title: Coordinate transcriptional and translational repression of p53 by TGF-β1 impairs the stress response.
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.
authors.affiliation: Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: López-Díaz
authors.forename: Philippe
authors.initials: P
authors.lastname: Gascard
authors.forename: Sri Kripa
authors.initials: SK
authors.lastname: Balakrishnan
authors.forename: Jianxin
authors.initials: J
authors.lastname: Zhao
authors.forename: Sonia V
authors.initials: SV
authors.lastname: Del Rincon
authors.forename: Charles
authors.initials: C
authors.lastname: Spruck
authors.forename: Thea D
authors.initials: TD
authors.lastname: Tlsty
authors.forename: Beverly M
authors.initials: BM
authors.lastname: Emerson
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D042361:Mammary Glands, Human / Q000166:cytology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D050704:E2F4 Transcription Factor; C489216:RPL26 protein, human; D012269:Ribosomal Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53