INDUCTION OF INHIBITORY SMAD6 AND SMAD7 MESSENGER-RNA BY TGF-BETA FAMILY MEMBERS

Smad6 and Smad7 function as intracellular antagonists in transforming growth factor-beta (TGF-beta) signaling. Here we report the isolation of human Smad6, which is closely related to Smad7. Smad6 and Smad7 mRN As were differentially expressed in lung cancer cell lines and were ra pidly and directly induced by TGF-beta 1, activin and bone morphogenet ic protein-7. Cross-talk between TGF-beta and other signaling pathways was demonstrated by the finding that epidermal growth factor (EGF) in duced the expression of inhibitory SMAD mRNA. Moreover, whereas the ph orbol ester PMA. alone had no effect, it potentiated the TGF-beta 1-in duced expression of Smad7 mRNA. Ectopic expression of anti-sense Smad7 RNA was found to increase the effect of TGF-beta 1, supporting its ro le as a negative regulator in TGF-beta signaling. Thus, expression of inhibitory Smads is induced by multiple stimuli, including the various TGF-beta family members, whose action they antagonize. (C) 1998 Acade mic Press.