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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

1,†
, 1,†
, 1
, 1
, 1
, 1
, 2
, 1,*  and 1,*
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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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