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.
Wakefield
L
L
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892.
Kim
S J
SJ
Glick
A
A
Winokur
T
T
Colletta
A
A
Sporn
M
M
D000818:Animals; D000970:Antineoplastic Agents; D002454:Cell Differentiation; D002455:Cell Division; D015870:Gene Expression; D006728:Hormones / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D013256:Steroids / Q000494:pharmacology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D006728:Hormones; D013256:Steroids; D016212:Transforming Growth Factor beta