RNA-binding Protein Musashi Homologue 1 Regulates Kidney Fibrosis by Translational Inhibition of p21 and Numb mRNA

Jadhav, Shreyas; Ajay, Amrendra K.; Trivedi, P.P.; Seematti, Jenifer; Pellegrini, Kathryn L.; Craciun, Florin L.; Vaidya, Vishal S.

doi:10.1074/jbc.m115.713289

Cited by 24 publications

(21 citation statements)

References 41 publications

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“…This strong reduction in LaminB1 can mediate nuclear dysfunction, impairing structural and functional properties. To verify possible downstream effects of MSI/tau aggregation, we evaluated the mRNA level of one of the identified MSI mRNA targets, Numb, that is inhibited by MSI (Jadhav et al, ; Sheng et al, ). Numb protein normally inhibits the activation of Notch receptors (Giebel & Wodarz, ).…”

Section: Resultsmentioning

confidence: 99%

Tau oligomers mediate aggregation of RNA‐binding proteins Musashi1 and Musashi2 inducing Lamin alteration

et al. 2019

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The exact mechanisms leading to neurodegeneration in Alzheimer's disease (AD) and other tauopathies are not yet entirely understood. However, it is known that several RNA‐binding proteins (RBPs) form toxic aggregates and also interact with tau in such granules in tauopathies, including AD. The Musashi (MSI) family of RBPs, consisting of two homologues: Musashi1 and Musashi2, have not been extensively investigated in neurodegenerative diseases. Here, using a tau inducible HEK (iHEK) model we investigate whether MSI proteins contribute to the aggregation of toxic tau oligomers (TauO). Wild‐type and mutant P301L tau iHEK cells are used to study the effect of different tau variants on the cellular localization of MSI proteins. Interestingly, we observe that tau co‐localizes with MSI in the cytoplasm and nuclei, altering the nuclear transport of MSI. Furthermore, incremental changes in the size and density of nuclear MSI/tau foci are observed. We also report here that TauO interact with MSI to cause the formation of distinct nuclear aggregates. Moreover, tau/MSI aggregates induce structural changes to LaminB1, leading to nuclear instability. These results illustrate a possible mechanism of neurodegeneration mediated by the aggregation of MSI proteins and TauO, suggesting that MSI plays a critical role in cellular dysfunction.

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Section: Resultsmentioning

confidence: 99%

Tau oligomers mediate aggregation of RNA‐binding proteins Musashi1 and Musashi2 inducing Lamin alteration

et al. 2019

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“…For example, several groups reported that both MSI1 and MSI2 bound NUMB mRNA in vivo and in vitro (3,72–74). However, while Musashi proteins repressed NUMB consistently in CNS tumors and some hematologic malignancies, HSCs lacking Msi2 have unchanged levels of the Numb protein(13).…”

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

220

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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“…3 B). MSI1 is an RNA-binding protein and was previously reported to act as a translational suppressor of Cdkn1a mRNA expression 2 , 21 , 25 , 33 – 42 . Therefore, we performed a luciferase assay to confirm that MSI1 negatively regulates Cdkn1a gene expression.…”

Section: Resultsmentioning

confidence: 99%

Interplay among p21Waf1/Cip1, MUSASHI-1 and Krüppel-like factor 4 in activation of Bmi1-CreER reserve intestinal stem cells after gamma radiation-induced injury

Orzechowska

Katano

Bialkowska

et al. 2020

Sci Rep

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Gamma radiation is a commonly used adjuvant treatment for abdominally localized cancer. Since its therapeutic potential is limited due to gastrointestinal (GI) syndrome, elucidation of the regenerative response following radiation-induced gut injury is needed to develop a preventive treatment. Previously, we showed that Krüppel-like factor 4 (KLF4) activates certain quiescent intestinal stem cells (ISCs) marked by Bmi1-CreER to give rise to regenerating crypts following γ irradiation. In the current study, we showed that γ radiation-induced expression of p21Waf1/Cip1 in Bmi1-CreER cells is likely mitigated by MUSASHI-1 (MSI1) acting as a negative regulator of p21Waf1/Cip1 mRNA translation, which promotes exit of the Bmi1-CreER cells from a quiescent state. Additionally, Bmi1-specific Klf4 deletion resulted in decreased numbers of MSI1+ cells in regenerating crypts compared to those of control mice. We showed that KLF4 binds to the Msi1 promoter and activates its expression in vitro. Since MSI1 has been shown to be crucial for crypt regeneration, this finding elucidates a pro-proliferative role of KLF4 during the postirradiation regenerative response. Taken together, our data suggest that the interplay among p21Waf1/Cip1, MSI1 and KLF4 regulates Bmi1-CreER cell survival, exit from quiescence and regenerative potential upon γ radiation-induced injury.

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RNA-binding Protein Musashi Homologue 1 Regulates Kidney Fibrosis by Translational Inhibition of p21 and Numb mRNA

Cited by 24 publications

References 41 publications

Tau oligomers mediate aggregation of RNA‐binding proteins Musashi1 and Musashi2 inducing Lamin alteration

Tau oligomers mediate aggregation of RNA‐binding proteins Musashi1 and Musashi2 inducing Lamin alteration

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

Interplay among p21Waf1/Cip1, MUSASHI-1 and Krüppel-like factor 4 in activation of Bmi1-CreER reserve intestinal stem cells after gamma radiation-induced injury

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