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Article: MYC protein inhibits transcription of the MicroRNA cluster MC-let-7a-1∼let-7d via noncanonical E-box

TitleMYC protein inhibits transcription of the MicroRNA cluster MC-let-7a-1∼let-7d via noncanonical E-box
Authors
Issue Date2011
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2011, v. 286 n. 46, p. 39703-39714 How to Cite?
AbstractThe human microRNA cluster MC-let-7a-1∼let-7d, with three members let-7a-1, let-7f-1, and let-7d, is an important cluster of the let-7 family. These microRNAs play critical roles in regulating development and carcinogenesis. Therefore, precise control of MC-let-7a-1∼let-7d level is critical for cellular functions. In this study, we first showed that the expression of these three members was significantly reduced in human hepatocellular carcinoma HepG2 cells as compared with the immortalizedhumanliver L02 cells.Wedemonstrated that the MC-let- 7a-1∼let-7d cluster was encoded by a single polycistronic transcript driven by a 10-kb upstream promoter, with two MYC-binding sites. Importantly, MYC inhibited MC-let-7a-1∼let-7d promoter activity via binding to the noncanonical E-box 3 downstream of the transcription start sites, whereas it enhanced promoter activity by binding to the canonical E-box 2 upstream of the transcription start sites. We found that although the binding affinity of MYC to E-box 2 was stronger than E-box 3, the binding quantum of MYC to E-box 3 was significantly higher in cancerous HepG2 cells as compared with the noncancerous L02 cells. In addition, forced expression of let-7 could reverse the MYC-mediated cell proliferation. These findings suggested that in L02 cells with a low level of MYC, MYC binds mainly to E-box 2 to enhance MC-let-7a-1∼let-7d expression. However, in HepG2 cells with an elevated MYC, the extra MYC could bind to E-box 3 to suppress the transcription of MC-let-7a-1∼let-7d and thus enable HepG2 cells to maintain a high level of MYC and a low level of let-7 microRNAs simultaneously. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/168586
ISSN
2020 Impact Factor: 5.157
2020 SCImago Journal Rankings: 2.361
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWang, Zen_US
dc.contributor.authorLin, Sen_US
dc.contributor.authorLi, JJen_US
dc.contributor.authorXu, Zen_US
dc.contributor.authorYao, Hen_US
dc.contributor.authorZhu, Xen_US
dc.contributor.authorXie, Den_US
dc.contributor.authorShen, Zen_US
dc.contributor.authorSze, Jen_US
dc.contributor.authorLi, Ken_US
dc.contributor.authorLu, Gen_US
dc.contributor.authorChan, DTMen_US
dc.contributor.authorPoon, WSen_US
dc.contributor.authorKung, HFen_US
dc.contributor.authorLin, MCMen_US
dc.date.accessioned2012-10-08T03:21:10Z-
dc.date.available2012-10-08T03:21:10Z-
dc.date.issued2011en_US
dc.identifier.citationJournal Of Biological Chemistry, 2011, v. 286 n. 46, p. 39703-39714en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/168586-
dc.description.abstractThe human microRNA cluster MC-let-7a-1∼let-7d, with three members let-7a-1, let-7f-1, and let-7d, is an important cluster of the let-7 family. These microRNAs play critical roles in regulating development and carcinogenesis. Therefore, precise control of MC-let-7a-1∼let-7d level is critical for cellular functions. In this study, we first showed that the expression of these three members was significantly reduced in human hepatocellular carcinoma HepG2 cells as compared with the immortalizedhumanliver L02 cells.Wedemonstrated that the MC-let- 7a-1∼let-7d cluster was encoded by a single polycistronic transcript driven by a 10-kb upstream promoter, with two MYC-binding sites. Importantly, MYC inhibited MC-let-7a-1∼let-7d promoter activity via binding to the noncanonical E-box 3 downstream of the transcription start sites, whereas it enhanced promoter activity by binding to the canonical E-box 2 upstream of the transcription start sites. We found that although the binding affinity of MYC to E-box 2 was stronger than E-box 3, the binding quantum of MYC to E-box 3 was significantly higher in cancerous HepG2 cells as compared with the noncancerous L02 cells. In addition, forced expression of let-7 could reverse the MYC-mediated cell proliferation. These findings suggested that in L02 cells with a low level of MYC, MYC binds mainly to E-box 2 to enhance MC-let-7a-1∼let-7d expression. However, in HepG2 cells with an elevated MYC, the extra MYC could bind to E-box 3 to suppress the transcription of MC-let-7a-1∼let-7d and thus enable HepG2 cells to maintain a high level of MYC and a low level of let-7 microRNAs simultaneously. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshHek293 Cellsen_US
dc.subject.meshHep G2 Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshMicrornas - Biosynthesis - Geneticsen_US
dc.subject.meshMultigene Familyen_US
dc.subject.meshProto-Oncogene Proteins C-Myc - Genetics - Metabolismen_US
dc.subject.meshResponse Elementsen_US
dc.subject.meshTranscription, Geneticen_US
dc.titleMYC protein inhibits transcription of the MicroRNA cluster MC-let-7a-1∼let-7d via noncanonical E-boxen_US
dc.typeArticleen_US
dc.identifier.emailLin, MCM:mcllin@hkucc.hku.hken_US
dc.identifier.authorityLin, MCM=rp00746en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1074/jbc.M111.293126en_US
dc.identifier.pmid21903590-
dc.identifier.scopuseid_2-s2.0-81155123696en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-81155123696&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume286en_US
dc.identifier.issue46en_US
dc.identifier.spage39703en_US
dc.identifier.epage39714en_US
dc.identifier.isiWOS:000296925700004-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridWang, Z=37035371600en_US
dc.identifier.scopusauthoridLin, S=37034534000en_US
dc.identifier.scopusauthoridLi, JJ=54583824400en_US
dc.identifier.scopusauthoridXu, Z=54584646000en_US
dc.identifier.scopusauthoridYao, H=13104506400en_US
dc.identifier.scopusauthoridZhu, X=34869035800en_US
dc.identifier.scopusauthoridXie, D=35070710200en_US
dc.identifier.scopusauthoridShen, Z=35759640300en_US
dc.identifier.scopusauthoridSze, J=7003867625en_US
dc.identifier.scopusauthoridLi, K=13604752100en_US
dc.identifier.scopusauthoridLu, G=36619108300en_US
dc.identifier.scopusauthoridChan, DTM=7402216549en_US
dc.identifier.scopusauthoridPoon, WS=7103025507en_US
dc.identifier.scopusauthoridKung, HF=7402514190en_US
dc.identifier.scopusauthoridLin, MCM=7404816359en_US
dc.identifier.issnl0021-9258-

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