Retinoids induce cellular differentiation and inhibit cellular proliferation. Proliferation of human breast carcinoma cells in vitro is markedly inhibited by these compounds. On the other hand, insulin-like growth factors (IGFs) and their receptors seem to be involved in the growth of certain breast carcinoma cells by autocrine or paracrine effects. Since the effects of both IGF-I and IGF-II may be modulated by specific binding proteins (IGF-BPs) we examined the possibility that one mechanism by which retinoic acid may inhibit cancer growth is by an alteration in these BPs, thereby blocking IGF's growth effect. Retinoic acid (RA; 1 microM) completely blocked the effect of IGF-I (50 ng/ml) on enhancing proliferation of MCF-7 cells in culture. This effect of RA was not associated with any significant change in specific IGF-I-binding sites on these cells. RA induced a 3-fold increase in IGF-binding activity in conditioned medium, measured using a polyethylene glycol-immunoglobulin precipitation assay and a charcoal absorption assay. This increase was associated with the appearance of 42- and 46-kDa IGF-BPs on ligand blotting. The effect of RA on these IGF-BPs was time and concentration dependent. In contrast, during some experiments the 27- and 36-kDa BPs actually decreased. These findings support the hypothesis that RA may inhibit the growth of certain breast carcinoma cells by increasing the secretion of certain IGF-BPs, which could directly modulate the growth effect of IGFs.
The production and binding of transforming growth factor P (TGFP) were compared in dermal fibroblast tines derived from scleroderma patients and normal control donors. The mean 2 SEM 24-hour level of secretion of TCFP by fibroblast lines derived from the involved skin of scleroderma patients was 30.8 f 5.5 pmoles/106 cells, and it was 29.7 f 5.8 pmoles/106 cells for fibroblast lines derived from the normal skin of the healthy donors. Thus, we found that the fibroblasts themselves produced TGFP. TGFP production was equivalent in fibroblast lines derived from clinically involved and uninvolved skin of scleroderma patients. is a heterodimer that contains 1 of each of these chains (2). TGFP3 has homology with the other forms (3).TGFP is produced and secreted in latent form by a variety of cell types, including normal human placenta cells (4). peripheral blood lymphocytes (51, activated T cells (6), platelets (7.8). and embryo fibroblasts (9). Latent TGFP becomes activated by proteases or by nonenzymatic means, such as acidification, alkalinization. or exposure to denaturing agents (9.10). Once activated, TGFP is able to bind to its receptors and exert biologic effects (11). Cells exposed to activated exogenous TGFpl may increase their own production of TGFPl messenger RNA (mKNA) and protein (12,131.Specific receptors for TGFP have been identified through binding of radiolabeled TGFP (2.14, IS). These receptors have high affinity for TGFPl and varying degrees of affinity for TGFPI.2 or T G F P . Type 1 and type I1 TGFP receptor species are 65-kd and 95-kd moieties, respectively. Type 111 receptors are 250-350-kd molecules that form a 560-600-kd disulfide-linked receptor complex, which represents the major TGFP receptor species in mammalian and avian fibroblasts and epithelial cells (16). The mechanism by which TGFP activates postreceptor cellular processes remains elusive, although recent evidence suggests that a yet-undescribed protein kinase may be involved (17).TCFP appears to play a major role in wound
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