OVEREXPRESSION OF INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-3 BY SENESCENT HUMAN FIBROBLASTS - ATTENUATION OF THE MITOGENIC RESPONSE TO IGF-I
OVEREXPRESSION OF INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-3 BY SENESCENT HUMAN FIBROBLASTS - ATTENUATION OF THE MITOGENIC RESPONSE TO IGF-I
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DOI：
10.1006/excr.1995.1234
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发表时间：
1995-08-01
影响因子：
3.7
通讯作者：
GOLDSTEIN, S
中科院分区：
文献类型：
--
作者：
GRIGORIEV, VG;MOERMAN, EJ;GOLDSTEIN, S
我们以前已经证明，衰老的人二倍体成纤维细胞（HDF）产生大量的IGF-结合蛋白-3（IGFBP-3）相比，早期通过积极增殖HDF。为了确定这种过量的IGFBP-3积累是否在衰老HDF中观察到的DNA合成衰减中起作用，我们检查了这些细胞对IGF-I和两种IGF-I功能类似物[QAYL]IGF-I和胰岛素的反应，这两种类似物对IGFBP-3具有极低的结合亲和力，但通过IGF-I质膜受体发挥其促有丝分裂作用。与IGF-I相比，衰老HDF显示DNA合成反应对[QAYL]IGF-I和胰岛素的敏感性增加。IGF结合活性在衰老HDF的条件培养基中显著高于年轻HDF的培养基，并且几乎所有这种增强的结合能力都可以由IGFBP-3解释。将重组IGFBP-3以相对于IGF-I为1：1的恒定摩尔比添加到年轻细胞中显著减弱了对IGF-I的响应，并且在2：1摩尔比时消除了响应。这些数据表明，当以摩尔过量存在时，衰老HDF培养基中积累的IGFBP-3可以结合并螯合IGF，从而导致衰老HDF对IGF-I的应答减弱的重要部分。(C)出版社：Academic Press
We have previously demonstrated that senescent human diploid fibroblasts (HDF) produce large amounts of IGF-binding protein-3 (IGFBP-3) in comparison to early-passage vigorously proliferative HDF. In order to determine whether this excess IGFBP-3 accumulation plays a role in the observed attenuation of DNA synthesis in senescent HDF, we examined the response of these cells to IGF-I and two IGF-I functional analogs, [QAYL]IGF-I and insulin, both of which have extremely low binding affinity for IGFBP-3 but which exert their mitogenic effect via the IGF-I plasma membrane receptor. Senescent HDF showed an increased sensitivity of DNA synthetic response to [QAYL]IGF-I and insulin compared to IGF-I. IGF binding activity was significantly higher in conditioned medium of senescent HDF than the medium of young HDF, and virtually all of this enhanced binding capacity could be accounted for by IGFBP-3. Addition of recombinant IGFBP-3 to young cells at a constant molar ratio of 1:1 with respect to IGF-I significantly attenuated the response to IGF-I and abolished the response at a 2:1 molar ratio. These data indicate that IGFBP-3 accumulated in medium of senescent HDF can bind and sequester IGFs when present in molar excess and thereby account for a significant part of the attenuated response of senescent HDF to IGF-I. (C) 1995 Academic Press, Inc.