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Transportin 2 regulates apoptosis through the RNA-binding protein HuR.

ABSTRACT: In response to severe stress, apoptotic cell death is engaged. Apoptosis is a well orchestrated process that involves the activation and implication of many factors. In this study, we identified a role for the nuclear trafficking factor TRN2 (transportin 2) in cell death. TRN2 is normally responsible for the nuclear import of the RNA-binding protein HuR. During apoptosis, however, HuR accumulates in the cytoplasm. This is due to the caspase-mediated cleavage of the cytoplasmic fraction of HuR. One of the cleavage fragments generated by this processing of HuR interacts with TRN2 and thus blocks the re-import of HuR into the nucleus. This concentrates HuR in the cytoplasm, advancing apoptosis. Therefore, increasing or decreasing the levels of TRN2 has an inverse consequential effect on cell death, demonstrating for the first time the role of a nucleocytoplasmic transport factor in apoptosis.

SUBMITTER: von Roretz C

PROVIDER: S-EPMC3138312 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other

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Transportin 2 regulates apoptosis through the RNA-binding protein HuR.

von Roretz Christopher C Macri Angelo M AM Gallouzi Imed-Eddine IE

The Journal of biological chemistry 20110606 29

In response to severe stress, apoptotic cell death is engaged. Apoptosis is a well orchestrated process that involves the activation and implication of many factors. In this study, we identified a role for the nuclear trafficking factor TRN2 (transportin 2) in cell death. TRN2 is normally responsible for the nuclear import of the RNA-binding protein HuR. During apoptosis, however, HuR accumulates in the cytoplasm. This is due to the caspase-mediated cleavage of the cytoplasmic fraction of HuR. O ...[more]

PMID: 21646354

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Project description:Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic enzyme in human malignancy. A heterozygous genetic alteration, arginine 132, promotes the conversion of ?-ketoglutarate to D-2-hydroxyglutarate (2-HG). Although pharmacologic inhibitors of mutant IDH1 are promising, resistance mechanisms to targeted therapy are not understood. Additionally, the role of wild-type IDH1 (WT.IDH1) in cancer requires further study. Recently, it was observed that the regulatory RNA-binding protein, HuR (ELAVL1), protects nutrient-deprived cancer cells without IDH1 mutations, by stabilizing WT.IDH1 transcripts. In the present study, a similar regulatory effect on both mutant (Mut.IDH1) and WT.IDH1 transcripts in heterozygous IDH1-mutant tumors is observed. In ribonucleoprotein immunoprecipitation assays of IDH1-mutant cell lines, wild-type and mutant IDH1 mRNAs each bound to HuR. Both isoforms were profoundly downregulated at the mRNA and protein levels after genetic suppression of HuR (siRNAs or CRISPR deletion) in HT1080 (R132C IDH1 mutation) and BT054 cells (R132H). Proliferation and invasion were adversely affected after HuR suppression and metabolomic studies revealed a reduction in Pentose Phosphate Pathway metabolites, nucleotide precursors, and 2-HG levels. HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198). IDH1-mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy. IMPLICATIONS: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme.

Dataset Information

Transportin 2 regulates apoptosis through the RNA-binding protein HuR.

Publications

Transportin 2 regulates apoptosis through the RNA-binding protein HuR.

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