REGULATION OF TRANSFORMING-GROWTH-FACTOR-BETA-INDUCED AND ACTIVIN-INDUCED TRANSCRIPTION BY MAMMALIAN MAD PROTEINS

Members of the transforming growth factor beta (TGF-beta) superfamily are involved in diverse physiological activities including development , tissue repair, hormone regulation, bone formation, cell growth, and differentiation. At the cellular level, these functions are initiated by the interaction of ligands with specific transmembrane receptors wi th intrinsic serine/threonine kinase activity. The signaling pathway t hat links receptor activation to the transcriptional regulation of the target genes is largely unknown. Recent work in Drosophila and Xenopu s signaling suggested that Mad (Mothers against dpp) functions downstr eam of the receptors of the TGF-beta family. Mammalian Mad1 has been r eported to respond to bone morphogenetic protein (BMP), but not to TGF -beta or activin. We report here the cloning and functional studies of a novel mammalian Mad molecule, Mad3, as well as a rat Mad1 homologue . Overexpression of Mad3 in a variety of cells stimulated basal transc riptional activity of the TGF-beta/activin-responsive reporter constru ct, p3TP-Lux. Furthermore, expression of Mad3 could potentiate the TGF -beta- and activin-induced transcriptional stimulation of p3TP-Lux. By contrast, overexpression of Mad1 inhibited the basal as sell as the T GF-beta/activin induced p3TP-Lux activity. These findings, therefore, support the hypothesis that Mad3 may serve as a mediator linking TGF-b eta/activin receptors to transcriptional regulation.