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J. Biol. Chem., Vol. 282, Issue 34, 24731-24742, August 24, 2007

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Activation of p53 by MEG3 Non-coding RNA^*

Yunli Zhou¹, Ying Zhong², Yingying Wang², Xun Zhang, Dalia L. Batista, Roger Gejman, Peter J. Ansell, Jing Zhao, Catherine Weng, and Anne Klibanski

From the Neuroendocrine Unit and the Neuropathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

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 p21^CIP1 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.

Received for publication, March 8, 2007 , and in revised form, June 11, 2007.

^* This work was supported by National Institutes of Health Grants R01DK40947 (to A. K.) and R03AG026060 (to Y. Z.), the Jarislowsky Foundation, and Laurie and Leo Guthart. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Both authors contributed equally to this work.

¹ To whom correspondence should be addressed: Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit St., Bulfinch 457, Boston, MA 02114. Tel.: 617-726-3870; Fax: 617-726-5072; E-mail: yzhou2{at}partners.org.

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