THE FPS/FES PROTEIN-TYROSINE KINASE PROMOTES ANGIOGENESIS IN TRANSGENIC MICE
THE FPS/FES PROTEIN-TYROSINE KINASE PROMOTES ANGIOGENESIS IN TRANSGENIC MICE
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DOI：
10.1128/mcb.14.10.6755
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发表时间：
1994-10-01
影响因子：
5.3
通讯作者：
PAWSON, T
中科院分区：
文献类型：
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作者：
GREER, P;HAIGH, J;PAWSON, T
Fps/fes原癌基因编码一种细胞质蛋白酪氨酸激酶，已知在造血细胞中高表达。为了研究fps/fes的生物学功能，在人的fps/fes基因中引入了一个活化性突变，该突变直接导致了fps/fes蛋白的氨基末端肉豆蔻酸化。这种突变的肉豆蔻化蛋白诱导了大鼠2成纤维细胞的转化。突变的fps/fes等位基因被整合到小鼠生殖系中，并被发现在转基因小鼠中适当表达，其组织特异性模式与内源性小鼠基因的模式没有区别。这些小鼠表现出广泛的血管丰富，进展为多灶性血管瘤。用RNase保护法检测到转基因人和内源性FPS/FES转录本在血管肿瘤中均有高水平表达，并通过原位RNA杂交将FPS/FES转录本定位于血管肿瘤和正常血管内皮细胞。原代培养的人脐静脉内皮细胞也表达fps/fes转录本和fps/fes酪氨酸激酶。这些结果表明FPS/FES的表达是血管内皮细胞所固有的，提示FPS/FES蛋白酪氨酸激酶在血管生成的调节中起直接作用。
The fps/fes proto-oncogene encodes a cytoplasmic protein-tyrosine kinase known to be highly expressed in hematopoietic cells. To investigate fps/fes biological function, an activating mutation was introduced into the human fps/fes gene which directs amino-terminal myristylation of the Fps/Fes protein. This mutant, myristylated protein induced transformation of Rat-2 fibroblasts. The mutant fps/fes allele was incorporated into the mouse germ line and was found to be appropriately expressed in transgenic mice, in a tissue-specific pattern indistinguishable from that of the endogenous mouse gene. These mice displayed widespread hypervascularity, progressing to multifocal hemangiomas. High level of both the transgenic human and endogenous murine fps/fes transcripts were detected in vascular tumors by using RNase protection, and fps/fes transcripts were localized to endothelial cells of both the vascular tumors and normal blood vessels by in situ RNA hybridization. Primary human umbilical vein endothelial cultures were also shown to express fps/fes transcripts and the Fps/Fes tyrosine kinase. These results indicate that fps/fes expression is intrinsic to cells of the vascular endothelial lineage and suggest a direct role of the Fps/Fes protein-tyrosine kinase in the regulation of angiogenesis.