GAS5 Gene


Growth arrest‐specific 5 (GAS5) is a nonprotein‐coding small nucleolar ribonucleic acid (snoRNA) host gene. Ten box C/D snoRNAs are encoded within the 11 introns of the human GAS5 gene, whereas the spliced exons have little protein‐coding potential. GAS5 has been classified as a member of the 5′ oligopyrimidine tract (5′ TOP) gene family. Growth‐dependent translation mediated by the 5′ TOP sequence determines the level of the GAS5 spliced transcript (GAS5 long noncoding RNA (lncRNA)) by a mechanism of translation‐linked RNA degradation. GAS5 lncRNA plays a critical role in arresting cell growth and inducing apoptosis. The decreased expression of GAS5 in multiple cancers suggests that GAS5 acts as a tumour suppressor. GAS5 lncRNA controls the gene expression of critical cell cycle and apoptosis regulators. GAS5 lncRNA suppresses steroid‐responsive transcription by direct association with several steroid receptors and acts as a molecular decoy. GAS5 lncRNA also sequestrates a specific functional microRNA.

Key Concepts

  • GAS5 is a nonprotein‐coding small nucleolar RNA host gene.
  • A translation‐linked mRNA decay pathway controls growth arrest‐specific accumulation of GAS5 by way of its 5′‐terminal oligopyrimidine tract (5′ TOP).
  • GAS5 functions to arrest cell growth and induce apoptosis.
  • GAS5 controls expression of genes for critical regulators of the cell cycle and apoptosis.
  • GAS5 binds to steroid hormone receptors through its 3′‐terminal stem‐loop structure to suppress steroid‐responsive transcription.
  • GAS5 sequestrates a specific functional microRNA.

Keywords: GAS5 gene; small nucleolar RNA; nonprotein‐coding gene; 5′ TOP; nonsense‐mediated RNA decay; long noncoding RNA; molecular decoy

Figure 1. GAS5 is a multi‐snoRNA host gene in human and mouse. White boxes represent the 12 exons of human and mouse GAS5; shaded boxes represent the snoRNA sequences present within 10 (in human) or 9 (in mouse) of the introns. The alternative splicing events observed in both human and mouse are indicated. The maps are not to scale.
Figure 2. Box C/D snoRNAs direct site‐specific 2′ O‐methylation of rRNA. Box C (RUGAUGA, where R stands for purine), box D′ (internal CUGA), box C′ (UGAUGA), box D (terminal CUGA) and rRNA sequences targeted for 2′ O‐methylation (2′ OMe) are shown.
Figure 3. Model explaining why GAS5 is a growth arrest‐specific transcript. In growing cells, spliced GAS5 RNA is translated and degraded by NMD. If translation is inhibited, the levels of the GAS5 transcript increase. Likewise, when cell growth is arrested, GAS5 RNA shifts from monosomes into submonosomal particles, where it accumulates and does not undergo translation.
Figure 4. GAS5 lncRNA is a suppressor of steroid hormone receptors. GAS5 binds to several steroid hormone receptors (GR is represented in this figure) through its 3′‐terminal stem loop. The sequestration of GR by GAS5 leads to transcriptional suppression of various GR‐responsive genes. Grey boxes represent the GR‐binding site in GAS5 and the GR‐responsive promoter.
Figure 5. GAS5 lncRNA acts as a molecular sponge of microRNA. GAS5 lncRNA sequestrates functional miR‐21 through interaction with the miR‐21‐binding site in GAS5 exon 4. The binding of miR‐21 results in downregulation of GAS5 lncRNA.


Amaldi F and Pierandrei‐Amaldi P (1997) TOP genes: a translationally controlled class of genes including those coding for ribosomal proteins. In: Jeanteur P (ed) Progress in Molecular and Subcellular Biology, pp. 1–17. Berlin: Springer.

Brameier M, Herwig A, Reinhardt R, et al. (2011) Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs. Nucleic Acids Research 39: 675–686.

Cao S, Liu W, Li F, et al. (2014) Decreased expression of lncRNA GAS5 predicts a poor prognosis in cervical cancer. International Journal of Clinical and Experimental Pathology 7: 6776–6783.

Coccia EM, Cicala C, Charlesworth A, et al. (1992) Regulation and expression of a growth arrest‐specific gene (gas5) during growth, differentiation, and development. Molecular and Cellular Biology 12: 3514–3521.

Dong S, Qu X, Li W, et al. (2015) The long non‐coding RNA, GAS5, enhances gefitinib‐induced cell death in innate EGFR tyrosine kinase inhibitor‐resistant lung adenocarcinoma cells with wide‐type EGFR via downregulation of the IGF‐1R expression. Journal of Hematology & Oncology 8: 43. DOI: 10.1186/s13045-015-0140-6.

Gee HE, Buffa FM, Camps C, et al. (2011) The small‐nucleolar RNAs commonly used for microRNA normalization correlate with tumour pathology and prognosis. British Journal of Cancer 104: 1168–1177.

Glover AR, Zhao JT, Ip JC, et al. (2015) Long noncoding RNA profiles of adrenocortical cancer can be used to predict recurrence. Endocrine‐Related Cancer 22: 99–109.

He X, Chen X, Zhang X, et al. (2015) An Lnc RNA (GAS5)/SnoRNA‐derived piRNA induces activation of TRAIL gene by site‐specifically recruiting MLL/COMPASS‐like complexes. Nucleic Acids Research 43: 3712–3725.

Hu G, Lou Z and Gupta M (2014) The long non‐coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c‐Myc translation. PLoS One 9: e107016.

Hudson WH, Pickard MR, de Vera IM, et al. (2014) Conserved sequence‐specific lincRNA‐steroid receptor interactions drive transcriptional repression and direct cell fate. Nature Communications 5: 5395. DOI: 10.1038/ncomms6395.

Ideue T, Sasaki YT, Hagiwara M and Hirose T (2007) Introns play an essential role in splicing‐dependent formation of the exon junction complex. Genes & Development 21: 1993–1998.

Isin M, Ozgur E, Cetin G, et al. (2014) Investigation of circulating lncRNAs in B‐cell neoplasms. Clinica Chimica Acta 431: 255–259.

Jin K, Mao XO, Eshoo MW, et al. (2002) cDNA microarray analysis of changes in gene expression induced by neuronal hypoxia in vitro. Neurochemical Research 27: 1105–1112.

Kino T, Hurt DE, Ichijo T, Nader N and Chrousos GP (2010) Noncoding RNA Gas5 is a growth arrest and starvation‐associated repressor of the glucocorticoid receptor. Science Signaling 3: ra8.

Kiss‐Laszlo Z, Henry Y, Bachellerie JP, Caizergues‐Ferrer M and Kiss T (1996) Site‐specific ribose methylation of pre‐ribosomal RNA: a novel function for small nucleolar RNAs. Cell 85: 1077–1088.

Liu Z, Wang W, Jiang J, et al. (2013) Downregulation of GAS5 promotes bladder cancer cell proliferation, partly by regulating CDK6. PLoS One 8: e73991.

Liu Y, Zhao J, Zhang W, et al. (2015) lncRNA GAS5 enhances G1 cell cycle arrest via binding to YBX1 to regulate p21 expression in stomach cancer. Scientific Reports 5: 10159. DOI: 10.1038/srep10159.

Lu X, Fang Y, Wang Z, et al. (2013) Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6. Cell and Tissue Research 354: 891–896.

Mourtada‐Maarabouni M, Pickard MR, Hedge VL, Farzaneh F and Williams GT (2009) GAS5, a non‐protein‐coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 28: 195–208.

Nakamura Y, Takahashi N, Kakegawa E, et al. (2008) The GAS5 (growth arrest‐specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B‐cell lymphoma. Cancer Genetics and Cytogenetics 182: 144–149.

Okada A, Kushima K, Aoki Y, et al. (2005) Identification of early‐responsive genes correlated to valproic acid‐ induced neural tube defects in mice. Birth Defects Research. Part A, Clinical and Molecular Teratology 73: 229–238.

Pickard MR, Mourtada‐Maarabouni M and Williams GT (2013) Long non‐coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. Biochimica et Biophysica Acta 1832: 1613–1623.

Pickard MR and Williams GT (2014) Regulation of apoptosis by long non‐coding RNA GAS5 in breast cancer cells: implications for chemotherapy. Breast Cancer Research and Treatment 145: 359–370.

Pickard MR and Williams GT (2015) Molecular and cellular mechanisms of action of tumor suppressor GAS5 lncRNA. Genes 6: 484–499.

Qiao HP, Gao WS, Huo JX and Yang ZS (2013) Long non‐coding RNA GAS5 functions as a tumor suppressor in renal cell carcinoma. Asian Pacific Journal of Cancer Prevention 14: 1077–1082.

Renganathan A, Kresoja‐Rakic J, Echeverry N, et al. (2014) GAS5 long non‐coding RNA in malignant pleural mesothelioma. Molecular Cancer 13: 119. DOI: 10.1186/1476-4598-13-119.

Schneider C, King RM and Philipson L (1988) Genes specifically expressed at growth arrest of mammalian cells. Cell 54: 787–793.

Shi X, Sun M, Liu H, et al. (2013) A critical role for the long non‐coding RNA GAS5 in proliferation and apoptosis in non‐small‐cell lung cancer. Molecular Carcinogenesis 54 (Suppl 1): E1–E12. DOI: 10.1002/mc.22120.

Smith CM and Steitz JA (1998) Classification of gas5 as a multi‐small‐nucleolar‐RNA (snoRNA) host gene and a member of the 5′‐terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Molecular and Cellular Biology 18: 6897–6909.

Sun M, Jin FY, Xia R, et al. (2014) Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer 14: 319. DOI: 10.1186/1476-4598-13-119.

Tani H, Torimura M and Akimitsu N (2013) The RNA degradation pathway regulates the function of GAS5 a non‐ coding RNA in mammalian cells. PLoS One 8: e55684.

Tu ZQ, Li RJ, Mei JZ and Li XH (2014) Down‐regulation of long non‐coding RNA GAS5 is associated with the prognosis of hepatocellular carcinoma. International Journal of Clinical and Experimental Pathology 7: 4303–4309.

Yacqub‐Usman K, Pickard MR and Williams GT (2015) Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate 75: 693–705.

Yin D, He X, Zhang E, et al. (2014) Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Medical Oncology 31 (11): 253. DOI: 10.1007/s12032-014-0253-8.

Zhang XQ, Sun S, Lam KF, et al. (2013a) A long non‐coding RNA signature in glioblastoma multiforme predicts survival. Neurobiology of Disease 58: 123–131.

Zhang Z, Zhu Z, Watabe K, et al. (2013b) Negative regulation of lncRNA GAS5 by miR‐21. Cell Death and Differentiation 20: 1558–1568.

Zhang N, Yang GQ, Shao XM, et al. (2016) GAS5 modulated autophagy is a mechanism modulating cisplatin sensitivity in NSCLC cells. European Review for Medical and Pharmacological Sciences 20: 2271–2277.

Further Reading

Filipowicz W and Pogacić V (2002) Biogenesis of small nucleolar ribonucleoproteins. Current Opinion in Cell Biology 14: 319–327.

Hirose T and Steitz JA (2001) Position within the host intron is critical for efficient processing of box C/D snoRNAs in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 98: 12914–12919.

Jeffries HBJ, Fumagalli S, Dennis PB, et al. (1997) Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70S6K. EMBO Journal 12: 3693–3704.

Lejeune F and Maquat LE (2005) Mechanistic links between nonsense‐mediated mRNA decay and pre‐mRNA splicing in mammalian cells. Current Opinion in Cell Biology 17: 309–315.

Rinn JL and Chang HY (2012) Genome regulation by long noncoding RNAs. Annual Review of Biochemistry 81: 145–166.

Smith CM and Steitz JA (1997) Sno storm in the nucleolus: new roles for myriad small RNPs. Cell 89: 669–672.

Wilusz JE, Sunwoo H and Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes & Development 23: 1494–1504.

Web Link

Growth arrest‐specific 5 (GAS5); Locus ID: 60674. LocusLink:

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Aly, Mahmoud Khamis, and Hirose, Tetsuro(Nov 2016) GAS5 Gene. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005019.pub3]