title: p53-directed translational control can shape and expand the universe of p53 target genes.
abstract: The increasing number of genome-wide transcriptome analyses focusing on p53-induced cellular responses in many cellular contexts keeps adding to the already numerous p53-regulated transcriptional networks. To investigate post-transcriptional controls as an additional dimension of p53-directed gene expression responses, we performed a translatome analysis through polysomal profiling on MCF7 cells upon 16 hours of doxorubicin or nutlin-3a treatment. The comparison between the transcriptome and the translatome revealed a considerable level of uncoupling, characterized by genes whose transcription variations did not correlate with translation variations. Interestingly, uncoupled genes were associated with apoptosis, DNA and RNA metabolism and cell cycle functions, suggesting that post-transcriptional control can modulate classical p53-regulated responses. Furthermore, even for well-established p53 targets that were differentially expressed both at the transcriptional and translational levels, quantitative differences between the transcriptome, subpolysomal and polysomal RNAs were evident. As we searched mechanisms underlying gene expression uncoupling, we identified the p53-dependent modulation of six RNA-binding proteins, where hnRNPD (AUF1) and CPEB4 are direct p53 transcriptional targets, whereas SRSF1, DDX17, YBX1 and TARDBP are indirect targets (genes modulated preferentially in the subpolysomal or polysomal mRNA level) modulated at the translational level in a p53-dependent manner. In particular, YBX1 translation appeared to be reduced by p53 via two different mechanisms, one related to mTOR inhibition and the other to miR-34a expression. Overall, we established p53 as a master regulator of translational control and identified new p53-regulated genes affecting translation that can contribute to p53-dependent cellular responses.
authors.affiliation: Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zaccara
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Tebaldi
authors.affiliation: Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Pederiva
authors.affiliation: Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: Y
authors.initials: Y
authors.lastname: Ciribilli
authors.affiliation: Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bisio
authors.affiliation: Laboratory of Transcriptional Networks, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: A
authors.identifier: 0000000287671637
authors.initials: A
authors.lastname: Inga
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000235:genetics; D010441:Peptide Chain Elongation, Translational / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051840:Y-Box-Binding Protein 1 / Q000235:genetics
chemical_list: C554939:CPEB4 protein, human; D004268:DNA-Binding Proteins; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D007093:Imidazoles; D009687:Nuclear Proteins; D010879:Piperazines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D000068103:Serine-Arginine Splicing Factors; C482205:nutlin 3; D012313:RNA; D004317:Doxorubicin; D004247:DNA; C102004:DDX17 protein, human; D053487:DEAD-box RNA Helicases