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

Mol Endocrinol. 1995 Mar;9(3):361-7. doi: 10.1210/mend.9.3.7539889.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology*
  • Cell Division / drug effects*
  • Cell Line
  • Culture Media, Conditioned
  • Embryo, Mammalian
  • Fibroblasts / cytology*
  • Fluorescent Antibody Technique
  • Humans
  • Insulin-Like Growth Factor Binding Proteins
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Microscopy, Confocal
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / genetics*
  • Signal Transduction
  • Transfection


  • Carrier Proteins
  • Culture Media, Conditioned
  • Insulin-Like Growth Factor Binding Proteins
  • RNA, Messenger
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1