B. Valentinis et al., THE HUMAN INSULIN-LIKE GROWTH-FACTOR (IGF) BINDING PROTEIN-3 INHIBITSTHE GROWTH OF FIBROBLASTS WITH A TARGETED DISRUPTION OF THE IGF-I RECEPTOR GENE, Molecular endocrinology, 9(3), 1995, pp. 361-367
The insulin-like growth factors (IGFs) are important mitogens that exe
rt their proliferative effects on cells via the type I IGF receptors (
IGF-R). The IGFs also associate with IGF binding proteins (IGFBPs). IG
F-inhibitory, IGF-stimulatory, and IGF-independent effects of IGFBPs o
n cell growth have been reported. We have asked whether the IGFBP-3 ha
s an effect on cell growth, which is independent of its ability to bin
d IGF-I and thus inhibit the activation of the IGF-I receptor. For thi
s purpose, we have used a fibroblast cell line (R(-)cells) derived fro
m 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 a
ffinity and specificity, R(-)cells transfected with a mammalian expres
sion vector containing the human (h) IGFBP-3 cDNA were selected (R(-)/
BP3) and found to express hlGFBP-3 mRNA (detected by Northern blots) a
nd to secrete hlGFBP-3 protein [detected by Western ligand blotting (W
LB), immunoblotting, and immunoprecipitation as well as immunofluoresc
ence confocal microscopy]. Growth of five different R(-)cells, and 10-
fold slower compared with W cells, grown under identical conditions. C
onfluent 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 conc
lude that the cellular production of IGFBPs serves as a negative regul
ator of cell proliferation which involves a cellular signaling pathway
separate from the IGF-IGF-R system.