Transcriptome-wide analysis uncovers the targets of the RNA-binding protein MSI2 and effects of MSI2's RNA-binding activity on IL-6 signaling.
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Authors
Duggimpudi, SujithaKloetgen, Andreas
Maney, Sathish Kumar
Münch, Philipp C
Hezaveh, Kebria
Shaykhalishahi, Hamed
Hoyer, Wolfgang
McHardy, Alice C
Lang, Philipp A
Borkhardt, Arndt
Hoell, Jessica I
Issue Date
2018-08-20
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Show full item recordAbstract
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.Citation
J Biol Chem. 2018;293(40):15359-15369. doi:10.1074/jbc.RA118.002243.Affiliation
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.PubMed ID
30126842PubMed Central ID
PMC6177596Additional Links
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177596/Type
ArticleOther
Language
enEISSN
1083-351Xae974a485f413a2113503eed53cd6c53
10.1074/jbc.RA118.002243
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