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首页> 外文期刊>Molecular and Cellular Biology >Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants.
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Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants.

机译：信号缺陷表皮生长因子受体突变体的抗癌活性。

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Overexpression and autocrine activation of the epidermal growth factor receptor (EGF-R) cause transformation of cultured cells and correlate with tumor progression in cancer patients. Dimerization and transphosphorylation are crucial events in the process by which receptors with tyrosine kinase activity generate normal and transforming cellular signals. Interruption of this process by inactive receptor mutants offers the potential to inhibit ligand-induced cellular responses. Using recombinant retroviruses, we have examined the effects of signalling-incompetent EGF-R mutants on the growth-promoting and transforming potential of ligand-activated, overexpressed wild-type EGF-R and the v-erbB oncogene product. Expression of a soluble extracellular EGF-R domain had little if any effect on the growth and transformation of NIH 3T3 cells by either tyrosine kinase. However, both a kinase-negative EGF-R point mutant (HERK721A) and an EGF-R lacking 533 C-terminal amino acids efficiently inhibited wild-type EGF-R-mediated, de novo DNA synthesis and cell transformation in a dose-dependent manner. Furthermore, coexpression with the v-erbBES4 oncogene product in NIH 3T3 cells resulted in transphosphorylation of the HERK721A mutant receptor and reduced soft-agar colony growth but had no effect in a focus formation assay. These results demonstrate that signalling-defective receptor tyrosine kinase mutants differentially interfere with oncogenic signals generated by either overexpressed EGF-R or the retroviral v-erbBES4 oncogene product.
机译：表皮生长因子受体（EGF-R）的过表达和自分泌激活导致培养细胞的转化，并与癌症患者的肿瘤进展相关。在具有酪氨酸激酶活性的受体产生正常的和转化的细胞信号的过程中，二聚化和转磷酸化是关键事件。非活性受体突变体中断该过程提供了抑制配体诱导的细胞应答的潜力。使用重组逆转录病毒，我们已经检查了无信号的EGF-R突变体对配体激活的，过表达的野生型EGF-R和v-erbB癌基因产物的生长促进和转化潜力的影响。可溶性细胞外EGF-R结构域的表达对任一酪氨酸激酶对NIH 3T3细胞的生长和转化几乎没有影响。但是，激酶阴性的EGF-R点突变体（HERK721A）和缺少533个C末端氨基酸的EGF-R均能有效抑制野生型EGF-R介导的从头DNA合成和细胞转化，并具有剂量依赖性方式。此外，在NIH 3T3细胞中与v-erbBES4癌基因产物共表达可导致HERK721A突变受体的转磷酸化，并降低软琼脂菌落的生长，但在病灶形成试验中没有作用。这些结果表明，信号缺陷受体酪氨酸激酶突变体差异性地干扰了由过表达的EGF-R或逆转录病毒v-erbBES4癌基因产物产生的致癌信号。

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