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

Fernando J. López-Díaz, Philippe Gascard, Sri Kripa Balakrishnan, Jianxin Zhao, Sonia V. delRincon, Charles Spruck, Thea D. Tlsty, Beverly M. Emerson

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)552-564
Number of pages13
JournalMolecular Cell
Volume50
Issue number4
DOIs
StatePublished - May 23 2013

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

López-Díaz, F. J., Gascard, P., Balakrishnan, S. K., Zhao, J., delRincon, S. V., Spruck, C., Tlsty, T. D., & Emerson, B. M. (2013). Coordinate Transcriptional and Translational Repression of p53 by TGF-β1 Impairs the Stress Response. Molecular Cell, 50(4), 552-564. https://doi.org/10.1016/j.molcel.2013.04.029