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Review
. 2020 Oct;22(4):3049-3056.
doi: 10.3892/mmr.2020.11435. Epub 2020 Aug 19.

GAS5‑mediated regulation of cell signaling (Review)

Yang Zhou  1 , Binghai Chen  1
Affiliations
Review

GAS5‑mediated regulation of cell signaling (Review)

Yang Zhou et al. Mol Med Rep. 2020 Oct.

Abstract

In recent years, an increasing number of long non‑coding RNAs (lncRNAs) have been discovered using microarrays and nucleic acid sequencing technology. LncRNAs exert crucial biological functions by regulating signaling pathways. In particular, the lncRNA growth arrest‑specific transcript 5 (GAS5) has been documented to serve a crucial role in numerous signaling pathways. This article discusses the latest developments in the association between GAS5 and microRNA (miRNA), p53, mTOR, glucocorticoid response element (GRE) and AKT in order to investigate the roles served by GAS5. miRNAs can activate related signaling pathways and GAS5 can combine with miRNA to regulate related signaling pathways. GAS5 may regulate p53 expression via derivation of snoRNA, but the underlying mechanism requires further investigation. GAS5 overxpresion reduces the expression level of mTOR, which is induced by inhibiting miR‑106a‑5p expression. GAS5 is a sponge of GR, and serves a role in controlling and maintaining glucocorticoid sensitivity and drug resistance via competitive combination with GR. GAS5 can interact with miRNAs, such as miR‑21 and miR‑532‑5p, to regulate the expression of AKT signaling pathway, affecting cell survival and apoptosis. Collectively, the data indicate that GAS5 serves a key role in the miRNA, p53, mTOR, GRE, and AKT signaling pathways. GAS5 regulates complex intracellular signaling pathways primarily through three modes of action, all of which are interrelated: Signal, decoy and guide. In the present article, latest developments in the association between GAS5 and a number of cellular signaling pathways are discussed to examine the tumor suppressive role of GAS5.

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Figures

Figure 1.
Figure 1.
Three main modes of GAS5 participation in signaling pathways. GAS5 participates in complex signaling pathways mainly through three modes of action: Signal, sponge and guide. The line representations are as follows: (A) Solid, direct effect; (B) dotted, indirect effect; (C) solid ellipse, the final position of the protein; and (D) dotted ellipse, the original position of the protein or the original position in the pathway. GAS5, growth arrest-specific 5.
Figure 2.
Figure 2.
GAS5 regulates gene expression, and the relationship between GAS5 and p53 network. (A) Regulation of gene expression by lncRNA GAS5. GAS5 regulates the expression level of genes and enhances the interaction of E2F1 and P27kip1 by activating E2F1. GAS5 binds to eIF4E to inhibit c-Myc mRNA expression. GAS5 indirectly enhances the expression of PTEN by directly inhibiting the expression of miR-21a-5p. (B) GAS5 and the p53 network. Feedback adjustment of lncRNA GAS5 and p53. Following DNA damage, GAS5 can derive snoRNA, which directly promotes the expression of p53 and inhibits the G1 phase in the interphase of cell division. Solid edges represent direct regulatory effects. Dotted edges represent indirect regulatory effects. lncRNA, long noncoding RNA; GAS5, growth arrest-specific 5; E2F1, E2F transcription factor 1; P27kip1; cyclin-dependent kinase inhibitor 1B; eIF4E, eukaryotic translation initiation factor 4E; PTEN, phosphatase and tensin homologue deleted on chromosome 10; miR, microRNA; snoRNA, small nucleolar RNA.
Figure 3.
Figure 3.
Relationship between GAS5 and miRNA, and the relationship between GAS5 and GRE. (A) The interaction of lncRNA GAS5 with miRNA. GAS5 activates PTEN, PDCD4 and miR-21 conjugates through competitive binding with miR-21. Additionally, GAS5 can directly bind to miR-103 to upregulate PTEN expression. (B) The association between lncRNA GAS5 and GRE. GAS5 competitively binds the DBD on the GR, preventing the binding of GR and GRE. Furthermore, GAS5 indirectly inhibits the expression of GR target genes cIAP2 and SGK1. Solid edges represent direct regulatory effects. Dotted edges represent indirect regulatory effects. lncRNA, long noncoding RNA; GAS5, growth arrest-specific 5; miRNA, microRNA; PTEN, phosphatase and tensin homologue deleted on chromosome 10; PDCD4, programmed cell death 4; GRE, glucocorticoid response element; DBD, DNA-binding domain; GR, glucocorticoid receptor; cIAP2, baculoviral IAP repeat-containing protein 3; SGK1, serum/glucocorticoid regulated kinase 1.
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