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

Sutherland, Jessie M.; Sobinoff, Alexander P.; Fraser, Barbara; Redgrove, Kate A.; Siddall, Nicole A; Koopman, Peter; Hime, Gary R.; McLaughlin, Eileen A.

doi:10.1002/jcp.26168

Cited by 7 publications

(6 citation statements)

References 51 publications

(72 reference statements)

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“…Here we reported that MSI1 shuttles into the cytosol under stress to form a complex with AGO2 that can stabilize or destabilize its target mRNAs. Sutherland and colleagues reported in 2017 that MSI2 translationally repressed Piwil1, another member of the Argonaute protein family, during male gamete development 30, directly linking musashi proteins with the Argonaute family. In our study, we identify the MSI1/AGO2 interaction by proteomic analysis from immunoprecipitation in cancer cells (Figure S4B-C).…”

Section: Discussionmentioning

confidence: 99%

Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2

Chen¹,

Wang²,

Beaugerie³

et al. 2020

Theranostics

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Carcinomatous progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. However, the underlined molecular mechanism remains obscure.Methods: We found Musashi-1 (MSI1) transported into cytosol under stress condition by confocal microscopy and cell fractionation. Argonaute 2 (AGO2) was then identified as a cytosolic binding partner of MSI1 by Mass Spectrametry, immunoprecipitation, and recombinant protein pull-down assay. We used RNA-IP to determine the MSI1/AGO2 associated regions on downstream target mRNAs. Finally, we overexpressed C-terminus of MSI1 to disrupt endogenous MSI1/AGO2 interaction and confirm it effects on tmor progression.Results: Malignant tumors exhibit elevated level of cytosolic Musashi-1 (MSI1), which translocates into cytosol in response to stress and promote tumor progression. Cytosolic MSI1 forms a complex with AGO2 and stabilize or destabilize its target mRNAs by respectively binding to their 3´ untranslated region or coding domain sequence. Both MSI1 translocation and MSI1/AGO2 binding are essential for promoting tumor progression. Blocking MSI1 shuttling by either chemical inhibition or point mutation attenuates the growth of GBM-xenografts in mice. Importantly, overexpression of the C-terminus of MSI1 disrupts endogenous MSI1/AGO2 interaction and effectively reduces stress-induced tumor progression.Conclusion: Our findings highlight novel molecular functions of MSI1 during stress-induced carcinomatous recurrence, and suggest a new therapeutic strategy for refractory malignancies by targeting MSI1 translocation and its interaction with AGOs.

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Section: Discussionmentioning

confidence: 99%

Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2

Chen¹,

Wang²,

Beaugerie³

et al. 2020

Theranostics

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“…Musashi has two N‐terminal RNA recognition motifs (RRM), RRM1 and RRM2, that mediate the binding to motifs located at the 3′‐UTR of target mRNA . MSI2 has been reported to act as a potent cooperative oncoprotein in hematopoietic malignancies and a variety of solid tumors …”

Section: Introductionmentioning

confidence: 99%

RNA‐binding protein Musashi2 stabilizing androgen receptor drives prostate cancer progression

et al. 2020

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractThe androgen receptor (AR) pathway is critical for prostate cancer carcinogenesis and development; however, after 18-24 months of AR blocking therapy, patients invariably progress to castration-resistant prostate cancer (CRPC), which remains an urgent problem to be solved. Therefore, finding key molecules that interact with AR as novel strategies to treat prostate cancer and even CRPC is desperately needed. In the current study, we focused on the regulation of RNA-binding proteins (RBPs) associated with AR and determined that the mRNA and protein levels of AR were highly correlated with Musashi2 (MSI2) levels. MSI2 was upregulated in prostate cancer specimens and significantly correlated with advanced tumor grades. Downregulation of MSI2 in both androgen sensitive and insensitive prostate cancer cells inhibited tumor formation in vivo and decreased cell growth in vitro, which could be reversed by AR overexpression. Mechanistically, MSI2 directly bound to the 3′-untranslated region (UTR) of AR mRNA to increase its stability and, thus, enhanced its transcriptional activity. Our findings illustrate a previously unknown regulatory mechanism in prostate cancer cell proliferation regulated by the MSI2-AR axis and provide novel evidence towards a strategy against prostate cancer. K E Y W O R D Sandrogen receptor, mRNA stability, Musashi2, novel anti-androgen therapy, prostate cancer

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“…Amongst the TBX transcription factors identified was TBX-1, which is translationally repressed by overexpression of MSI2 at both genomic and proteomic levels. 75 We observed a 1.8-fold upregulation in the soluble profile of MSI2. This protein was recently shown to be upregulated in non-small cell lung cancer, and to support metastasis by promoting epithelialmesenchymal transition (EMT) through transforming growth factor beta (TGF-β) signalling and tight junction proteins.…”

Section: Discussionmentioning

confidence: 61%

Time‐resolved proteomic profiling of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

et al. 2021

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Background and objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with none able to reverse disease or stop its progression. We explored the major molecular changes in COPD pathogenesis. Methods: We employed quantitative label-based proteomics to map the changes in the lung tissue proteome of cigarette smoke-induced experimental COPD that is induced over 8 weeks and progresses over 12 weeks. Results: Quantification of 7324 proteins enabled the tracking of changes to the proteome. Alterations in protein expression profiles occurred in the induction phase, with 18 and 16 protein changes at 4-and 6-week time points, compared to age-matched controls, respectively. Strikingly, 269 proteins had altered expression after 8 weeks when the hallmark pathological features of human COPD emerge, but this dropped to 27 changes at 12 weeks with disease progression. Differentially expressed proteins were validated using other mouse and human COPD bronchial biopsy samples. Major changes in RNA biosynthesis (heterogeneous nuclear ribonucleoproteins C1/C2 [HNRNPC] and RNA-binding protein Musashi homologue 2 [MSI2]) and modulators of inflammatory responses (S100A1) were notable. Mitochondrial dysfunction and changes in oxidative stress proteins also occurred. Conclusion:We provide a detailed proteomic profile, identifying proteins associated with the pathogenesis and disease progression of COPD establishing a platform to develop effective new treatment strategies.

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

Cited by 7 publications

References 51 publications

Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2

Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2

RNA‐binding protein Musashi2 stabilizing androgen receptor drives prostate cancer progression

Time‐resolved proteomic profiling of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

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