TY - JOUR
T1 - The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies
AU - Ji, Ming
AU - Rao, Enyu
AU - Ramachandrareddy, Himabindu
AU - Shen, Yulei
AU - Jiang, Chunsun
AU - Chen, Jianxiu
AU - Hu, Yiqiao
AU - Rizzino, Angie
AU - Chan, Wing C.
AU - Fu, Kai
AU - McKeithan, Timothy W.
N1 - Funding Information:
Supported by University of Nebraska Medical Center Eppley Cancer Center pilot grants (T.W.M. and K.F.), a clinical investigator career development award from Lymphoma Research Foundation/Millennium Pharmaceuticals Inc. (K.F.), a National Cancer Institute grant ( U01-CA114778-03 to W.C.C.), and a National Institute of General Medical Sciences grant ( GM-080751 to A.R.).
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2011.06.008
DO - 10.1016/j.ajpath.2011.06.008
M3 - Article
C2 - 21806958
AN - SCOPUS:80053203847
VL - 179
SP - 1645
EP - 1656
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -