Journal Article

FZJ-2018-07288

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Transcriptome-wide analysis uncovers the targets of the RNA-binding protein MSI2 and effects of MSI2's RNA-binding activity on IL-6 signaling

Duggimpudi, S. ; Kloetgen, A. ; Maney, S. K. ; Münch, P. C. ; Hezaveh, K. ; Shaykhalishahi, H. ; Hoyer, W.FZJ* ; McHardy, A. C. ; Lang, P. A. ; Borkhardt, A. ; Hoell, J. I. (Corresponding author)

2018
Soc.72889 Bethesda, Md.

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Please use a persistent id in citations: http://hdl.handle.net/2128/20505  doi:10.1074/jbc.RA118.002243

Abstract: The RNA-binding protein Musashi 2 (MSI2) has emerged as an important regulator in cancer initiation, progression, and drug resistance. Translocations and deregulation of the MSI2 gene are diagnostic of certain cancers, including chronic myeloid leukemia (CML) with translocation t(7;17), acute myeloid leukemia (AML) with translocation t(10;17), and some cases of B-precursor acute lymphoblastic leukemia (pB-ALL). To better understand the function of MSI2 in leukemia, the mRNA targets that are bound and regulated by MSI2 and their MSI2-binding motifs need to be identified. To this end, using photoactivatable ribonucleoside cross-linking and immunoprecipitation (PAR-CLIP) and the Multiple EM for Motif Elicitation (MEME) analysis tool, here we identified MSI2’s mRNA targets and the consensus RNA-recognition element (RRE) motif recognized by MSI2 (UUAG). Of note, MSI2 knockdown altered the expression of several genes with roles in eukaryotic initiation factor 2 (eIF2), hepatocyte growth factor (HGF), and epidermal growth factor (EGF) signaling pathways. We also show that MSI2 regulates classic interleukin-6 (IL-6) signaling by promoting the degradation of the mRNA of IL-6 signal transducer (IL6ST or GP130), which, in turn, affected the phosphorylation statuses of signal transducer and activator of transcription 3 (STAT3) and the mitogen-activated protein kinase ERK. In summary, we have identified multiple MSI2-regulated mRNAs and provided evidence that MSI2 controls IL6ST activity that control oncogenic signaling networks. Our findings may help inform strategies for unraveling the role of MSI2 in leukemia to pave the way for the development of targeted therapies.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)

Appears in the scientific report 2018

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Database coverage:
; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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