Activation of Smad1-mediated transcription by p300/CBP

Smad 1 is the intracellular effector of bone morphogenetic proteins (BMPs), a growth factor family well known to stimulate bone and cartilage formatio n. Smad1 becomes phosphorylated by the cognate BMP transmembrane receptor p rotein kinases, associates with the common mediator Smad4 and translocates to the nucleus where it is involved in regulation of gene transcription. In this report we demonstrate that Smad1 interacts with the paralogous coacti vators p300 and CBP both in vitro and in vivo. The N- and C-termini of Smad 1 negatively interfere with binding to p300/CBP, and the C-terminal half o f Smad1 harbors two interaction domains both binding to the same region nea r the C-terminus of p300/CBP. We show that Smad1 as well as a Ga14 fusion w ith the C-terminal half of Smad1 stimulate gene transcription in a cooperat ive fashion with p300/CBP. Phosphorylation of Smad1 enhances its binding to CBP and thereby further stimulates Smad1-dependent transcription. These re sults provide a mechanism how phosphorylated Smad1 regulates gene activity by interaction with p300/CBP, and factors associated with these bridging co activators, (C) 1999 Elsevier Science B.V. All rights reserved.