A Conserved Three-nucleotide Core Motif Defines Musashi RNA Binding Specificity

Zearfoss, N. Ruth; Deveau, Laura M.; Clingman, Carina C.; Schmidt, Eric; Johnson, Emily; Massi, Francesca; Ryder, Seán

doi:10.1074/jbc.m114.597112

Cited by 84 publications

(92 citation statements)

References 39 publications

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“…In Musashi-targeted genes, RRM1 and RRM2 recognition sequences are found in a close proximity at the 3′-end of the mRNAs (7). MSI1 specifically recognizes motifs (Figure 2B, 3A) variously defined as [(G/A)U(n)AGU (n =1–3)] (3), r(GUAG) and r(UAG) (62), (UAG) (54,63) and other poly-U motifs(55). MSI2 has been suggested to preferentially interact with an ACCUUUUUAGAA′ motif, and other poly-U sequences(37), UAG motifs(63) and UAG containing motifs +/− additional flanking nucleotides(56).…”

Section: Mechanisms Of Post-transcriptional Regulation By Musashi Promentioning

confidence: 99%

“…MSI1 specifically recognizes motifs (Figure 2B, 3A) variously defined as [(G/A)U(n)AGU (n =1–3)] (3), r(GUAG) and r(UAG) (62), (UAG) (54,63) and other poly-U motifs(55). MSI2 has been suggested to preferentially interact with an ACCUUUUUAGAA′ motif, and other poly-U sequences(37), UAG motifs(63) and UAG containing motifs +/− additional flanking nucleotides(56). In general, it is thought that both proteins recognize similar sequences and thus likely regulate similar mRNA targets (2,62).…”

Section: Mechanisms Of Post-transcriptional Regulation By Musashi Promentioning

confidence: 99%

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Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

221

240

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Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. While much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act post-transcriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBPs) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as regulators of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers, glioblastoma, and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGF-β/SMAD3, MYC, cMET, and others. Based on these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance. While RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target.

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Section: Mechanisms Of Post-transcriptional Regulation By Musashi Promentioning

confidence: 99%

Section: Mechanisms Of Post-transcriptional Regulation By Musashi Promentioning

confidence: 99%

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

221

240

View full text Add to dashboard Cite

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“…For many proteins the intrinsic specificity of their individual RBDs appears to be insufficient to accomplish the biologically required binding accuracy for RBPs 3,22,23,104 . Strategies have therefore evolved to enhance the intrinsic specificity of many proteins in order to better discriminate between cognate and non-cognate binding sites.…”

Section: Specific Vs Non-specific Interactionsmentioning

confidence: 99%

Specificity and nonspecificity in RNA–protein interactions

Jankowsky

Harris

2015

Nat Rev Mol Cell Biol

240

251

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Gene expression is regulated by complex networks of interactions between RNAs and proteins. Proteins that interact with RNA have been traditionally viewed as either specific or non-specific; specific proteins interact preferentially with defined RNA sequence or structure motifs, whereas non-specific proteins interact with RNA sites devoid of such characteristics. Recent studies indicate that the binary “specific vs. non-specific” classification is insufficient to describe the full spectrum of RNA–protein interactions. Here, we review new methods that enable quantitative measurements of protein binding to large numbers of RNA variants, and the concepts aimed as describing resulting binding spectra: affinity distributions, comprehensive binding models and free energy landscapes. We discuss how these new methodologies and associated concepts enable work towards inclusive, quantitative models for specific and non-specific RNA–protein interactions.

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“…These findings indicated that Tbx1 could be a direct mRNA target of MSI2. The proposed MSI2‐mRNA binding interactions are further supported by the identification of five multiple Musashi core recognition and binding sequences (UAG) in the Tbx1 3′ UTR (Supplemental Figure S4) (Zearfoss et al, ). To verify this interaction, RNA‐immunoprecipitation (RNA‐IP) was performed using dissociated whole adult mouse testis cells, and indicated significantly enriched Tbx1 mRNA expression (+3.51, p < 0.05) in MSI2‐IP, compared to the control‐IP and sample input, supporting a putative MSI2 protein‐ Tbx1 mRNA interaction (Figure c).…”

Section: Resultsmentioning

confidence: 87%

RNA binding protein Musashi‐2 regulates PIWIL1 and TBX1 in mouse spermatogenesis

Sutherland

Sobinoff

Fraser

et al. 2017

Journal Cellular Physiology

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RNA-binding proteins (RBP) are important facilitators of post-transcriptional gene regulation. We have previously established that nuclear overexpression of the RBP Musashi-2 (MSI2) during male germ cell maturation is detrimental to sperm cell development and fertility. Herein we determine the genes and pathways impacted by the upregulation of Msi2. Microarray analysis and qPCR confirmed differential gene expression in factors fundamental to the cell cycle, cellular proliferation, and cell death. Similarly, comparative protein expression analysis via iTRAQ, immunoblot, and immunolocalization, identified differential expression and localization of important regulators of transcription, translation, RNA processing, and spermatogenesis. Specifically, the testis-expressed transcription factor, Tbx1, and the piRNA regulator of gamete development, Piwil1, were both found to be targeted for translational repression by MSI2. This study provides key evidence to support a fundamental role for MSI2 in post-transcriptional regulation during male gamete development.

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A Conserved Three-nucleotide Core Motif Defines Musashi RNA Binding Specificity

Cited by 84 publications

References 39 publications

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Specificity and nonspecificity in RNA–protein interactions

RNA binding protein Musashi‐2 regulates PIWIL1 and TBX1 in mouse spermatogenesis

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