Stem Cells, Cancer, and MUSASHI in Blood and Guts

Kharas, Michael G.; Lengner, Christopher J.

doi:10.1016/j.trecan.2017.03.007

Cited by 44 publications

(63 citation statements)

References 63 publications

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“…[15][16][17] As such, it mediates mRNA stability and translation of proteins involved in oncogenic pathways. [18][19][20] Overexpression and knockdown studies indicate that MSI2 is a promising therapeutic target for cancer. 3,13,16,21,22 Human MSI2 is a 328 amino acid protein that contains two RNA recognition motifs (RRMs) spanning G21-K111 (RRM1) and K110-P187 (RRM2).…”

Section: Introductionmentioning

confidence: 99%

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

et al. 2019

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Musashi‐2 (MSI2) belongs to Musashi family of RNA binding proteins (RBP). Like Musashi‐1 (MSI1), it is overexpressed in a variety of cancers and is a promising therapeutic target. Both MSI proteins contain two N‐terminal RNA recognition motifs and play roles in posttranscriptional regulation of target mRNAs. Previously, we have identified several inhibitors of MSI1, all of which bind to MSI2 as well. In order to design MSI2‐specific inhibitors and compare the differences of binding mode of the inhibitors, we set out to solve the structure of MSI2‐RRM1, the key motif that is responsible for the binding. Here, we report the crystal structure and the first NMR solution structure of MSI2‐RRM1, and compare these to the structures of MSI1‐RBD1 and other RBPs. A high degree of structural similarity was observed between the crystal and solution NMR structures. MSI2‐RRM1 shows a highly similar overall folding topology to MSI1‐RBD1 and other RBPs. The structural information of MSI2‐RRM1 will be helpful for understanding MSI2‐RNA interaction and for guiding rational drug design of MSI2‐specific inhibitors.

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Section: Introductionmentioning

confidence: 99%

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

et al. 2019

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“…MSI2 is a master RNA‐binding protein and posttranscriptional regulator that primarily controls mRNA stability and translation (Kudinov et al, 2017). It maintains the undifferentiated state of stem cells and cancer cells, serves in tissue regeneration, and is controlled through Notch pathways of stem cells (Takahashi et al, 2013; Kharas and Lengner, 2017). Although MSI2 and its isoform MSI1 are more commonly found in neoplastic cells (Kudinov et al, 2017), MSI2 is expressed throughout the SCN, as shown in the current study, within neurons and GFAP‐positive astrocytes of SCN explant tissue before and after culture and in brain sections from perfused mice.…”

Section: Discussionmentioning

confidence: 99%

“…The mRNA altered by Msi2 KO, KD, and OE has been described in several tissues: skin (Bennett et al, 2016; Ma et al, 2017), intestinal epithelium (Wang et al, 2015), hematopoietic stem cells (Park et al, 2014; Rentas et al, 2016; Kharas and Lengner, 2017). As summarized in Table 3, these studies describe MSI2 effects on cell differentiation, migration, and cell‐cell interactions that may be relevant to any neurogenesis or circuit remodeling in the SCN.…”

Section: Discussionmentioning

confidence: 99%

“…The most likely MSI2 targets were derived from published high‐throughput crosslinking immunoprecipitation (CLIP) and gene expression data generated after knockout (KO), knockdown (KD) or overexpression (OE) of Msi2 in mice or various cell types (Wu et al, 2010; Park et al, 2014; Wang et al, 2015; Bennett et al, 2016; Rentas et al, 2016; Kharas and Lengner, 2017). Data from in situ hybridization (ISH) experiments using sections from adult mouse brain were obtained from the Allen Institute Mouse Brain Atlas (ABA) and are available online at http://mouse.brain-map.org (Lein et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

“…8 (Cox et al, 2013) 9 Long (32‐hr) period detected. MSI‐2‐binding results were derived from several studies of MSI2 KO, KD or overexpression (Wu et al, 2010; Park et al, 2014; Wang et al, 2015; Bennett et al, 2016; Rentas et al, 2016; Kharas and Lengner, 2017).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Musashi‐2 and related stem cell proteins in the mouse suprachiasmatic nucleus and their potential role in circadian rhythms

Beligala

Malik

et al. 2019

Intl J of Devlp Neuroscience

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Background The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus contains the master circadian clock of the body and an unusually large number of cells expressing stem cell‐related proteins. These seemingly undifferentiated cells may serve in entrainment of the SCN circadian clock to light cycles or allow it to undergo neural plasticity important for modifying its rhythmic output signals. These cells may also proliferate and differentiate into neurons or glia in response to episodic stimuli or developmental events requiring alterations in the SCN's control of physiology and behavior. Problem To characterize expression of stem cell related proteins in the SCN and the effects of stem‐like cells on circadian rhythms. Methods Explant cultures of mouse SCN were maintained in medium designed to promote survival and growth of stem cells but not neuronal cells. Several stem cell marker proteins including SRY‐box containing gene 2 (SOX2), nestin, vimentin, octamer‐binding protein 4 (OCT4), and Musashi RNA‐binding protein 2 (MSI2) were identified by immunocytochemistry in histological sections from adult mouse SCN and in cultures of microdissected SCN. A bioinformatics analysis located potential SCN targets of MSI2 and related RNA‐binding proteins. Results Cells expressing stem cell markers proliferated in culture. Immunostained brain sections and bioinformatics supported the view that MSI2 regulates immature properties of SCN neurons, potentially providing flexibility in SCN neural circuits. Explant cultures had ongoing mitotic activity, indicated by proliferating‐cell nuclear antigen, and extensive cell loss shown by propidium iodide staining. Cells positive for vasoactive intestinal polypeptide (VIP) that are highly enriched in the SCN were diminished in explant cultures. Despite neuronal cell loss, tissue remained viable for over 7 weeks in culture, as shown by bioluminescence imaging of explants prepared from SCN of Per1::luc transgenic mice. The circadian rhythm in SCN gene expression persisted in brain slice cultures in stem cell medium. Prominent, widespread expression of RNA‐binding protein MSI2 supported the importance of posttranscriptional regulation in SCN functions and provided further evidence of stem‐like cells. Conclusion The results show that the SCN retains properties of immature neurons and these properties persist in culture conditions suitable for stem cells, where the SCN stem‐like cells also proliferate. These properties may allow adaptive circadian rhythm adjustments. Further exploration should examine stem‐like cells of the SCN in vivo, how they may affect circadian rhythms, and whether MSI2 serves as a master regulator of SCN stem‐like properties.

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RNA –Protein Interactions: A New Approach for Drugging RNA Biology

Soueid,

Garner

2024

RNA as a Drug Target

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Stem Cells, Cancer, and MUSASHI in Blood and Guts

Cited by 44 publications

References 63 publications

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

Musashi‐2 and related stem cell proteins in the mouse suprachiasmatic nucleus and their potential role in circadian rhythms

RNA –Protein Interactions: A New Approach for Drugging RNA Biology

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