共 61 条
Activation of p53 by MEG3 non-coding RNA
被引:540
作者:

Zhou, Yunli
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Zhong, Ying
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Wang, Yingying
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Zhang, Xun
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Batista, Dalia L.
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Gejman, Roger
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Ansell, Peter J.
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Zhao, Jing
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Weng, Catherine
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA

Klibanski, Anne
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机构: Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA
机构:
[1] Massachusetts Gen Hosp, Neuendrocrine Unit, Boston, MA 02114 USA
[2] Harvard Univ, Sch Med, Boston, MA 02114 USA
[3] Massachusetts Gen Hosp, Neuropathol Unit, Boston, MA 02114 USA
关键词:
D O I:
10.1074/jbc.M702029200
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
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.
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页码:24731 / 24742
页数:12
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