LincRNA-p21 acts as a mediator of ING1b-induced apoptosis.
ING1b is a tumor suppressor that affects transcription, cell cycle control and apoptosis. ING1b is deregulated in disease, and its activity is closely linked to that of p53. In addition to regulating protein-coding genes, we found that ING1b also influences the expression of large intergenic non-coding RNAs (lincRNAs). In particular, lincRNA-p21 was significantly induced after DNA-damage stress or by ING1b overexpression. Furthermore, lincRNA-p21 expression in response to DNA damage was significantly attenuated in cells lacking ING1b. LincRNA-p21 is also a target of p53 and can trigger apoptosis in mouse cell models. We found that this function of lincRNA-p21 is conserved in human cell models. Moreover, ING1b and p53 could function independently to influence lincRNA-p21 expression. However, their effects become more additive under conditions of stress. In particular, ING1b regulates lincRNA-p21 levels by binding to its promoter and is required for induction of lincRNA-p21 by p53. The ability of ING1b to cause apoptosis is also impaired in the absence of lincRNA-p21. Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21. Our findings suggest that ING1b induces lincRNA-p21 expression independently of histone 3 lysine 4 trimethylation mark recognition and that lincRNA-p21 functions downstream of ING1b. Thus, regulation at the level of lincRNA-p21 may represent the point at which ING1b and p53 pathways converge to induce apoptosis under specific stress conditions.
Department of Biochemistry and Molecular Biology, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.
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Tran
Department of Biochemistry and Molecular Biology, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.
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Rajarajacholan
Department of Biochemistry and Molecular Biology, Visual Genomics Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.
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Soh
Department of Biochemistry and Molecular Biology, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.
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Kim
Department of Biochemistry and Molecular Biology, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.
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Thalappilly
Department of Biochemistry and Molecular Biology, Visual Genomics Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.
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Sensen
Department of Biochemistry and Molecular Biology, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1 Alberta, Canada.
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Riabowol
D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D025521:Tumor Suppressor Proteins