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Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions.

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.

SUBMITTER: Zhang X

PROVIDER: S-EPMC2840681 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions.

Zhang Xun X Rice Kimberley K Wang Yingying Y Chen Wendy W Zhong Ying Y Nakayama Yuki Y Zhou Yunli Y Klibanski Anne A

Endocrinology 20091223 3

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 c ...[more]

PMID: 20032057

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Project description:Maternally expressed gene 3 (MEG3, mouse homolog Gtl2) encodes a long noncoding RNA (lncRNA) that is expressed in many normal tissues, but is suppressed in various cancer cell lines and tumors, suggesting it plays a functional role as a tumor suppressor. Hypermethylation has been shown to contribute to this loss of expression. We now demonstrate that MEG3 expression is regulated by the retinoblastoma protein (Rb) pathway and correlates with a change in cell proliferation. Microarray analysis of mouse embryonic fibroblasts (MEFs) isolated from mice with genetic deletion of all three Rb family members (TKO) revealed a significant silencing of Gtl2/MEG3 expression compared to WT MEFs, and re-expression of Gtl2/MEG3 caused decrease in cell proliferation and increased apoptosis. MEG3 levels also were suppressed in A549 lung cancer cells compared with normal human bronchial epithelial (NHBE) cells, and, similar to the TKO cells, re-constitution of MEG3 led to a decrease in cell proliferation and elevated apoptosis. Activation of pRb by treatment of A549 and SK-MES-1 cells with palbociclib, a CDK4/6 inhibitor, increased the expression of MEG3 in a dose-dependent manner, while knockdown of pRb/p107 attenuated this effect. In addition, expression of phosphorylation-deficient mutant of pRb increased MEG3 levels in both lung cancer cell types. Treatment of these cells with palbociclib also decreased the expression of pRb-regulated DNA methyltransferase 1 (DNMT1), while conversely, knockdown of DNMT1 resulted in increased expression of MEG3. As gene methylation has been suggested for MEG3 regulation, we found that palbociclib resulted in decreased methylation of the MEG3 locus similar to that observed with 5-aza-deoxycytidine. Anti-sense oligonucleotide silencing of drug-induced MEG3 expression in A549 and SK-MES-1 cells partially rescued the palbociclib-mediated decrease in cell proliferation, while analysis of the TCGA database revealed decreased MEG3 expression in human lung tumors harboring a disrupted RB pathway. Together, these data suggest that disruption of the pRb-DNMT1 pathway leads to a decrease in MEG3 expression, thereby contributing to the pro-proliferative state of certain cancer cells.

Dataset Information

Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions.

Publications

Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions.

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