Coordinate Transcriptional and Translational Repression of p53 by TGF-β1 Impairs the Stress Response

• Published in: Molecular cell Vol. 50; no. 4; pp. 552 - 564
• Main Authors: López-Díaz, Fernando J., Gascard, Philippe, Balakrishnan, Sri Kripa, Zhao, Jianxin, del Rincon, Sonia V., Spruck, Charles, Tlsty, Thea D., Emerson, Beverly M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.05.2013
• Subjects: apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Base Sequence; Blotting, Western; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line; Cell Survival - drug effects; Cell Survival - genetics; Cells, Cultured; dissociation; drug resistance; E2F4 Transcription Factor - genetics; E2F4 Transcription Factor - metabolism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; gene expression regulation; Gene Expression Regulation - drug effects; genes; Humans; Immunohistochemistry; Mammary Glands, Human - cytology; messenger RNA; Molecular Sequence Data; polyribosomes; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; protein synthesis; proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; Smad Proteins - genetics; Smad Proteins - metabolism; stress response; Stress, Physiological - drug effects; Stress, Physiological - genetics; transcription; transcription (genetics); transforming growth factor beta 1; Transforming Growth Factor beta1 - pharmacology; translation (genetics); Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.04.029

Cellular stress results in profound changes in RNA and protein synthesis. How cells integrate this intrinsic, p53-centered program with extracellular signals is largely unknown. We demonstrate that TGF-β1 signaling interferes with the stress response through coordinate transcriptional and translational repression of p53 levels, which reduces p53-activated transcription, and apoptosis in precancerous cells. Mechanistically, E2F-4 binds constitutively to the TP53 gene and induces transcription. TGF-β1-activated Smads are recruited to a composite Smad/E2F-4 element by an E2F-4/p107 complex that switches to a Smad corepressor, which represses TP53 transcription. TGF-β1 also causes dissociation of ribosomal protein RPL26 and elongation factor eEF1A from p53 mRNA, thereby reducing p53 mRNA association with polyribosomes and p53 translation. TGF-β1 signaling is dominant over stress-induced transcription and translation of p53 and prevents stress-imposed downregulation of Smad proteins. Thus, crosstalk between the TGF-β and p53 pathways defines a major node of regulation in the cellular stress response, enhancing drug resistance. [Display omitted] •TGF-β impairs the stress response to increase cancer cell survival•TGF-β coordinately represses both TP53 transcription and p53 translation•Smad proteins repress the p53 promoter and increase cellular drug resistance•TGF-β1 is dominant over stress-induced transcription and translation programs