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Ephrin-B1 reverse signaling controls a posttranscriptional feedback mechanism via miR-124.

ABSTRACT: Eph receptors and ephrins exhibit complex and highly dynamic expression patterns during embryonic development. In addition, changes in their expression levels are often associated with pathological situations in adults. Yet, little is known about the mechanisms regulating their expression. Here we report that the expression of ephrin-B1 is controlled by a feedback loop involving posttranscriptional regulatory mechanisms. We observed that the EfnB1 3' untranslated region (3'-UTR) confers instability to mRNA transcripts, and we identified miR-124 as a posttranscriptional repressor of EfnB1 expression. Furthermore, we showed that miR-124 is itself regulated by ephrin-B1 reverse signaling, thus revealing the existence of a mutually repressive interaction between ephrin-B1 and this microRNA (miRNA). Lastly, we demonstrated the relevance of this mutual inhibition for neuronal differentiation. Our results suggest that miRNAs could be important effectors of Eph/ephrin signaling to refine domains of expression and to regulate function.

SUBMITTER: Arvanitis DN

PROVIDER: S-EPMC2863709 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Ephrin-B1 reverse signaling controls a posttranscriptional feedback mechanism via miR-124.

Arvanitis Dina N DN Jungas Thomas T Behar Annie A Davy Alice A

Molecular and cellular biology 20100322 10

Eph receptors and ephrins exhibit complex and highly dynamic expression patterns during embryonic development. In addition, changes in their expression levels are often associated with pathological situations in adults. Yet, little is known about the mechanisms regulating their expression. Here we report that the expression of ephrin-B1 is controlled by a feedback loop involving posttranscriptional regulatory mechanisms. We observed that the EfnB1 3' untranslated region (3'-UTR) confers instabil ...[more]

PMID: 20308325

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Project description:Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes.SignificanceEphrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.

Dataset Information

Ephrin-B1 reverse signaling controls a posttranscriptional feedback mechanism via miR-124.

Publications

Ephrin-B1 reverse signaling controls a posttranscriptional feedback mechanism via miR-124.

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