Noncoding RNA Gas5 Is a Growth Arrest and Starvation-Associated Repressor of the Glucocorticoid Receptor

By T. Kino, D. Hurt, T. Ichijo, N. Nader, George P. Chrousos. Science Signaling, 2010

1,243 citations recorded by the source corpus.

Gas5 is a noncoding RNA that acts as a decoy glucocorticoid response element to inhibit glucocorticoid-mediated transcription. Noncoding RNA Decoys Steroid receptors are transcription factors that are activated by ligand binding, which allows these proteins to bind specific sequences called “response elements” in the promoters of target genes to stimulate transcription. Now, Kino et al. find that a noncoding RNA can also interact with steroid receptors and inhibit their binding to the DNA response elements, thereby repressing steroid receptor activity. The authors found that the noncoding RNA growth arrest–specific 5 (Gas5), which accumulates in cells that have been deprived of nutrients or growth factors, bound to the glucocorticoid receptor and competed with DNA glucocorticoid response elements for binding to the receptor, thereby inhibiting glucocorticoid-mediated transcription. This sensitized cells to undergo apoptosis in response to stress by preventing the glucocorticoid-mediated transcription of antiapoptotic genes. Gas5 also interacted with other steroid receptors and inhibited their transcriptional activity, suggesting that decoy RNA response elements may be a common mechanism for regulating transcription factor activity. The availability of nutrients influences cellular growth and survival by affecting gene transcription. Glucocorticoids also influence gene transcription and have diverse activities on cell growth, energy expenditure, and survival. We found that the growth arrest–specific 5 (Gas5) noncoding RNA, which is abundant in cells whose growth has been arrested because of lack of nutrients or growth factors, sensitized cells to apoptosis by suppressing glucocorticoid-mediated induction of several responsive genes, including the one encoding cellular inhibitor of apoptosis 2. Gas5 bound to the DNA-binding domain of the glucocorticoid receptor (GR) by acting as a decoy glucocorticoid response element (GRE), thus competing with DNA GREs for binding to the GR. We conclude that Gas5 is a “riborepressor” of the GR, influencing cell survival and metabolic activities during starvation by modulating the transcriptional activity of the GR.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/28516956b4c2ba89312829384412154b93b8d075

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Citations in the corpus

Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution (2015, background): “Other more recent examples include MALAT1, NEAT1, and MIAT (Gomafu) which are localized to nuclear bodies [16-20] and the lncRNA GAS5 which shuttles between the nucleus and cytoplasm [21].”
The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression (2012, background): “Other regulatory lncRNAs such as GAS5 (Kino et al. 2010), LINC00568 (also known as ncRNA-a1), CYP4A22-AS1 (also known as ncRNA-a3) (Ørom et al. 2010), MIAT (Ishii et al. 2006), and MEG3 (Zhou et al. 2007) were nuclear enriched in at least two different cell types, consistent with their reported…”
Long Noncoding RNAs: Past, Present, and Future (2013, background): “…RNA that, in addition to being a host for snoRNAs (Smith and Steitz 1998), binds the DNA-binding domain of nuclear glucocorticoid receptors and precludes contact with glucocorticoid response elements on genomic DNA (Kino et al. 2010). lncRNAs may even influence the cellular localization of TFs.”
lincRNAs: Genomics, Evolution, and Mechanisms (2013, positive): “However, other studied lincRNAsare found mostly in the cytoplasm (Coccia et al., 1992; Kino et al., 2010; Cell 154, July 3, 2013 ª2013 Elsevier Inc. 33 Yoon et al., 2012).”
A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. (2015, background): “The expression level of NKILA in MCF7 cells was similar to Gas5 in HeLa cells (Kino et al., 2010).”
Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1 (2017, background): “Some lncRNPs can affect gene expression at the transcriptional level; for example, lncRNA ANRIL represses p16INK4 transcription by interacting with the PRC2 complex at the INK4 locus,24 and lncRNA GAS5 binds glucocorticoid receptors (GCRs) and thus acts as a decoy to prevent the transcriptional acti”
Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs (2012, background): “The lncRNA Gas5 (growth arrest specific 5), which is highly expressed in cells that have arrested growth, serves as a negative regulator of glucocorticoid receptors (GR), a specific class of nuclear receptors (77).”
The multidimensional mechanisms of long noncoding RNA function (2017, background): “For instance, the lncRNA GAS5 has been identified as a functional and physical interactor of the glucocorticoid receptor (GR) [58].”