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

• 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

SummaryCellular 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.

Graphical AbstractFigure optionsDownload high-quality image (257 K)Download as PowerPoint slide