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

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.

Low Serum Levels of MicroRNA-19 Are Associated with a Stricturing Crohnʼs Disease Phenotype

“…1B-D); as was miR-17-5p (P ¼ 0.049), which is cotranscribed with miR-19 in cells. 24 However, due to high sequence homology, miR-17-5p could not be distinguished accurately from miR-106a in the array (Fig. 1C, D).…”

miR-92a inhibits vascular smooth muscle cell apoptosis: role of the MKK4–JNK pathway

“…These growth factors activate key transcription factors which, in turn, lead to upregulation of miRNAs. The VEGF-, EGF- and PDGF-responsive transcription factors, including E2F3 and Pim-1, have been reported to positively regulate miR17-92 expression [26–28]. The promoter regions of miR17-92 genes contain an E2F binding site (TTTSSCGC), and binding of E2F3 to these promoter regions activates their expression and promotes cell proliferation [27, 28].…”

“…The promoter regions of miR17-92 genes contain an E2F binding site (TTTSSCGC), and binding of E2F3 to these promoter regions activates their expression and promotes cell proliferation [27, 28]. Thomas et al [26] reported that the proto-oncogene Pim-1 is part of the network that regulates transcription of the miR-17-92 cluster. Therefore, the transcriptional program activated by serum to promote proliferation may at the same time inhibit apoptosis through a miR-92a-dependent mechanism.…”

Regulation of the miRNA expression by TEL/AML1, BCR/ABL, MLL/AF4 and TCF3/PBX1 oncoproteins in acute lymphoblastic leukemia (Review)

“…Several miRNAs are overexpressed in BCR/ABL1-positive ALL (27,33) (Table I). BCR/ABL has been shown to upregulate Pim-1 (34,35), E2F3 (36) and c-Myc (35) who regulate the transcriptional expression of miR-17-92 clusters. Recently, it was reported that BIM, a proapoptotic member, is a direct target of miR-17-92 clusters (37).…”