The RNA-Binding Protein Musashi1: A Major Player in Intestinal Epithelium Renewal and Colon Cancer Development

Plateroti, Michelina; Araújo, Patrícia Rosa de; Silva, Acarizia Eduardo da; Penalva, Luiz O. F.

doi:10.1007/s11888-012-0141-6

Cited by 7 publications

(13 citation statements)

References 96 publications

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“…MSI1 has long been described as a potential central actor in intestinal physiology (reviewed in ref. ). Although Msi1 ‐KO mice have been developed , eventual intestinal‐developmental or adult‐physiological abnormalities in those mice have never been reported.…”

Section: Discussionmentioning

confidence: 97%

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A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness

et al. 2015

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The intestinal epithelium is very peculiar for its continuous cell renewal, fuelled by multipotent stem cells localized within the crypts of Lieberkühn. Several lines of evidence have established the evolutionary conserved RNA-binding protein Musashi1 as a marker of adult stem cells, including those of the intestinal epithelium, and revealed its roles in stem cell self-renewal and cell fate determination. Previous studies from our laboratories have shown that Musashi1 controls stem cell-like features in medulloblastoma, glioblastoma and breast cancer cells, and has pro-proliferative and pro-tumorigenic properties in intestinal epithelial progenitor cells in vitro. In order to undertake a detailed study of Musashi1’s function in the intestinal epithelium in vivo, we have generated a mouse model, referred to as v-Msi, overexpressing Musashi1 specifically in the entire intestinal epithelium. Compared with wild type litters, v-Msi1 mice exhibited increased intestinal crypt size accompanied by enhanced proliferation. Comparative transcriptomics by RNA-seq revealed Musashi1’s association with gut stem cell signature, cell cycle, DNA replication and drug metabolism. Finally, we identified and validated three novel mRNA targets that are stabilized by Musashi1, Ccnd1 (Cyclin D1), Cdk6 and Sox4. In conclusion, the targeted expression of Musashi1 in the intestinal epithelium in vivo increases the cell proliferation rate and strongly suggests its action on stem cells activity. This is due to the modulation of a complex network of gene functions and pathways including drug metabolism, cell cycle and DNA synthesis and repair.

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Section: Discussionmentioning

confidence: 97%

“…Along the same lines, v ‐Msi1 young adult animals did not develop intestinal cancers as expected from the literature (reviewed in ref. ). Although this result initially seems contradictory to our previous observations in primary cultures , a direct comparison is misleading.…”

Section: Discussionmentioning

confidence: 97%

A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness

et al. 2015

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“…Msi1 silencing inhibits multiple cancer relevant phenotypes and abolishes growth of multiple tumor types including glioblastoma [14,15,17,[20][21][22]. We evaluated if luteolin treatment could produce similar results in GBM cells.…”

Section: Luteolin Inhibits Proliferation Colony Formation Migrationmentioning

confidence: 99%

“…Msi gene deletion inhibited tumorigenesis in different mouse models of intestinal cancer [38]. Msi1 contributes to tumorigenesis in colon cancer by activating multiple pathways such as Notch and the PDK-Akt-mTORC1 axis [20,37,39]. Transgenic expression of Msi1 in the intestine increased cell proliferation and expansion of the progenitor layer.…”

Section: Musashi1 As Oncogenic Factor In Multiple Tumor Typesmentioning

confidence: 99%

Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells

Li²,

Ivanov

et al. 2018

RNA Biology

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RNA binding proteins have emerged as critical oncogenic factors and potential targets in cancer therapy. In this study, we evaluated Musashi1 (Msi1) targeting as a strategy to treat glioblastoma (GBM); the most aggressive brain tumor type. Msi1 expression levels are often high in GBMs and other tumor types and correlate with poor clinical outcome. Moreover, Msi1 has been implicated in chemo-and radio-resistance. Msi1 modulates a range of cancer relevant processes and pathways and regulates the expression of stem cell markers and oncogenic factors via mRNA translation/stability. To identify Msi1 inhibitors capable of blocking its RNA binding function, we performed a~25,000 compound fluorescence polarization screen. NMR and LSPR were used to confirm direct interaction between Msi1 and luteolin, the leading compound. Luteolin displayed strong interaction with Msi1 RNA binding domain 1 (RBD1). As a likely consequence of this interaction, we observed via western and luciferase assays that luteolin treatment diminished Msi1 positive impact on the expression of pro-oncogenic target genes. We tested the effect of luteolin treatment on GBM cells and showed that it reduced proliferation, cell viability, colony formation, migration and invasion of U251 and U343 GBM cells. Luteolin also decreased the proliferation of patient-derived glioma initiating cells (GICs) and tumor-organoids but did not affect normal astrocytes. Finally, we demonstrated the value of combined treatments with luteolin and olaparib (PARP inhibitor) or ionizing radiation (IR). Our results show that luteolin functions as an inhibitor of Msi1 and demonstrates its potential use in GBM therapy.

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“…One group of studies indicates that Msi1 promotes epithelial cell growth by supporting canonical Wnt signaling while repressing p21 and the negative regulator of Notch signaling, Numb 16,40 . It was posited that through these pathways, Msi1 activity promotes self-renewal of an active crypt base columnar (CBC) stem cell population (these studies are collectively reviewed in 42 ). In contrast, other studies conclude that Msi activity does not promote canonical Wnt or Notch signaling 38,41 .…”

Section: Role Of Msi Family In the Intestinementioning

confidence: 99%

Stem Cells, Cancer, and MUSASHI in Blood and Guts

Kharas

Lengner

2017

Trends in Cancer

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The mammalian MSI family of RNA binding proteins play important roles as oncoproteins in a wide array of tumors including leukemias, glioblastoma, and pancreatic, breast, lung, and colorectal cancers,. Interestingly, the mammalian Msi genes, Msi1 and Msi2 have been most thoroughly investigated in two highly proliferative tissues prone to oncogenic transformation: the hematopoietic lineage and the intestinal epithelium. Despite their vast phenotypic differences, Msi proteins appear to play an analogous role in governing the stem cell compartment in both of these tissues, potentially providing a paradigm for a more broad understanding of Msi function and its oncogenic activities. In this review we focus on MSI function in the blood and the intestine and discuss therapeutic strategies for targeting this pathway.

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The RNA-Binding Protein Musashi1: A Major Player in Intestinal Epithelium Renewal and Colon Cancer Development

Cited by 7 publications

References 96 publications

A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness

A Mouse Model of Targeted Musashi1 Expression in Whole Intestinal Epithelium Suggests Regulatory Roles in Cell Cycle and Stemness

Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells

Stem Cells, Cancer, and MUSASHI in Blood and Guts

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