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

International Journal of Molecular Sciences

Maren Thomas¹  Kerstin Lange-Grünweller¹  Dorothee Hartmann¹  Lara Golde¹  Julia Schlereth¹  Dennis Streng¹  Achim Aigner²  Arnold Grünweller¹ 

[1] Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany; E-Mails:;Medizinische Fakultät, Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Klinische Pharmakologie, Universität Leipzig, 04107 Leipzig, Germany; E-Mail:

关键词: miRNA;    miR-17-92 cluster;    Pim-1;    miRNA promoter;    c-Myc;    HP1γ;    RNAi;   

DOI  :  10.3390/ijms140612273

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland