DIFFERENTIAL EXPRESSION OF THE TGF-BETA ISOFORMS IN EMBRYOGENESIS SUGGESTS SPECIFIC ROLES IN DEVELOPING AND ADULT TISSUES

The TGF-beta's are multifunctional, pleiotropic molecules with major effects in control of cellular migration, cellular proliferation, and elaboration of extracellular matrix. Thus far, five distinct isoforms of TGF-beta have been described, each approximately 65-85% homologous and containing the characteristic 9 positionally conserved cysteine residues. Although the actions of the activated mature forms of the different isoforms on cells are qualitatively similar in most cases, there are a few examples of distinct activities. For example, TGF-beta's 1 and 3, but not TGF-beta-2, inhibit the growth of large vessel endothelial cells, and TGF-beta's 2 and 3, but not TGF-beta-1, inhibit the survival of cultured embryonic chick ciliary ganglionic neurons. In addition, selective targeting of the latent forms of the TGF-beta's is suggested by the observation that latent TGF-beta-2 is the prominent isoform found in body fluids such as amniotic fluid, breast milk, and the aqueous and vitreous humor of the eye; it is noteworthy in this regard that TGF-beta-2 is unique among various isoforms in that it lacks a RGD integrin-binding sequence in its precursor. The most dramatic differences in the TGF-beta isoforms are seen at the level of expression, where there is now a wealth of data demonstrating both spatially and temporally distinct expression of both the mRNAs and proteins in developing tissues, regenerating tissues, and in pathologic responses. Moreover, the post-transcriptional regulation of TGF-beta expression by members of the steroid/retinoid family of nuclear receptors is also isoform-specific; thus, treatment of keratinocytes with retinoids induces secretion of TGF-beta-2, whereas treatment of breast cancer cells with gestodene, a synthetic progestin, induces secretion of TGF-beta-1. Recent characterization of the 5' regulatory regions of the human TGF-beta-1, 2, and 3 genes suggests that distinct features of the promoters, including the presence of TATAA boxes and transcription factor binding sites, form the basis for the observed differential transcription.