title: The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies.
abstract: A cluster of six microRNAs (miRNAs), miR-17-92, is processed from the transcript of C13orf25, a gene amplified in some lymphomas and solid tumors. We find that levels of the miRNAs in the cluster do not vary entirely in parallel with each other or with the primary RNA in B-cell lines or normal cells, suggesting that processing or stability of the miRNAs is differentially regulated. Using luciferase reporter assays, we identified the region required for maximum promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually have only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. MYC is known to regulate C13orf25; surprisingly, mutation of a putative promoter MYC-binding site enhanced promoter activity. We found that the inhibitory MYC family member MXI1 bound to this region. The chromatin structure of a >22.5-kb region encompassing the gene contains peaks of activating histone marks, suggesting the presence of enhancers, and we confirmed that at least two regions have enhancer activity. Because the miR-17-92 cluster acts as an important oncogene in several cancers and targets genes important in regulating cell proliferation and survival, further studies of its transcriptional control are warranted.
authors.affiliation: School of Life Science, Nanjing University, Nanjing, China; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.forename: Enyu
authors.initials: E
authors.lastname: Rao
authors.forename: Himabindu
authors.initials: H
authors.lastname: Ramachandrareddy
authors.forename: Yulei
authors.initials: Y
authors.lastname: Shen
authors.forename: Chunsun
authors.initials: C
authors.lastname: Jiang
authors.forename: Jianxiu
authors.initials: J
authors.lastname: Chen
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
authors.forename: Angie
authors.initials: A
authors.lastname: Rizzino
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.forename: Timothy W
authors.initials: TW
authors.lastname: McKeithan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D024721:E-Box Elements / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci / Q000235:genetics; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D049409:Luciferases, Firefly / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D062085:RNA, Long Noncoding; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D006657:Histones; D049409:Luciferases, Firefly; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C568997:MIR17HG, human; C079440:MXI1 protein, human