| First Author | Azar R | Year | 2009 |
| Journal | EMBO J | Volume | 28 |
| Issue | 22 | Pages | 3514-22 |
| PubMed ID | 19834456 | Mgi Jnum | J:154683 |
| Mgi Id | MGI:4397734 | Doi | 10.1038/emboj.2009.291 |
| Citation | Azar R, et al. (2009) 4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation. EMBO J 28(22):3514-22 |
| abstractText | Assembly of the multi-subunit eukaryotic translation initiation factor-4F (eIF4F) is critical for protein synthesis and cell growth and proliferation. eIF4F formation is regulated by the translation-inhibitory protein 4E-BP1. While proliferation factors and intracellular pathways that impinge upon 4E-BP1 phosphorylation have been extensively studied, how they control 4E-BP1 expression remains unknown. Here, we show that Smad4, a transcription factor normally required for TGFbeta-mediated inhibition of normal cell proliferation, enhances 4E-BP1 gene-promoter activity through binding to a conserved element. 4E-BP1 expression is specifically modulated by treatment with TGFbeta and by manipulations of the natural Smad4 regulators (co-Smads) in cells isolated from Smad4(+/+) human tumours, whereas no response is observed in cells isolated from Smad4(-/-) human tumours or in cells where Smad4 has been knocked down by specific siRNAs. In addition, cells where 4E-BP1 has been knocked down (inducible shRNAs in human pancreatic cancer cells or siRNAs in non-malignant human keratinocytes) or has been knocked out (mouse embryonic fibroblasts isolated from 4E-BP1(-/-) mice) proliferate faster and are resistant to the antiproliferative effect of TGFbeta. Thus, 4E-BP1 gene appears critical for TGFbeta/Smad4-mediated inhibition of cell proliferation. |
