Smad3 is a direct mediator of transcriptional activation by the TGFβ receptor. Its target genes in epithelial cells include cyclin-dependent kinase inhibitors that generate a cytostatic reponse. We defined how, in the same context, Smad3 can also mediate transcriptional repression of the growth-promoting gene c-myc. A complex containing Smad3, the transcription factors E2F4/5 and DP1, and the corepressor p107 preexists in the cytoplasm. In response to TGFβ, this complex moves into the nucleus and associates with Smad4, recognizing a composite Smad-E2F site on c-myc for repression. Previously known as the ultimate recipients of cdk regulatory signals, E2F4/5 and p107 act here as transducers of TGFβ receptor signals upstream of cdk. Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)