DIMINISHED EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR (IGF) BINDING PROTEIN-5 AND ACTIVATION OF IGF-I-MEDIATED AUTOCRINE GROWTH IN SIMIAN-VIRUS 40-TRANSFORMED HUMAN FIBROBLASTS

The reduced growth factor requirements of murine fibroblasts transform ed by simian virus 40 (SV 40) have been attributed to insulin-like gro wth factor (IGF)-I induction by T antigen and consequent activation of IGF-I receptor signaling. The present study shows that the autonomous growth of SV 40-transformed human fibroblasts also requires type-I IG F-I receptor activation but that this is not due to de novo induction of IGF-I gene expression since untransformed human fibroblasts, which fail to proliferate in the absence of serum, also showed IGF-I gene ex pression under serum-free conditions. DNA synthesis assays confirmed t hat untransformed cells were responsive to exogenous IGF and indicated that transformed cells were already maximally stimulated, In untransf ormed fibroblasts. IGF binding was principally to abundant membrane-as sociated IG FBP-5, whereas in transformed fibroblasts this protein was minimally expressed, and IGF binding was to IGF receptors. Loss of de tectable membrane-associated IGFBP-5 in transformed cells was associat ed with diminished IGFBP-5 gene expression and with loss of IGF-II gen e expression. Exogenous IGFBP-5 associated with the membranes of trans formed cells and inhibited the autocrine growth of these cells. These findings suggest that loss of IGFBP-5 in SV 40 transformed fibroblasts facilitates interaction of endogenously produced IGF-I with the IGF-I receptor and increases their sensitivity to autocrine stimulation.