Activation of p53 by MEG3 Non-coding RNA

MEG3 is a maternally expressed imprinted gene suggested to function as a non-coding RNA. Our previous studies suggest that MEG3 has a function of tumor suppression. The tumor suppressor p53 plays a central role in tumor suppression and mediates the functions of many other tumor suppressors. Therefore, we hypothesized that MEG3 functions through activation of p53. We found that transfection of expression constructs for MEG3 and its isoforms results in a significant increase in p53 protein levels and dramatically stimulates p53-dependent transcription from a p53-responsive promoter. Using this as the functional assay, we demonstrated that the open reading frames encoded by MEG3 transcripts are not required for MEG3 function, and the folding of MEG3 RNA is critical to its function, supporting the concept that MEG3 functions as a non-coding RNA. We further found that MEG3 stimulates expression of the growth differentiation factor 15 (GDF15) by enhancing p53 binding to the GDF15 gene promoter. Interestingly, MEG3 does not stimulate p21CIP1 expression, suggesting that MEG3 can regulate the specificity of p53 transcriptional activation. p53 degradation is mainly mediated by the mouse double minute 2 homolog (MDM2). We found that MDM2 levels were down-regulated in cells transfected with MEG3, suggesting that MDM2 suppression contributes at least in part to p53 accumulation induced by MEG3. Finally, we found that MEG3 is able to inhibit cell proliferation in the absence of p53. These data suggest that MEG3 non-coding RNA may function as a tumor suppressor, whose action is mediated by both p53-dependent and p53-independent pathways. MEG3 is a maternally expressed imprinted gene suggested to function as a non-coding RNA. Our previous studies suggest that MEG3 has a function of tumor suppression. The tumor suppressor p53 plays a central role in tumor suppression and mediates the functions of many other tumor suppressors. Therefore, we hypothesized that MEG3 functions through activation of p53. We found that transfection of expression constructs for MEG3 and its isoforms results in a significant increase in p53 protein levels and dramatically stimulates p53-dependent transcription from a p53-responsive promoter. Using this as the functional assay, we demonstrated that the open reading frames encoded by MEG3 transcripts are not required for MEG3 function, and the folding of MEG3 RNA is critical to its function, supporting the concept that MEG3 functions as a non-coding RNA. We further found that MEG3 stimulates expression of the growth differentiation factor 15 (GDF15) by enhancing p53 binding to the GDF15 gene promoter. Interestingly, MEG3 does not stimulate p21CIP1 expression, suggesting that MEG3 can regulate the specificity of p53 transcriptional activation. p53 degradation is mainly mediated by the mouse double minute 2 homolog (MDM2). We found that MDM2 levels were down-regulated in cells transfected with MEG3, suggesting that MDM2 suppression contributes at least in part to p53 accumulation induced by MEG3. Finally, we found that MEG3 is able to inhibit cell proliferation in the absence of p53. These data suggest that MEG3 non-coding RNA may function as a tumor suppressor, whose action is mediated by both p53-dependent and p53-independent pathways. RNAs that do not encode any proteins and function at the RNA level are non-coding RNAs (ncRNAs). 3The abbreviations used are: ncRNAnon-coding RNABrdUrdbromodeoxyuridineChIPchromatin immunoprecipitationCMVcytomegalovirusGDF15growth differentiation factor 15ORFopen reading framewtwild typeMEG3maternally expressed gene 3rRNAribosomal RNAGFPgreen fluorescent proteinTRITCtetramethylrhodamine isothiocyanateLIlabeling indexAct Dactinomycin DE3ubiquitin-protein isopeptide ligaseMDM2mouse double minute 2 homolog In recent years, emerging evidence indicates that they play important roles in regulating cellular and biological functions (1Mattick J.S. Makunin I.V. Hum. Mol. Genet. 2006; 15: R17-R29Crossref PubMed Scopus (1853) Google Scholar, 2Pang K.C. Frith M.C. Mattick J.S. Trends Genet. 2006; 22: 1-5Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar). Besides the well known transfer RNAs and ribosomal RNAs, ncRNAs can be categorized into small nuclear RNAs, small nucleolar RNAs, micro-RNAs, small interfering RNAs, and medium/large ncRNAs that do not belong to the aforementioned RNAs (1Mattick J.S. Makunin I.V. Hum. Mol. Genet. 2006; 15: R17-R29Crossref PubMed Scopus (1853) Google Scholar, 3Mattick J.S. Makunin I.V. Hum. Mol. Genet. 2005; 14: R121-R132Crossref PubMed Scopus (414) Google Scholar). Small nuclear RNAs and small nucleolar RNAs are usually 60–300 nucleotides long and are mainly involved in ribosome biogenesis and RNA splicing (4Matera A.G. Terns R.M. Terns M.P. Nat. Rev. Mol. PubMed Scopus Google Scholar). and small interfering RNAs are nucleotides long and function to regulate gene expression at the level J.S. Makunin I.V. Hum. Mol. Genet. 2005; 14: R121-R132Crossref PubMed Scopus (414) Google Scholar). The medium/large ncRNAs are usually in and may are that they do not encode any ncRNAs in this are they to functions K.C. Frith M.C. Mattick J.S. Trends Genet. 2006; 22: 1-5Abstract Full Text Full Text PDF PubMed Scopus (506) Google and in a of cellular to growth of and is to be tumor suppressor PubMed Scopus Google Scholar). The of cell has to inhibit growth of cells Google Scholar). 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These studies suggest that the MEG3 gene may play a role in tumor suppression. suppression is a cellular the of and the tumor suppressor p53 plays a central role in tumor suppression PubMed Scopus Google Scholar). a transcription p53 functions by regulating expression of its PubMed Scopus Google Scholar, 2005; PubMed Scopus Google Scholar). p53 is by many as and 2005; PubMed Scopus Google Scholar). activation to cell the of the and the cellular Nat. Rev. PubMed Scopus Google Scholar). p53 tumor through to cell as of tumor 2006; PubMed Scopus Google Scholar). Therefore, functional of p53 has found in PubMed Scopus Google Scholar). The of p53 is a in the p53 that p53 with and in whose the function of as that to and from p53 PubMed Scopus Google Scholar). p53 plays a critical role in tumor suppression functions of other tumor as Genet. PubMed Scopus Google PubMed Scopus Google Full Text Full Text PDF PubMed Scopus Google Trends Full Text Full Text PDF PubMed Scopus Google and J.S. 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