Smad6 Recruits Transcription Corepressor CtBP To Repress Bone Morphogenetic Protein-Induced Transcription

Abstract

Smad6 and Smad7 are inhibitory Smads induced by transforming growth factor β-Smad signal transduction pathways in a negative-feedback mechanism. Previously it has been thought that inhibitory Smads bind to the type I receptor and block the phosphorylation of receptor-activated Smads, thereby inhibiting the initiation of Smad signaling. Conversely, few studies have suggested the possible nuclear functions of inhibitory Smads. Here, we present compelling evidence demonstrating that Smad6 repressed bone morphogenetic protein-induced Id1 transcription through recruiting transcriptional corepressor C-terminal binding protein (CtBP). A consensus CtBP-binding motif, PLDLS, was identified in the linker region of Smad6. Our findings show that mutation in the motif abolished the Smad6 binding to CtBP and subsequently its repressor activity of transcription. We conclude that the nuclear functions and physical interaction of Smad6 and CtBP provide a novel mechanism for the transcriptional regulation by inhibitory Smads.

ACKNOWLEDGMENTS

We thank Rik Derynck for critically reading the manuscript; Xiao-Fan Wang for advice, Kohei Miyazono for providing numerous reagents including Smad6 cDNA, deletion mutants, and Smad6/7 chimeras; Richard Goodman for providing Flag-CtBP; Eric Olson for providing myc-CtBP; Xiao-Hong Sun for providing Id1 cDNA; and Tetsuya Taga and Robert Benezra for providing the Id1-luc reporter. Smad6 adenovirus was kindly provided by Jingsong Zhao with permission from Kohei Miyazono. Sincere thanks also go to Irene Harrison for her critical reading and editing.

This work was supported by grants from American Cancer Society (RSG-02-145-01-CCG to X.L. and RSG-00-214-01-CCG to X.-H.F.) and the National Institutes of Health (F32 GM70690 to Y.J.S., R01 CA95731 to F.C.B., R01 GM53874 to Y.S., and R01 GM63773 to X.-H.F.). X.-H.F. is a Leukemia & Lymphoma Society Scholar.