REGULATION OF TRANSFORMING GROWTH-FACTOR-BETA SUBTYPES BY MEMBERS OF THE STEROID-HORMONE SUPERFAMILY

Transforming growth factor-beta-s (TGF-beta-s) are potent regulators of cell growth and differentiation. Expression of the closely related TGF-beta subtypes in vivo is differentially regulated both temporally and spatially. Members of the steroid hormone superfamily may play an important role in this gene- and tissue-specific regulation. We have shown that anti-estrogens induce the production of TGF-beta-1 in mammary carcinoma cells and fetal fibroblasts, whereas retinoic acid specifically induces TGF-beta-2 in primary epidermal keratinocytes. The induction of TGF-beta-2 by retinoids is accompanied by an increase in TGF-beta-2 mRNAs, but little change in transcription rates, suggesting an effect of retinoids on message stability or processing. In contrast, TGF-beta-1 mRNA levels are unchanged by anti-estrogen treatment, suggesting these compounds may regulate the translatability of the TGF-beta-1 message or some post-translational processing event. We have identified a stable stem-loop structure in the 5' untranslated region (UTR) of the TGF-beta-1 mRNA that inhibits translation of a heterologous reporter gene, and we are investigating the possibility that anti-estrogens may regulate the activity of this element, and hence the translatability of the TGF-beta-1 message. A significant fraction (25-90%) of the TGF-beta induced by retinoids and anti-estrogens is in the biologically active rather than the latent form. We have shown that active TGF-beta has a much shorter in vivo half-life than latent TGF-beta, suggesting that the TGF-beta induced by retinoids and steroids may act locally at the site of production. Since many tumor cells retain sensitivity to the growth inhibitory effects of active TGF-beta, the use of members of the steroid hormone superfamily for inducing this potent growth inhibitor locally at the tumor site may have therapeutic potential.