The human insulin-like growth factor (IGF) binding protein-3 inhibits the growth of fibroblasts with a targeted disruption of the IGF-I receptor gene.

Abstract

The insulin-like growth factors (IGFs) are important mitogens that exert their proliferative effects on cells via the type I IGF receptors (IGF-R). The IGFs also associate with IGF binding proteins (IGFBPs). IGF-inhibitory, IGF-stimulatory, and IGF-independent effects of IGFBPs on cell growth have been reported. We have asked whether the IGFBP-3 has an effect on cell growth, which is independent of its ability to bind IGF-I and thus inhibit the activation of the IGF-I receptor. For this purpose, we have used a fibroblast cell line (R- cells) derived from mouse embryos homozygous for a targeted disruption of the IGF-R gene. When compared with wild type cells (W), which bind IGF-I with high affinity and specificity, R- cells transfected with a mammalian expression vector containing the human (h) IG-FBP-3 cDNA were selected (R-/BP3) and found to express hIGFBP-3 mRNA (detected by Northern blots) and to secrete hIGFBP-3 protein [detected by Western ligand blotting (WLB), immunoblotting, and immunoprecipitation as well as immunofluorescence confocal microscopy]. Growth of five different R- cells, and 10-fold slower compared with W cells, grown under identical conditions. Confluent R- cells. These experiments show that the overexpression of IGFBP-3 has an inhibitory effect on cell growth which does not involve IGF binding to, or signal transduction via, the type I IGF-R. We conclude that the cellular production of IGFBPs serves as a negative regulator of cell proliferation which involves a cellular signaling pathway separate from the IGF-IGF-R system.

Insulin-like growth factor binding protein-3 (IGFBP-3) acts as an invasion-metastasis suppressor in ovarian endometrioid carcinoma

“…The constitutive expression vector, pKIGFBP-3, containing the full-length coding sequence of the hIGFBP-3 cDNA under the control of the hb-actin promoter, and the SV2-neo selection gene (containing resistance to G418) was used as previously described (Valentinis et al, 1995). The pK plasmid without hIGFBP-3 insert was used as control.…”

Interactions of High Affinity Insulin-like Growth Factor-binding Proteins with the Type V Transforming Growth Factor-β Receptor in Mink Lung Epithelial Cells

“…They coordinate and regulate the biological activities of IGF-I and IGF-II by serving as transporter proteins or carriers and by scavenging IGFs from IGF receptors (1)(2)(3). High affinity IGFBPs have also been shown to induce cellular responses in an IGF-independent manner (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). These IGF-independent actions of high affinity IGFBPs are believed to be mediated by specific cell-surface receptors or membrane proteins (6, 16 -18).…”

Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis

“…Transcription of the IGFBP3 gene has been shown to be increased by direct interaction of wildtype p53 with consensus p53 DNA binding sites within the IGFBP3 promoter (Buckbinder et al, 1995). The e ects of IGFBP3 on cells in culture have been attributed to both IGF-IR-dependent and -independent mechanisms (Valentinis et al, 1995;Conover and Powell, 1991). Exposure of human breast cancer cells in culture to IGFBP3 has been shown to inhibit growth and predispose the cells toward ceramide-induced apoptosis (Gill et al, 1997).…”