Cited by 326Cancer-related molecular mechanisms researchRNA Research and SplicingRNA and protein synthesis mechanisms

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Maternally Expressed Gene 3 (MEG3) Noncoding Ribonucleic Acid: Isoform Structure, Expression, and Functions

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Zhang, Xun, Rice, Kimberley, Wang, Yingying, Chen, Wendy, Zhong, Ying, Nakayama, Yuki, Zhou, Yunli, Klibanski, Anne·2010·Endocrinology

DOI 10.1210/en.2009-0657PMC PMC2840681

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Abstract

Maternally expressed gene 3 (MEG3) is an imprinted gene highly expressed in the human pituitary. However, MEG3 expression is lost in human gonadotroph-derived pituitary adenomas and most human tumor cell lines. Expression of MEG3 in tumor cells results in growth suppression, p53 protein increase, and activation of p53 downstream targets. The MEG3 gene encodes a noncoding RNA of approximately 1700 nucleotides. There are 12 different MEG3 gene transcripts, generated by alternative splicing. They contain the common exons 1-3 and exons 8-10, but each uses one or more exons 4-7 in a different combination in the middle. MEG3 isoform expression patterns are tissue and cell type specific. Functionally, each isoform stimulates p53-mediated transactivation and suppresses tumor cell growth. We analyzed the secondary RNA folding structure of each MEG3 isoform, using the computer program mfold. All MEG3 RNA isoforms contain three distinct secondary folding motifs M1, M2, and M3. Deletion analysis showed that motifs M2 and M3 are important for p53 activation. Furthermore, a hybrid MEG3 RNA, containing a piece of artificially synthesized sequence different from the wild type but folding into a similar secondary structure, retained the functions of both p53 activation and growth suppression. These results support the hypothesis that a proper folding structure of the MEG3 RNA molecule is critical for its biological functions. This study establishes for the first time the structure-function relationship of a large noncoding RNA and provides a first look into the molecular mechanisms of the biological functions of a large noncoding RNA.

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Authors: Zhang, X., Rice, K., Wang, Y., Chen, W., Zhong, Y., Nakayama, Y., Zhou, Y., & Klibanski, A.
Affiliations: Harvard University (US)
Corresponding author: Klibanski, Anne
ORCID: Zhang, Xun
Wang, Yingying
Chen, Wendy
Zhong, Ying
Nakayama, Yuki
Zhou, Yunli
Klibanski, Anne
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2009-12-23
Volume: 151
Issue: 3
Pages: 939-947
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2009-0657
PMC: PMC2840681
OpenAlex: W2066815559
Cited by: 325
References: 19
Citations by year: 2026: 5 · 2025: 9 · 2024: 17 · 2023: 25 · 2022: 16 · 2021: 23 · 2020: 35 · 2019: 21 · 2018: 29 · 2017: 30 · 2016: 17 · 2015: 28 · 2014: 21 · 2013: 18 · 2012: 17
FWCI: 3.47
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Endocrinology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK040947, R01-DK-40947)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords: MEG3, imprinted genes, non-coding RNA, RNA isoforms, alternative splicing, p53 activation, structure-function relationship, pituitary adenoma, tumor growth inhibition
MeSH terms: Base Sequence, Cell Line, Humans, Molecular Sequence Data, Nucleic Acid Conformation, Pituitary Neoplasms, Proteins, Structure-Activity Relationship, Gene Expression, Tumor Suppressor Protein p53, DNA, Complementary, RNA, Untranslated, RNA, Long Noncoding

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Maternally Expressed Gene 3 (MEG3) Noncoding Ribonucleic Acid: Isoform Structure, Expression, and Functions

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