Wig-1 regulates cell cycle arrest and cell death through the p53 targets FAS and 14-3-3σ.
Wig-1, also known as ZMAT3, is a p53 target gene that encodes an RNA-binding zinc-finger protein involved in the regulation of mRNA stability through binding to AU-rich elements (AREs). We have used microarray analysis to identify novel Wig-1 target mRNAs. We identified 2447 transcripts with >fourfold differential expression between Wig-1 and control small interfering (si)RNA-treated HCT116 cells. Several p53 target genes were among the deregulated transcripts. We found that Wig-1 regulates FAS and 14-3-3σ mRNA independently of p53. We show that Wig-1 binds to FAS mRNA 3'-UTR and decreases its stability through an ARE in the 3'-UTR. Depletion of Wig-1 was associated with increased cell death and reduced cell cycle arrest upon DNA damage. Our results suggest a role of Wig-1 as a survival factor that directs the p53 stress response toward cell cycle arrest rather than apoptosis through the regulation of FAS and 14-3-3σ mRNA levels.
Cancer Center Karolinska (CCK), Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
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Bersani
Cancer Center Karolinska (CCK), Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
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Xu
Cancer Center Karolinska (CCK), Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
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Vilborg
Cancer Center Karolinska (CCK), Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
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Lui
Cancer Center Karolinska (CCK), Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
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Wiman
D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D020413:3' Untranslated Regions; D063307:AU Rich Elements; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005095:Exoribonucleases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
D048948:14-3-3 Proteins; D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C491901:FAS protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C436503:ZMAT3 protein, human; D019014:fas Receptor; D005095:Exoribonucleases; C413442:SFN protein, human; D002945:Cisplatin