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

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TitleMYC protein inhibits transcription of the MicroRNA cluster MC-let-7a-1∼let-7d via noncanonical E-box
AuthorsWang, Z3
Lin, S3 5
Li, JJ5
Xu, Z5
Yao, H4
Zhu, X2
Xie, D3
Shen, Z1
Sze, J5
Li, K3
Lu, G5
Chan, DTM5
Poon, WS5
Kung, HF3 5
Lin, MCM5
Issue Date2011
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
CitationJournal Of Biological Chemistry, 2011, v. 286 n. 46, p. 39703-39714 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M111.293126
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.
ISSN0021-9258
2011 Impact Factor: 4.773
2011 SCImago Journal Rankings: 0.793
DOIhttp://dx.doi.org/10.1074/jbc.M111.293126
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorWang, Z
dc.contributor.authorLin, S
dc.contributor.authorLi, JJ
dc.contributor.authorXu, Z
dc.contributor.authorYao, H
dc.contributor.authorZhu, X
dc.contributor.authorXie, D
dc.contributor.authorShen, Z
dc.contributor.authorSze, J
dc.contributor.authorLi, K
dc.contributor.authorLu, G
dc.contributor.authorChan, DTM
dc.contributor.authorPoon, WS
dc.contributor.authorKung, HF
dc.contributor.authorLin, MCM
dc.date.accessioned2012-10-08T03:21:10Z
dc.date.available2012-10-08T03:21:10Z
dc.date.issued2011
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.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationJournal Of Biological Chemistry, 2011, v. 286 n. 46, p. 39703-39714 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M111.293126
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M111.293126
dc.identifier.epage39714
dc.identifier.issn0021-9258
2011 Impact Factor: 4.773
2011 SCImago Journal Rankings: 0.793
dc.identifier.issue46
dc.identifier.pmid21903590
dc.identifier.scopuseid_2-s2.0-81155123696
dc.identifier.spage39703
dc.identifier.urihttp://hdl.handle.net/10722/168586
dc.identifier.volume286
dc.languageeng
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
dc.publisher.placeUnited States
dc.relation.ispartofJournal of Biological Chemistry
dc.relation.referencesReferences in Scopus
dc.subject.meshHek293 Cells
dc.subject.meshHep G2 Cells
dc.subject.meshHumans
dc.subject.meshMicrornas - Biosynthesis - Genetics
dc.subject.meshMultigene Family
dc.subject.meshProto-Oncogene Proteins C-Myc - Genetics - Metabolism
dc.subject.meshResponse Elements
dc.subject.meshTranscription, Genetic
dc.titleMYC protein inhibits transcription of the MicroRNA cluster MC-let-7a-1∼let-7d via noncanonical E-box
dc.typeArticle
Author Affiliations
  1. Shanghai Jiaotong University
  2. Guangdong Medical College
  3. Sun Yat-Sen University
  4. Kunming Medical University
  5. Chinese University of Hong Kong