TGF-β attenuates the DNA damage response by repressing p53 transcription and translation.

  • Major finding: TGF-β attenuates the DNA damage response by repressing p53 transcription and translation.

  • Mechanism: TGF-β1 recruits SMAD to E2F4–p107 on the TP53 gene and dissociates RPL26 and eEF1A from TP53 mRNA.

  • Impact: TGF-β1 protects cells from chemotherapy-induced cell death and enhances drug resistance.

In response to cellular stresses, activation of the tumor suppressor p53 induces cell-cycle arrest or apoptosis to prevent accumulation of malignant cells. Dysregulation of p53 activity in tumors occurs via posttranslational modifications and mutations, but little is known about the regulation of p53 biosynthesis during tumorigenesis. In addition, recent studies have suggested the existence of cross-talk between TGF-β signaling and the p53 pathway, but the role of TGF-β in the p53 stress response is unclear. López-Díaz and colleagues found that TGF-β1 stimulation of precancerous or metastatic cells but not normal epithelial cells diminished the activation of p53 target genes after chemotherapy-induced DNA damage and protected cells from stress-induced apoptosis. Moreover, TGF-β1 treatment reduced DNA damage-induced stabilization of wild-type and mutant p53 proteins in a subset of cancer cell lines via coordinate suppression of p53 transcription and translation. Inhibition of TP53 transcription was dependent on TGF-β–driven recruitment of SMAD transcription factors to a preassembled E2F transcription factor 4 (E2F4)–retinoblastoma-like 1 (p107) complex located at a SMAD binding element in the TP53 promoter; binding of SMAD2/3 at this sequence switched the activity of E2F4–p107 to a corepressor complex and decreased transcriptional initiation complex assembly at the TP53 promoter. Furthermore, TGF-β1 stimulation decreased the interaction of ribosomal protein L26 (RPL26), which is necessary for p53 translation, and eukaryotic elongation factor 1A (eEF1A) with TP53 mRNA, thereby inhibiting p53 translation at the elongation stage. Consistent with a role for TGF-β signaling in blocking the p53 stress response, TGF-β1 enhanced cell survival and increased resistance to doxorubicin and paclitaxel, whereas SMAD4 depletion was sufficient to overcome this effect. These results suggest that this inhibition of p53 synthesis enables the survival of aberrant cells and that TGF-β switches to a tumor promoter early in tumorigenesis.

López-Díaz FJ, Gascard P, Balakrishnan SK, Zhao J, del Rincon SV, Spruck C, et al. Coordinate transcriptional and translational repression of p53 by TGF-β1 impairs the stress response. Mol Cell 2013;50:552–64.

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