴细胞白血病相关的染色体易位激活。我们已经使用基因靶向研究研究了LMO2在血源器官的小鼠发育中的生理作用。它表明，LMO2对于蛋黄囊促红细胞生成和成年造血是必不可少的。尽管血管生成是可分配的，但在血管生成过程中也需要该蛋白质。 LMO2由两个串联重复的LIM结构域组成，它们在蛋白质 - 蛋白质相互作用中起重要作用。我们认为，在胎儿肝造血和血管生成过程中，包括TAL1，LDB1和GATA1/2/3在内的LMO2复合物尤为重要。 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机理作为胚胎血管生成。我们通过在小鼠皮下dorsa中注入LMO2 NULL ES细胞，并将其与野生型ES细胞进行了比较，观察到了teratocarcinoma中血管系统的生长。如果没有LMO2，则成熟的血管不会在变质癌中生长。该结果表明，LMO2在肿瘤新可核酸化中也很重要。我们还研究了转录因子的表达模式，这些转录因子在人肾细胞癌中被证明在胚胎血管生成中很重要。 LMO2，TAL1和ID1在肾细胞癌的内皮中特别表达。这些因素通过上调FLK1来参与肿瘤血管生成，后者是血管内皮生长剂（VEGF）的受体。