B-cell Receptor Activation Induces BIC/miR-155 Expression through a Conserved AP-1 Element

Yin, Qinyan; Wang, Xia; McBride, Jane; Fewell, Claire; Flemington, Erik K.

doi:10.1074/jbc.m708218200

Cited by 210 publications

(222 citation statements)

References 30 publications

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“…This correlation substantiates our findings and provides an insight into the Eμ-miR-155 mouse model, which mostly develops pre-B-cell leukemia but has a B-cell gene expression signature resembling the miR-155 overexpressing human ABC-DLBCL. This is also in line with the role of miR-155 in B-cell activation and its induction with BCR cross-linking (17). Altogether this implies the overlapping molecular signatures from multiple malignancies, which can take different courses.…”

Section: Resultssupporting

confidence: 58%

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Sandhu

Volinia

Costinean

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

121

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Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.NfκB | Ingenuity Pathway Analysis M icroRNAs (miRNAs) are 18-24-nucleotide-long noncoding RNA molecules that regulate gene expression in many cellular processes including proliferation, differentiation, and development. Recent studies have established that expression of miRNAs is widely altered in a variety of cancers and miR-155 is one of the most frequently overexpressed miRNAs in various solid and hematological malignancies (1). miR-155 is highly upregulated in Hodgkin, primary mediastinal, and diffuse large B-cell lymphomas (DLBCL) (2, 3) and is almost absent or significantly down-regulated in primary cases of Burkitt lymphoma (4). Overexpression of bic, host mRNA of miR-155, caused increased incidence of leukemia and a decrease in latency of lymphoma development in chickens with elevated levels of MYC (5). Overexpression of miR-155 in mice B cells (Eμ-miR-155) has been shown to cause pre-B-cell leukemia/high-grade lymphoma (6), whereas deletion of bic/miR-155 in mice has been attributed to immunodeficiency and impaired T-cell-dependent antibody response (7,8). Additionally, sustained miR-155 expression in stem cell progenitors induced a myeloproliferative disease in transplanted mice (9). Despite the availability of multiple animal models and a ...

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Section: Resultssupporting

confidence: 58%

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Sandhu

Volinia

Costinean

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

121

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“…We further analyzed the effect of IL-10 on transcriptional regulation of the BIC gene through the use of a luciferase reporter plasmid containing 1200 bp of the BIC promoter region (25). In addition, we investigated whether any of the IL-10 effects were mediated through STAT3 by using small interfering RNA (siRNA) targeted against STAT3.…”

Section: Il-10 Inhibits Mir-155 Expression In Response To Tlr4mentioning

confidence: 99%

IL-10 Inhibits miR-155 Induction by Toll-like Receptors

McCoy

Sheedy

Qualls

et al. 2010

Journal of Biological Chemistry

234

180

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IL-10 is a potent anti-inflammatory cytokine that is crucial for down-regulating pro-inflammatory genes, which are induced by Toll-like receptor (TLR) signaling. In this study, we have examined whether modulation of microRNAs plays a role in the inhibitory effect of IL-10 on TLR4 signaling. Analyzing microRNAs known to be induced by TLR4, we found that IL-10 could inhibit the expression of miR-155 in response to lipopolysaccharide but had no effect on miR-21 or miR-146a. IL-10 inhibited miR-155 transcription from the BIC gene in a STAT3-dependent manner. This inhibitory effect of IL-10 on miR-155 led to an increase in the expression of the miR-155 target, SHIP1. This is the first example of IL-10 playing a role in microRNA function and suggests that through its inhibitory effect on miR-155, IL-10 has the ability to promote anti-inflammatory gene expression.

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“…The pGL3 reporter construct containing BIC wild type promoter (pGL3-BIC-WT) was a generous gift from Dr Erik Flemington and has previously been described. 53 The STAT5A or STAT5B expression plasmids [wild type, or constitutively active (CA)] were a kind gift from Dr Peter Lobie and have previously been described. 54 Transient transfection with siRNA/miRNA inhibitors (antagomiRs).…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%