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 Emerson

Research output: Contribution to journalArticle

22 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Switch Genes
Smad Proteins
Peptide Elongation Factors
Co-Repressor Proteins
Messenger RNA
Polyribosomes
Ribosomal Proteins
p53 Genes
Drug Resistance
Down-Regulation
RNA
Apoptosis
Proteins

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., ... Emerson, B. (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

Coordinate Transcriptional and Translational Repression of p53 by TGF-β1 Impairs the Stress Response. / López-Díaz, Fernando J.; Gascard, Philippe; Balakrishnan, Sri Kripa; Zhao, Jianxin; delRincon, Sonia V.; Spruck, Charles; Tlsty, Thea D.; Emerson, Beverly.

In: Molecular Cell, Vol. 50, No. 4, 23.05.2013, p. 552-564.

Research output: Contribution to journalArticle

López-Díaz, FJ, Gascard, P, Balakrishnan, SK, Zhao, J, delRincon, SV, Spruck, C, Tlsty, TD & Emerson, B 2013, 'Coordinate Transcriptional and Translational Repression of p53 by TGF-β1 Impairs the Stress Response', Molecular Cell, vol. 50, no. 4, pp. 552-564. https://doi.org/10.1016/j.molcel.2013.04.029
López-Díaz FJ, Gascard P, Balakrishnan SK, Zhao J, delRincon SV, Spruck C et al. Coordinate Transcriptional and Translational Repression of p53 by TGF-β1 Impairs the Stress Response. Molecular Cell. 2013 May 23;50(4):552-564. https://doi.org/10.1016/j.molcel.2013.04.029
López-Díaz, Fernando J. ; Gascard, Philippe ; Balakrishnan, Sri Kripa ; Zhao, Jianxin ; delRincon, Sonia V. ; Spruck, Charles ; Tlsty, Thea D. ; Emerson, Beverly. / Coordinate Transcriptional and Translational Repression of p53 by TGF-β1 Impairs the Stress Response. In: Molecular Cell. 2013 ; Vol. 50, No. 4. pp. 552-564.
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