Dawson T P, Radulescu A, Wynford-Thomas D
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.
Cancer Res. 1995 Feb 15;55(4):915-20.
There is substantial evidence supporting the existence of insulin-like growth factor 1 (IGF-1) autocrine circuits in many tumor types, although the underlying inducing event has remained undefined. In order to address this matter, we have generated several immortalized human thyroid epithelial cell lines containing a zinc-inducible mutant H-ras gene and used these to investigate the relationship between expression of mutant p21ras and secretion of IGF-1. Induction of the transgene in the presence of zinc ions (Zn2+) was confirmed by Northern blot analysis and immunocytochemistry. IGF-1 levels in serum-free medium, stripped of binding proteins, were monitored using a sensitive radioimmunoassay. Expression of mutant p21ras in these cells, induced by Zn2+, resulted in an approximate 30-fold increase in the IGF-1 production rate, reaching a level exceeding that of human embryo fibroblasts. The data presented here suggest that an activating mutation of a ras oncogene may directly account for IGF-1 secretion in some human tumor cells.
有大量证据支持在许多肿瘤类型中存在胰岛素样生长因子1（IGF-1）自分泌回路，尽管潜在的诱导事件仍不明确。为了解决这个问题，我们构建了几种含有锌诱导型突变H-ras基因的永生化人甲状腺上皮细胞系，并利用这些细胞系研究突变型p21ras的表达与IGF-1分泌之间的关系。通过Northern印迹分析和免疫细胞化学证实了在锌离子（Zn2+）存在下转基因的诱导。使用灵敏的放射免疫测定法监测去除结合蛋白的无血清培养基中的IGF-1水平。由Zn2+诱导的这些细胞中突变型p21ras的表达导致IGF-1产生率增加约30倍，达到超过人胚胎成纤维细胞的水平。此处给出的数据表明，ras癌基因的激活突变可能直接导致某些人类肿瘤细胞中IGF-1的分泌。
