An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I.

Abstract

The insulin-like growth factors IGF-I and IGF-ll circulate in blood bound to carrier proteins. The higher molecular mass IGF-binding protein complex (150 kDa) is composed of subunits, and one subunit that forms this complex is growth hormone dependent. In addition, many cell types and tissues secrete another form of IGF binding protein that is not growth hormone dependent. Both forms of the IGF binding protein are believed to inactivate the IGFs and to function as delivery systems to tissues. This conclusion was based on studies that determined the effects of impure preparations of these binding proteins or that examined the effect of these proteins only on the insulin-like actions of the IGFs. We report here that a pure preparation of the extracellular form of the IGF binding protein (purified from human amniotic fluid) markedly potentiated replication of several cell types in response to human IGF-I. Secondary cultures of human, mouse, and chicken embryo fibroblasts as well as porcine aortic smooth muscle cells showed marked enhancement of their DNA synthesis response (2.8-to 4.4-fold increases) to IGF-I in the presence of this protein. These responses were synergistic since the sum of the responses to either IGF-I or to the binding protein alone was between 8 and 17% of the increase obtained in cultures exposed to both peptides. The binding protein not only potentiated the DNA synthesis response but also enhanced the increase in cell number in response to IGF-I. This stimulation is specific for growth factors that bind to the binding protein since incubation with insulin, which binds to the type

Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: a potential local regulator of IGF action.

“…IGF-BP I and IGF-BP III have been shown to inhibit or enhance the action of the IGFs depending on the culture conditions (16)(17)(18). These findings are consistent with a role for BPs in regulating the responsiveness of cells to IGFs.…”

“…At each step during the purification of BP, aliquots of fractions were diluted with DMEM containing 1 mg of bovine serum albumin per ml and used for the following assays. (i) BP assay: This assay was based on the principle that polyethylene glycol (PEG) precipitated the large molecular weight BP-IGF complex and not the small molecular weight IGF (18). Briefly, 50 p.1 of sample was incubated with 25,000-50,000 cpm of 1251-labeled IGF-I or IGF-II (1251-IGF-I or 125I-IGF-II) for 60 min at room temperature in 0.1 M Hepes/0.…”

Insulin-Like Growth Factor I in Substrate-Deprived, Growth-Retarded Fetal Rats

“…Recent evidence, however, suggests that the biologic action of IGF-I is strongly modified by the relative concentrations of its binding proteins in plasma, amniotic fluid, and a variety of tissues (27)(28)(29)(30)(31)(32). Thus, a measurement in blood or tissue of the IGF-I concentration after removal of the binding proteins gives only one index of the biologic action of this growth factor.…”

Production of immunoreactive insulin-like growth factor-I (IGF-I) and IGF-I binding proteins by human lung tumours

“…BPs have been shown to inhibit the effects of IGF-I and IGF-II on fibroblast DNA synthesis (Knauer & Smith, 1980). Binding of these proteins to cell surfaces increases the binding of IGF-I to its receptor (Clemmons et al, 1986) and IGF-I BPs have been shown markedly to potentiate the replication of human mouse and chicken embryo fibroblasts in response to IGF-I stimulation (Elgin et al, 1987). Hence the production of IGF-I BPs by SCLC cells raises the possibility that these proteins similarly modulate the mitogenic responsiveness of SCLC to IGF-I stimulation.…”