Activation of p53 by MEG3 Non-coding RNA*

By Yunli Zhou, Y. Zhong, Yingying Wang, Xun Zhang, D. Batista, R. Gejman, P. Ansell, Catherine Weng, A. Klibanski. Journal of Biological Chemistry, 2007

634 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/823d3593e5dfd56616099466e2d0e3f162cbf784

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Citations in the corpus

microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer (2011, background): “Moreover, expression of MEG3 has been shown to suppress growth and Oncogene modulate p53 expression and stimulate p53-mediated transactivation of downstream targets in colon and brain cancer cells (Zhou et al., 2007; Zhang et al., 2010a).”
Large-scale prediction of long non-coding RNA functions in a coding–non-coding gene co-expression network (2011, background): “For example, the lncRNA MEG3 activates the expression of Tp53 and enhances its binding affinity to the promoter of its target gene, Gdf15, implying a role for MEG3 in regulating the expression and transcriptional activation of Tp53 (7).”
Blinded by the Light: The Growing Complexity of p53. (2009, background): “This noncoding RNA seems to selectively affect p53 in human cells by downregulating Mdm2 expression, increasing p53 expression, and stimulating p53 activation of at least one target gene (growth differentiation factor 15; GDF15), all without affecting p21 transcription (Zhou et al., 2007).”
Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB (2013, background): “It is interesting to note that recent studies have demonstrated the role of other lncRNAs as the potential mediators of p53 signaling network [29,40,41].”
MEG3 noncoding RNA: a tumor suppressor (2012, background): “…of MEG3 expression has been found in all cancer cell lines examined including those derived from brain, bladder, bone marrow, breast, cervix, colon, liver, lung, meninges, and prostate (Table 1; Zhang et al. 2003, 2010a, Astuti et al. 2005, Zhou et al. 2007, Braconi et al. 2011, Wang et al. 2012).”
Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution (2015, background): “MEG3 is an imprinted lncRNA which is downregulated in many types of cancers and previously hypothesized to function as a tumor suppressor in a mechanism that is still not well understood [69-71].”
The Genetic Signatures of Noncoding RNAs (2009, background): “6 kb; maternally expressed from the Dlk1-Gtl2 imprinted locus Regulates p53 expression, inhibits cell proliferation in the absence of p53 Overexpression, mutagenesis [192]”