4E-BP1 is a target of Smad4 essential for TGFβ-mediated inhibition of cell proliferation

Autor: Stéphane Pyronnet, Christiane Susini, Rania Azar, Corinne Bousquet, Amandine Alard
Přispěvatelé: Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chirurgie Générale et Digestive [Rangueil], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise
Rok vydání: 2009
Předmět:
Small interfering RNA
Cell Cycle Proteins
MESH: Base Sequence
MESH: Mice
Knockout
environment and public health
MESH: Down-Regulation
Mice
Transforming Growth Factor beta
MESH: RNA
Small Interfering
MESH: Smad4 Protein
MESH: Animals
RNA
Small Interfering
Cells
Cultured
Smad4 Protein
Mice
Knockout
Regulation of gene expression
biology
General Neuroscience
MESH: Gene Expression Regulation
Neoplastic
Transfection
Cell biology
Gene Expression Regulation
Neoplastic
MESH: Response Elements
biological phenomena
cell phenomena
and immunity
Intracellular
MESH: Cells
Cultured
Down-Regulation
Response Elements
MESH: Phosphoproteins
Article
General Biochemistry
Genetics and Molecular Biology
MESH: Cell Proliferation
Animals
Humans
MESH: Mice
Molecular Biology
Transcription factor
MESH: Transforming Growth Factor beta
MESH: Adaptor Proteins
Signal Transducing
Adaptor Proteins
Signal Transducing
Cell Proliferation
MESH: Humans
Base Sequence
General Immunology and Microbiology
Cell growth
MESH: Transfection
Transforming growth factor beta
Phosphoproteins
Embryonic stem cell
enzymes and coenzymes (carbohydrates)
biology.protein
Zdroj: EMBO Journal
EMBO Journal, 2009, 28 (22), pp.3514-22. ⟨10.1038/emboj.2009.291⟩
ISSN: 1460-2075
0261-4189
DOI: 10.1038/emboj.2009.291
Popis: International audience; 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.
Databáze: OpenAIRE
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