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

Abstract

Summary 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 TGFβ1 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, E2F4 binds constitutively to the TP53 gene and induces transcription. TGFβ1-activated Smads are recruited to a composite Smad/E2F4 element by an E2F4/p107 complex that switches to a Smad co-repressor, which represses TP53 transcription. TGFβ1 also causes dissociation of ribosomal protein RPL26 and elongation factor eEF1A from p53 mRNA, thereby reducing p53 mRNA association with polyribosomes and p53 translation. TGFβ1-signalling is dominant over stress-induced transcription and translation of p53 and prevents stress-imposed downregulation of Smad proteins. Thus, crosstalk between the TGFβ and p53 pathways defines a major node of regulation in the cellular stress response, enhancing drug resistance.

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing

“…Such technologies will be critical for examining individual cells from tissue biopsies of heterogeneous populations. For example, we recently identified that TGF-β1 signaling represses the gene expression program induced by DNA damage, and our immunohistochemistry studies revealed heterogeneity of this phenomenon in different cancer cells present in the same tumor (44). Although not all rare variants are relevant to personalized cancer treatment, some have the potential to drive drug resistance or serve as biomarkers of therapeutic success.…”

“…Briefly, 25,000 cells were plated in each well of 12-well plates and after 24 h were treated with vehicle-ethanol or up to 100 nM paclitaxel-containing media. After 4 d, cells were fixed with 10% formaldehyde, and the IC 50 was established by Giemsa staining (44). Cell number was plotted as a percent of cells relative to vehicle control with SE from four replicated wells from a representative experiment.…”

TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion

“…However, the mechanism by which p53 expression in stromal cells is regulated by proteins secreted from cancer cells currently remains unknown. One possibility is that TGF-β contributes to the downregulation of p53 because it activates normal fibroblasts to support cancer and repress p53 expression through the induction of MDM2 (31,32). Alternatively, cancer-derived exosomes may also be involved in down-regulating p53 expression in stromal cells because cancer cells release exosomes expressing specific proteins and RNAs to influence the expression of various proteins (33,34).…”

Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

“…The evidence found cis-platinum treatment of MDA-MB-231 breast cancer cells increased both TgF-β mRNA levels and the secretion of active TGF-β, which enhanced growth arrest that facilitated repair of damage, thus rendering these cells resistant to cis-platinum killing (41). In the report of López-Díaz et al, TGF-β was shown protected cells from DoxR, 5-fluorouracil and paclitaxel-induced cell death specifically though Smad 4-mediated complex (42). Moreover, TgF-β pretreatment was able to attenuate the TAM cytotoxic effect and decrease the apoptosis ratio in breast cancer (43).…”