The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies

Ming Ji, Enyu Rao, Himabindu Ramachandrareddy, Yulei Shen, Chunsun Jiang, Jianxiu Chen, Yiqiao Hu, A Angie Rizzino, Wing C. Chan, Kai Fu, Timothy W. McKeithan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1645-1656
Number of pages12
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
StatePublished - Oct 1 2011

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MicroRNAs
B-Lymphocytes
Histone Code
Binding Sites
Neoplasms
Mutation
Sequence Deletion
Neoplasm Genes
Luciferases
Oncogenes
Genes
Chromatin
Lymphoma
Cell Survival
Transcription Factors
Cell Proliferation
RNA
Cell Line

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Ji, M., Rao, E., Ramachandrareddy, H., Shen, Y., Jiang, C., Chen, J., ... McKeithan, T. W. (2011). The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies. American Journal of Pathology, 179(4), 1645-1656. https://doi.org/10.1016/j.ajpath.2011.06.008

The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies. / Ji, Ming; Rao, Enyu; Ramachandrareddy, Himabindu; Shen, Yulei; Jiang, Chunsun; Chen, Jianxiu; Hu, Yiqiao; Rizzino, A Angie; Chan, Wing C.; Fu, Kai; McKeithan, Timothy W.

In: American Journal of Pathology, Vol. 179, No. 4, 01.10.2011, p. 1645-1656.

Research output: Contribution to journalArticle

Ji, M, Rao, E, Ramachandrareddy, H, Shen, Y, Jiang, C, Chen, J, Hu, Y, Rizzino, AA, Chan, WC, Fu, K & McKeithan, TW 2011, 'The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies', American Journal of Pathology, vol. 179, no. 4, pp. 1645-1656. https://doi.org/10.1016/j.ajpath.2011.06.008
Ji, Ming ; Rao, Enyu ; Ramachandrareddy, Himabindu ; Shen, Yulei ; Jiang, Chunsun ; Chen, Jianxiu ; Hu, Yiqiao ; Rizzino, A Angie ; Chan, Wing C. ; Fu, Kai ; McKeithan, Timothy W. / The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies. In: American Journal of Pathology. 2011 ; Vol. 179, No. 4. pp. 1645-1656.
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