MONOCLONAL-ANTIBODY TO THE TYPE-I INSULIN-LIKE GROWTH-FACTOR (IGF-I) RECEPTOR BLOCKS IGF-I RECEPTOR-MEDIATED DNA-SYNTHESIS - CLARIFICATION OF THE MITOGENIC MECHANISMS OF IGF-I AND INSULIN IN HUMAN-SKIN FIBROBLASTS
MONOCLONAL-ANTIBODY TO THE TYPE-I INSULIN-LIKE GROWTH-FACTOR (IGF-I) RECEPTOR BLOCKS IGF-I RECEPTOR-MEDIATED DNA-SYNTHESIS - CLARIFICATION OF THE MITOGENIC MECHANISMS OF IGF-I AND INSULIN IN HUMAN-SKIN FIBROBLASTS
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DOI：
10.1073/pnas.83.3.664
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发表时间：
1986-02-01
影响因子：
11.1
通讯作者：
MOSES, AC
中科院分区：
文献类型：
--
作者：
FLIER, JS;USHER, P;MOSES, AC
胰岛素和胰岛素样生长因子I型（IGF-I）刺激人皮肤成纤维细胞的生物反应重叠谱。虽然已知胰岛素和IGF-I可刺激[3 H]胸苷掺入这些细胞的DNA中，但介导该效应的受体的身份尚未完全阐明。小鼠抗人IGF-I受体抗体α IR-3特异性结合人胎盘膜中的IGF-I而非胰岛素受体;它还以剂量依赖性方式特异性抑制125 I标记的IGF-I而非125 I标记的胰岛素与人皮肤成纤维细胞悬浮液的结合。α IR-3竞争性抑制IGF-I介导的对[3 H]胸苷掺入DNA的刺激。这种抑制依赖于α IR-3的浓度，并且在固定抗体浓度存在下，可以被高浓度的IGF-I部分克服。相反，在< 1 μ g/ml的浓度下，胰岛素刺激[3 H]胸苷掺入的作用不被α IR-3抑制。然而，较高浓度（> 1 μ g/ml）的胰岛素对[3 H]胸苷掺入的增量效应被α IR-3抑制。α IR-3是人皮肤成纤维细胞中IGF-I受体介导的有丝分裂的高度特异性拮抗剂。通过使用这种抗体，直接表明胰岛素可以通过IGF-I受体刺激DNA合成，但也可以通过胰岛素受体本身激活这种作用。
Insulin and insulin-like growth factor type I (IGF-I) stimulate an overlapping spectrum of biological responses in human skin fibroblasts. Although insulin and IGF-I are known to stimulate the incorporation of [3H]thymidine into DNA in these cells, the identity of the receptor(s) that mediates this effect has not been fully clarified. The mouse anti-human IGF-I receptor antibody .alpha.IR-3 binds with specificity to IGF-I but not to insulin receptors in human placental membranes; it also specifically inhibits the binding of 125I-labeled IGF-I but not 125I-labeled insulin to suspensions of human skin fibroblasts in a dose-dependent manner. .alpha.IR-3 competitively inhibits IGF-I-mediated stimulation of [3H]thymidine incorporation into DNA. This inhibition is dependent on the concentration of .alpha.IR-3 and in the presence of a fixed antibody concentration can be partially overcome by high concentrations of IGF-I. In contrast, at concentrations of < 1 .mu.g/ml, the effect of insulin to stimulate [3H]thymidine incorporation is not inhibited by .alpha.IR-3. However, the incremental effects of higher concentrations (> 1 .mu.g/ml) of insulin on [3H]thymidine incorporation are inhibited by .alpha.IR-3. .alpha.IR-3 is a highly specific antagonist of IGF-I receptor-mediated mitogenesis in human skin fibroblasts. By using this antibody, it is shown directly that insulin can act through the IGF-I receptor to stimulate DNA synthesis but can also activate this effect through the insulin receptor itself.