An E2F/miR-20a Autoregulatory Feedback Loop

Sylvestre, Yannick; Guire, Vincent De; Querido, Emmanuelle; Mukhopadhyay, Utpal K.; Bourdeau, Véronique; Major, François; Ferbeyre, Gerardo; Chartrand, Pascal

doi:10.1074/jbc.m608939200

Cited by 542 publications

(515 citation statements)

References 42 publications

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“…45 Thus, upregulation of the cluster could lead to a differentiation block in specific AML subtypes. Our studies suggest that increased expression of the miR-17-92 cluster is not controlled by c-MYC or E2F1/3, transcription factors known to upregulate the cluster in solid tumors and in some B lymphomas, [22][23][24] although loss of a repressor in the PU.1 signaling pathway is not being ruled out. We also show that ATRA-induced activation of differentiation in HL-60 cells causes significant suppression of the miR-17-92 cluster (Figures 4b and e, Supplementary Figure S5D).…”

Section: Discussionmentioning

confidence: 73%

“…The miR-17-92 cluster was reported to be directly activated by the c-MYC oncogene or E2F transcription factors in a cell type-specific manner. 14,[22][23][24] We checked whether either of these transcription factors was controlling PHLPP2 expression through miR-17-92 in AML cells. First, silencing c-myc in HL-60 cells (Figure 3a) showed no significant effect on the miR-17-92 primary transcript (Figure 3b), individual mature miRNAs belonging to miR-17-92 cluster (Figure 3c) or on PHLPP2 protein levels ( Figure 3d).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies showed that transcription factors c-MYC and E2F bind to the promoter region of the host gene, MIR17HG. [22][23][24] In AML cells, neither c-MYC nor E2F silencing affected miR-17-92 expression, but C/EBPβ binding to the intronic promoter could repress the cluster, suggesting that transcriptional regulation of the miR-17-92 cluster in AML is independent of its host gene. C/EBPβ is a member of the C/EBP family of basic region/leucine zipper transcription factors, important for differentiation of liver, adipose tissue and hematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

“…12 Known major activators of the miR-17-92 cluster are transcription factor c-MYC and members of the E2F family, whereas p53 acts as a repressor under hypoxic conditions. [22][23][24][25] As PHLPP2 phosphatases are potential therapeutic targets, it is important to understand mechanisms that regulate PHLPP2 protein expression. Most recent investigations of this tumor-suppressor family have focused primarily on its regulation in solid tumors and their derivative cell lines, rather than in hematological malignancies.…”

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confidence: 99%

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Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

et al. 2016

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PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein.Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells. Phosphatases are pivotal components of intracellular signaling cascades, controlling essential processes like metabolism, apoptosis, proliferation and differentiation. 1 The PH-domain leucine-rich repeat protein phosphatase (PHLPP) family serine-threonine phosphatases are emerging as central factors in cell survival and death regulation. The PHLPP2 is a member of this family. 2,3 To date four PHLPP substrates, Akt, PKC, Mst1 and S6K1, have been identified, all kinases involved in cell survival or apoptosis. 4-7 Dephosphorylation inactivates Akt, S6K1 and PKC, and subsequently cell survival signaling, whereas dephosphorylation of Mst1 activates its apoptotic function.PHLPP protein expression and activity is suppressed through various mechanisms in cancers. Although most studies on PHLPP2 have focused on genetic alterations in solid tumors, 8 PHLPP2 protein expression in small cell lung and colorectal cancers is also restricted through translational suppression 9 and post-transcriptional control by microRNAs (miR or miRNAs), miR-205 and miR-224. 10,11 The PHLPP2 3' untranslated region (3'UTR) harbors complementary binding sites for a subset of miRNAs belonging to the miRNA-17-92 cluster. 12 This cluster comprises six miRNAs on chromosome 13, transcribed as a single polycistronic unit. 13,14 Also known as oncomir-1, the cluster enhances cell proliferation or inhibits apoptosis by suppressing targets such as Bim, E2F1 and PTEN and is markedly overexpressed in human cancers. [15][16][17][18][19][20][21] Reduced levels of PHLPP2 in chemoresistant miR-17-92 overexpressing mantle cell lymphomas had suggested that the phosphatase could be a target of oncomir-1. 12 Kno...

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Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

et al. 2016

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“…8 By chromatin immunoprecipitation (ChIP) in HeLa cells, endogenous E2F1, E2F2, and E2F3 were found to directly bind the promoter of the gene and regulate its transcription. 21 The primary transcript initiates from a consensus initiator sequence downstream of a nonconsensus TATA box. 23 This TATA box is flanked by a TP53 binding site that medi-ates repression under hypoxic conditions.…”

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confidence: 99%

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

Rao

Ramachandrareddy

et al. 2011

The American Journal of Pathology

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A cluster of six microRNAs (miRNAs), miR-17-92, is processed from the transcript of C13orf25, a gene amplified in some lymphomas and solid tumors. We find that levels of the miRNAs in the cluster do not vary entirely in parallel with each other or with the primary RNA in B-cell lines or normal cells, suggesting that processing or stability of the miRNAs is differentially regulated. Using luciferase reporter assays, we identified the region required for maximum promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually have only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. MYC is known to regulate C13orf25; surprisingly, mutation of a putative promoter MYCbinding site enhanced promoter activity. We found that the inhibitory MYC family member MXI1 bound to this region. The chromatin structure of a >22.5-kb region encompassing the gene contains peaks of activating histone marks, suggesting the presence of enhancers, and we confirmed that at least two regions have enhancer activity. Because MicroRNAs (miRNAs) are single-stranded RNAs of ϳ22 nucleotides that negatively regulate expression of their target genes posttranscriptionally. 1-4 Various miRNAs are overexpressed or underexpressed in different types of cancer in humans and may function as either tumor suppressors or oncogenes. 5-13 A cluster of six miRNAs (miR-17-92, comprising miR-17, miR18a, miR-20a, miR-19a, miR-19b-1, and miR-92a-1) is processed from the transcript of C13orf25 (also known as MIR17HG or MIRHG1), a gene amplified in some lymphomas and solid tumors 5,14 -17 and overexpressed in a large fraction of lymphomas. 5 Overexpression of miR-17-92 accelerates lymphomagenesis in mouse models. 5,8 The miRNAs in the cluster can target transcripts of genes, such as E2F1, PTEN, and BIM, which are important in cell proliferation and apoptosis. 18 -22 The transcriptional regulation of the miR-17-92 cluster, however, is poorly understood.C13orf25 is activated by MYC and E2F transcription factors, and MYC was first shown to bind to a region containing a conserved CATGTG sequence in the first intron of the gene locus. 8 By chromatin immunoprecipitation (ChIP) in HeLa cells, endogenous E2F1, E2F2, and E2F3 were found to directly bind the promoter of the gene and regulate its transcription. 21 The primary transcript initiates from a consensus initiator sequence downstream of a nonconsensus TATA box. 23 This TATA box is flanked by a TP53 binding site that medi-

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Alteration in microRNA‐17‐92 dynamics accounts for differential nature of cellular proliferation

2018

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MicroRNAs associated with the mir-17-92 cluster are crucial regulators of the mammalian cell cycle, as they inhibit transcription factors related to the E2F family that tightly control decision-making events for a cell to commit for active cellular proliferation. Intriguingly, in many solid cancers, these mir-17-92 cluster members are overexpressed, whereas in some hematopoietic cancers they are down-regulated. Our proposed model of the Myc/E2F/mir-17-92 network demonstrates that the differential expression pattern of mir-17-92 in different cell types can be conceived due to having a contrasting E2F dynamics induced by mir-17-92. The model predicts that by explicitly altering the mir-17-92-related part of the network, experimentally it is possible to control cellular proliferation in a cell type-dependent manner for therapeutic intervention.

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An E2F/miR-20a Autoregulatory Feedback Loop

Cited by 542 publications

References 42 publications

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

Alteration in microRNA‐17‐92 dynamics accounts for differential nature of cellular proliferation

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