E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression.
Smad3 is a direct mediator of transcriptional activation by the TGFbeta 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 TGFbeta, 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 TGFbeta receptor signals upstream of cdk. Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners.
Chen
Chang-Rung
CR
Cell Biology Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Kang
Yibin
Y
Siegel
Peter M
PM
Massagué
Joan
J
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D020868:Gene Silencing; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; C092558:E2F5 protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C493844:RBL1 protein, human; D018125:Receptors, Transforming Growth Factor beta; D050720:Retinoblastoma-Like Protein p107; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C493735:TFDP1 protein, human; C094103:TFDP2 protein, human; D015534:Trans-Activators; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta