Post-transcriptional and post-translational regulation of insulin-like growth factor binding protein-3 and-4 by insulin-like growth factor-I in uterine myometrial cells

Involution of the uterus induced by oestrogen depletion is associated with a decrease in uterine insulin-like growth factor (IGF)-1 and an increase in IGF binding protein (IGFBP) gene expression, We examined the effects of IG F-1 on primary uterine myometrial cell proliferation, and on IGFBP-3 and IG FBP-4 gene expression. IGF-1 enhanced DNA synthesis in these cells. In cond itioned media, IGF-1 increased IGFBP-3 accumulation by release of cell asso ciated IGFBP-3. A low dose of IGF-1 increased IGFBP-4 accumulation, and a h igh dose caused IGFBP-4 to disappear. in cell-free conditioned media IGF-1 protected IGFBP-3 and enhanced IGFBP-4 proteolysis. Go-incubation of [(125) ]-IGFBP-4 with cell-free conditioned media cleaved IGFBP-4 into 18 and 12 k Da fragments. Northern blot analysis indicated that IGF-1 increased IGFBP-4 mRNA accumulation by stabilizing the mRNA while IGFBP-3 gene expression wa s slightly decreased. The results demonstrate that IGF-1 regulates IGFBP-4 post-trancriptionally and post-translationally, whereas IGFBP-3 is only aff ected post-translationally. By enhancing IGFBP-4 proteolysis, increasing ce ll-associated IGFBP-3 and stabilizing IGFBP-3, IGF-1 may initiate a mitogen ic response. (C) 2000 Harcourt Publishers Ltd.