THE TUMOR-SUPPRESSOR SMAD4 DPC4 AND TRANSCRIPTIONAL ADAPTER CBP/P300 ARE COACTIVATORS FOR SMAD3 IN TGF-BETA-INDUCED TRANSCRIPTIONAL ACTIVATION/

Smads regulate transcription of defined genes in response to TGF-beta receptor activation, although the mechanisms of Smad-mediated transcri ption are not well understood. We demonstrate that the TGF-beta-induci ble Smad3 uses the tumor suppressor Smad4/DPC4 and CBP/p300 as transcr iptional coactivators, which associate with Smad3 in response to TGF-b eta. The association of CBP with Smad3 was localized to the carboxyl t erminus of Smad3, which is required for transcriptional activation, an d a defined segment in CBP. Furthermore, CBP/p300 stimulated both TGF- beta- and Smad-induced transcription in a Smad4/DPC4-dependent fashion . Smad3 transactivation and TGF-beta-induced transcription were inhibi ted by expressing E1A, which interferes with CBP functions. The coacti vator functions and physical interactions of Smad4 and CBP/p300 with S mad3 allow a model for the induction of gene expression in response to TGF-beta.