TY - JOUR
T1 - Coordinate Transcriptional and Translational Repression of p53 by TGF-β1 Impairs the Stress Response
AU - López-Díaz, Fernando J.
AU - Gascard, Philippe
AU - Balakrishnan, Sri Kripa
AU - Zhao, Jianxin
AU - delRincon, Sonia V.
AU - Spruck, Charles
AU - Tlsty, Thea D.
AU - Emerson, Beverly M.
N1 - Funding Information:
We gratefully acknowledge Dr. Martha Stampfer for providing variant HMECs, Drs. Inder Verma and Gustavo Tiscornia for p53 and shGT4 shRNA-coding plasmids and advice, Ms. Ruo Huang for expert technical assistance, Dr. Martin Widschwendter for human breast tumors, and Emerson lab members for helpful discussions. This work was supported by NCI Grant U54CA143803, the Chambers Medical Foundation, and Cancer Center Grant P30 CA014195. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. Author contributions are as follows: F.J.L.-D. designed the project scope, led the team, performed the experiments, and analyzed the data. P.G. and J.Z. performed the IHC experiments and data analyses. S.V.d.R. performed western blots on tumor lysates. S.K.B. contributed to Figures 2H, S1B, and S5F. C.S. purified RNA from frozen tumors. T.D.T. provided tissues and advice. B.M.E. designed the project scope, analyzed the data, and supervised the work. F.J.L.-D. and B.M.E. wrote the paper.
PY - 2013/5/23
Y1 - 2013/5/23
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2013.04.029
DO - 10.1016/j.molcel.2013.04.029
M3 - Article
C2 - 23706820
AN - SCOPUS:84878177599
SN - 1097-2765
VL - 50
SP - 552
EP - 564
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -