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Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany
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; in revised form: 14 May 2013 / Accepted: 22 May 2013 / Published: 7 June 2013
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
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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.
Thomas M, Lange-Grünweller K, Hartmann D, Golde L, Schlereth J, Streng D, Aigner A, Grünweller A, Hartmann RK. Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1. International Journal of Molecular Sciences. 2013; 14(6):12273-12296.
Thomas, Maren; Lange-Grünweller, Kerstin; Hartmann, Dorothee; Golde, Lara; Schlereth, Julia; Streng, Dennis; Aigner, Achim; Grünweller, Arnold; Hartmann, Roland K. 2013. "Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1." Int. J. Mol. Sci. 14, no. 6: 12273-12296.