Abstract
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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / genetics
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Base Sequence
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Line
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Cell Survival / drug effects
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Cell Survival / genetics
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Cells, Cultured
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E2F4 Transcription Factor / genetics
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E2F4 Transcription Factor / metabolism
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Gene Expression Regulation / drug effects*
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Humans
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Immunohistochemistry
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Mammary Glands, Human / cytology
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Molecular Sequence Data
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Ribosomal Proteins / genetics
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Ribosomal Proteins / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Smad Proteins / genetics
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Smad Proteins / metabolism
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Stress, Physiological / drug effects*
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Stress, Physiological / genetics
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Transforming Growth Factor beta1 / pharmacology*
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
Substances
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E2F4 Transcription Factor
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RPL26 protein, human
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Ribosomal Proteins
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Smad Proteins
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Transforming Growth Factor beta1
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Tumor Suppressor Protein p53