RAPID INDUCTION OF HEPARIN-BINDING EPIDERMAL GROWTH-FACTOR DIPHTHERIA-TOXIN RECEPTOR EXPRESSION BY RAF AND RAS ONCOGENES
RAPID INDUCTION OF HEPARIN-BINDING EPIDERMAL GROWTH-FACTOR DIPHTHERIA-TOXIN RECEPTOR EXPRESSION BY RAF AND RAS ONCOGENES
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DOI：
10.1101/gad.9.16.1953
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发表时间：
1995-08-15
影响因子：
10.5
通讯作者：
MCMAHON, M
中科院分区：
文献类型：
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作者：
MCCARTHY, SA;SAMUELS, ML;MCMAHON, M
我们已经使用差异显示PCR来寻找由Delta Raf-1：ER诱导的mRNA，这是Raf-1激酶的一种雌二醇依赖形式。通过这种方法，编码肝素结合表皮生长因子（HB-EGF）的基因被鉴定为致癌Raf激酶的立即早期转录靶点。Delta Raf-1：ER和B-Raf的条件致癌形式Delta B-Raf：ER的激活导致快速和持续诱导HB-EGF mRNA表达和成熟HB-EGF从细胞中分泌。中和抗HB-EGF抗血清防止了在Delta Raf-1：ER转化的细胞中观察到的c-Jun氨基末端激酶的延迟激活。这些结果表明，不同的信号转导途径可以通过多肽生长因子的分泌进行串扰。此外，细胞转化的致癌Ras，这也诱导HB-EGF的表达，表现出显着增加的敏感性白喉毒素的细胞毒性作用，其中膜锚定HB-EGF前体作为细胞表面受体。
We have used differential display PCR to search for mRNAs induced by Delta Raf-1:ER, an estradiol-dependent form of the Raf-1 kinase. Through this approach the gene encoding heparin-binding epidermal growth factor (HB-EGF) was identified as an immediate-early transcriptional target of oncogenic Raf kinases. Activation of Delta Raf-1:ER and a conditional oncogenic form of B-Raf, Delta B-Raf:ER, resulted in rapid and sustained induction of HB-EGF mRNA expression and secretion of mature HB-EGF from cells. Neutralizing anti-HB-EGF antisera prevented the delayed activation of the c-Jun amino-terminal kinases that is observed in cells transformed by Delta Raf-1:ER. These results demonstrate that distinct signaling pathways can cross talk via the secretion of polypeptide growth factors. Furthermore, cells transformed by oncogenic Ras, which also induced HB-EGF expression, demonstrated a marked increase in sensitivity to the cytotoxic action of diphtheria toxin, for which the membrane anchored HB-EGF precursor acts as a cell-surface receptor.