Dataset Information

Nuclear pore component Nup155 is part of the p53 network in liver cancer

ABSTRACT: Cancer-relevant signalling pathways rely on bidirectional nucleocytoplasmic transport events through the nuclear pore complex (NPC). However, mechanisms by which individual NPC components (Nups) participate in the regulation of these pathways remain poorly understood. We discovered by integrating large scale proteomics, polysome fractionation and a focused RNAi approach that Nup155 controls mRNA translation of p21 (CDKN1A), a key mediator of the p53 response. The underlying mechanism involves transcriptional regulation of the putative tRNA and rRNA methyltransferase FTSJ1 by Nup155. Furthermore, we observed that Nup155 and FTSJ1 are p53 repression targets and accordingly found a correlation between the p53 status, Nup155 and FTSJ1 expression in murine and human hepatocellular carcinoma (HCC). Our data suggest an unanticipated regulatory network linking translational control by and repression of a structural NPC component modulating the p53 pathway through its effectors.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Alessandro Ori

LAB HEAD: Alessandro Ori

PROVIDER: PXD012373 | Pride | 2019-04-09

REPOSITORIES: Pride

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Publications

Nucleoporin Nup155 is part of the p53 network in liver cancer.

Holzer Kerstin K Ori Alessandro A Cooke Amy A Dauch Daniel D Drucker Elisabeth E Riemenschneider Philip P Andres-Pons Amparo A DiGuilio Amanda L AL Mackmull Marie-Therese MT Baßler Jochen J Roessler Stephanie S Breuhahn Kai K Zender Lars L Glavy Joseph S JS Dombrowski Frank F Hurt Ed E Schirmacher Peter P Beck Martin M Singer Stephan S

Nature communications 20190514 1

Cancer-relevant signalling pathways rely on bidirectional nucleocytoplasmic transport events through the nuclear pore complex (NPC). However, mechanisms by which individual NPC components (Nups) participate in the regulation of these pathways remain poorly understood. We discover by integrating large scale proteomics, polysome fractionation and a focused RNAi approach that Nup155 controls mRNA translation of p21 (CDKN1A), a key mediator of the p53 response. The underlying mechanism involves tran ...[more]

PMID: 31089132

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Project description:Recently, more than a thousand large intergenic non-coding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediated apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulating their localization to sets of previously active genes. Gene expression profiles of different p53 inducible mouse embryonic fibroblasts (p53LSL/LSL MEFs) across different time points after DNA damage. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 transcriptional response. [1] MEF profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration or adenoGFP as control for 24h and treated with 500nM doxorubicin for the indicated times. [2] hnRNPKKD profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration for 24h, transfected with siRNA oligos targeting different transcripts for 24h and then treated with 100nM doxorubicin for 13h. [3] lincP21KD profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration for 24h, transfected with siRNA oligos targeting different transcripts for 24h and then treated with 100nM doxorubicin for 13h. [4] RAS profiling: For p53 restoration, cultured tumor cell lines were incubated with 500nM 4-hydroxytamoxifen for the indicated times.

Dataset Information

Nuclear pore component Nup155 is part of the p53 network in liver cancer

Publications

Nucleoporin Nup155 is part of the p53 network in liver cancer.

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