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Int. J. Mol. Sci. 2013, 14(6), 12273-12296; doi:10.3390/ijms140612273
Article

Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1

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1 Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany 2 Medizinische Fakultät, Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Klinische Pharmakologie, Universität Leipzig, 04107 Leipzig, Germany These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 29 March 2013 / Revised: 14 May 2013 / Accepted: 22 May 2013 / Published: 7 June 2013
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Abstract

The human polycistronic miRNA cluster miR-17-92 is frequently overexpressed in hematopoietic malignancies and cancers. Its transcription is in part controlled by an E2F-regulated host gene promoter. An intronic A/T-rich region directly upstream of the miRNA coding region also contributes to cluster expression. Our deletion analysis of the A/T-rich region revealed a strong dependence on c-Myc binding to the functional E3 site. Yet, constructs lacking the 5'-proximal ~1.3 kb or 3'-distal ~0.1 kb of the 1.5 kb A/T-rich region still retained residual specific promoter activity, suggesting multiple transcription start sites (TSS) in this region. Furthermore, the protooncogenic kinase, Pim-1, its phosphorylation target HP1γ and c-Myc colocalize to the E3 region, as inferred from chromatin immunoprecipitation. Analysis of pri-miR-17-92 expression levels in K562 and HeLa cells revealed that silencing of E2F3, c-Myc or Pim-1 negatively affects cluster expression, with a synergistic effect caused by c-Myc/Pim-1 double knockdown in HeLa cells. Thus, we show, for the first time, that the protooncogene Pim-1 is part of the network that regulates transcription of the human miR-17-92 cluster.
Keywords: miRNA; miR-17-92 cluster; Pim-1; miRNA promoter; c-Myc; HP1γ; RNAi miRNA; miR-17-92 cluster; Pim-1; miRNA promoter; c-Myc; HP1γ; RNAi
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Thomas, M.; Lange-Grünweller, K.; Hartmann, D.; Golde, L.; Schlereth, J.; Streng, D.; Aigner, A.; Grünweller, A.; Hartmann, R.K. Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1. Int. J. Mol. Sci. 2013, 14, 12273-12296.

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