POSTTRANSCRIPTIONAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA 1

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In many cell types there is a large discrepancy between the measured levels of TGF-beta1 mRNA and protein. Furthermore, TGF-beta1 is generally secreted in a bio-logically latent form that must be activated prior to binding to the cell surface. This suggests that translational or post- translational mechanisms play an important role in the regulation of TGF- beta1 production. Clinically important members of the steroid hormone superfamily affect both these processes. To investigate translational regulation, expression constructs have been made in which various portions of the 5' and 3' untranslated regions (UTRs) of the TGF-beta1 cDNA have been deleted. The intrinsic translatability of the mRNAs is determined by in vitro translation, while in vivo translation efficiency of the same constructs in stably transfected breast cancer cell lines gives information on involvement of any transacting factors. Results are complex but indicate that (i) translational efficiency depends on which of the alternate transcriptional start sites are employed, (ii) the 3'-UTR stimulates translation, and (iii) the 3' and 5'-UTRs combined have non- additive effects, suggesting cross-talk between the two ends of the mRNA. Methodology has been developed for accurate measurement of TGF-betas in the plasma of human subjects. Normal controls show significant levels of circulating TGF-beta1 in the plasma (2.5 +/- 1.4 ng/ml; n=37). This suggests a hitherto unsuspected endocrine role for TGF-beta. Circulating TGF-beta is in the biologically latent form and is not associated with alpha-2-macroglobulin. An understanding of the mechanisms whereby steroids and related compounds regulate the production and activity of the TGF-beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer.