DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1

Lerner, Mikael; Harada, Masahiko; Lovén, Jakob; Castro, Juan; Davis, Zadie; Oscier, David; Henriksson, Marie Arsenian; Sangfelt, Olle; Grandér, Dan; Corcoran, Martin

doi:10.1016/j.yexcr.2009.07.001

Cited by 156 publications

(150 citation statements)

References 50 publications

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“…Cyclin E1 is transcriptionally regulated by E2F (3) and, as shown by us here and previously by others, posttranscriptionally regulated by the miR-15 and miR-16 families (37,(39)(40)(41). In addition, as shown here, E2Fs transcriptionally regulate the miR-15 and miR-16 families.…”

Section: Resultssupporting

confidence: 76%

“…Nevertheless, given that the seeds of miR-15 and miR-16 are highly similar and miR-16 was shown by others to negatively regulate cyclin E (40), we consider it reasonable to extrapolate that E2F1 upregulates the expression of 4 distinct miRs, namely, miR-15a, miR-16-1 and miR-15b, miR-16-2, all of which target cyclin E. Given this scenario, E2F1-regulated miRs likely exert a significant effect on cyclin E expression. Notably, data from other studies suggest that miR-15 and miR-16 downregulate not only cyclin E but also a number of other pivotal regulators of cell-cycle progression, such as cyclin D1, cyclin D3, and CDK6 (37)(38)(39)(40)(41). Thus, these 4 miRs can collaborate to restrict E2F-induced cell-cycle progression by targeting multiple proliferation-related genes.…”

Section: Discussionmentioning

confidence: 99%

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miR-15 and miR-16 Are Direct Transcriptional Targets of E2F1 that Limit E2F-Induced Proliferation by Targeting Cyclin E

Ofir

Hacohen

Ginsberg

2011

Molecular Cancer Research

165

149

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microRNAs (miR) are small noncoding RNA molecules that have recently emerged as critical regulators of gene expression and are often deregulated in cancer. In particular, miRs encoded by the miR-15a, miR-16-1 cluster seem to act as tumor suppressors. Here, we evidence that the miR-15a, miR-16-1 cluster and related miR-15b, miR-16-2 cluster comprise miRs regulated by E2F1, a pivotal transcription factor that can induce both proliferation and cell death. E2F1 is a critical downstream target of the tumor suppressor retinoblastoma (RB). The RB pathway is often inactivated in human tumors resulting in deregulated E2F activity. We show that expression levels of the 4 mature miRs, miR-15a, miR-16-1 and miR-15b, miR-16-2, as well as their precursor primiRNAs, are elevated upon activation of ectopic E2F1. Moreover, activation of endogenous E2Fs upregulates expression of these miRs and endogenous E2F1 binds their respective promoters. Importantly, we corroborate that miR-15a/b inhibits expression of cyclin E, the latter a key direct transcriptional target of E2F pivotal for the G 1 /S transition, raising the possibility that E2F1, miR-15, and cyclin E constitute a feed-forward loop that modulates E2F activity and cell-cycle progression. In support of this, ectopic expression of miR-15 inhibits the G 1 /S transition, and, conversely, inhibition of miR-15 expression enhances E2F1-induced upregulation of cyclin E1 levels. Furthermore, inhibition of both miR-15 and miR-16 enhances E2F1-induced G 1 /S transition. In summary, our data identify the miR-15 and miR-16 families as novel transcriptional targets of E2F, which, in turn, modulates E2F activity. Mol Cancer Res; 9(4); 440-7. Ó2011 AACR.

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Section: Resultssupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

miR-15 and miR-16 Are Direct Transcriptional Targets of E2F1 that Limit E2F-Induced Proliferation by Targeting Cyclin E

Ofir

Hacohen

Ginsberg

2011

Molecular Cancer Research

165

149

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“…14 The demonstration that the DLEU2 promoter can control miR15a/16-1 expression is a likely explanation for the two cases we found with deletion of the DLEU2 promoter region but not the miR15a/16-1 cluster. 26 We refine two BCRs, proximal and distal, to the MDR that may be prone to breakage and recombination in CLL B cells. In light of the BCRs identified here, it is clear that 13q deletions can be grouped thus: class I deletions are confined to a 2 Mb region where breakpoints often occur in the two BCRs identified, which in addition to the genes within the MDR, include FLJ31945, FAM10A4, BCMS and DLEU7; class II deletions extended beyond this region in either a centromeric and/or telomeric direction, encompassing a large number of additional genes.…”

Section: Discussionmentioning

confidence: 98%

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

et al. 2010

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Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb-96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio ¼ 12.3; P ¼ 0.005), (b) in progressive patients, class II deletions were enriched (P ¼ 0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2-49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (Po0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.

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“…It has been estimated that miRNAs may regulate up to 30% of all genes in the human genome (Lewis et al 2005). The miR-15a/16-1 cluster is located in the host gene DLEU2 at chromosome 13q14.3, a genomic region frequently deleted in B-cell chronic lymphocytic leukemia, myeloma, and mantle cell lymphoma (Lerner et al 2009). The cluster is highly conserved among mammalian species (Yue & Tigyi 2010), and these two miRNAs of the cluster are cotranscribed and downregulated in more than two-thirds of chronic lymphocytic leukemia (CLL) patients (Calin et al 2002, Cimmino et al 2005.…”

Section: Discussionmentioning

confidence: 99%

Expressions of miR-15a and its target gene HSPA1B in the spermatozoa of patients with varicocele

Mou

et al. 2014

Reproduction

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Hyperthermia and oxidative stresses are the two central elements contributing to varicocele-related sperm damage. Growing evidence indicates that microRNAs (miRNAs) are involved in the regulation of the heat and oxidative stress responses. In this study, we analyzed the expressions of several stress-related miRNAs in the sperm and found that the expression of miR-15a was significantly decreased in patients with varicocele compared with the control. Furthermore, miR-15a repressed the expression of HSPA1B, which is a typical stressinduced chaperone protein, through directly binding its 3 0 -UTR. The expressions of miR-15a and HSPA1B exhibited an inverse correlation in sperm. Our results provide a valuable insight into the varicocele-related sperm impairment and male infertility, and may help to develop potential therapeutic targets and novel biomarkers for male infertility.

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DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1

Cited by 156 publications

References 50 publications

miR-15 and miR-16 Are Direct Transcriptional Targets of E2F1 that Limit E2F-Induced Proliferation by Targeting Cyclin E

miR-15 and miR-16 Are Direct Transcriptional Targets of E2F1 that Limit E2F-Induced Proliferation by Targeting Cyclin E

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

Expressions of miR-15a and its target gene HSPA1B in the spermatozoa of patients with varicocele

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