The Musashi-1-type 2 deiodinase pathway regulates astrocyte proliferation.

Autor:	Mohácsik P; Laboratory of Molecular Cell Metabolism, HUN-REN Institute of Experimental Medicine, Budapest, Hungary., Halmos E; Laboratory of Molecular Cell Metabolism, HUN-REN Institute of Experimental Medicine, Budapest, Hungary., Dorogházi B; Laboratory of Molecular Cell Metabolism, HUN-REN Institute of Experimental Medicine, Budapest, Hungary., Ruska Y; Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary., Wittmann G; Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary., Bianco AC; Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, Illinois, USA., Fekete C; Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary., Gereben B; Laboratory of Molecular Cell Metabolism, HUN-REN Institute of Experimental Medicine, Budapest, Hungary. Electronic address: gereben.balazs@koki.hun-ren.hu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107477. Date of Electronic Publication: 2024 Jun 13.
DOI:	10.1016/j.jbc.2024.107477
Abstrakt:	Thyroid hormone (TH) is a critical regulator of cellular function and cell fate. The circulating TH level is relatively stable, while tissue TH action fluctuates according to cell type-specific mechanisms. Here, we focused on identifying mechanisms that regulate TH action through the type 2 deiodinase (D2) in glial cells. Dio2 mRNA has an unusually long 3'UTR where we identified multiple putative MSI1 binding sites for Musashi-1 (MSI1), a highly conserved RNA-binding cell cycle regulator. Binding to these sites was confirmed through electrophoretic mobility shift assay. In H4 glioma cells, shRNA-mediated MSI1 knockdown increased endogenous D2 activity, whereas MSI1 overexpression in HEK293T cells decreased D2 expression. This latter effect could be prevented by the deletion of a 3.6 kb region of the 3'UTR of Dio2 mRNA containing MSI1 binding sites. MSI1 immunoreactivity was observed in 2 mouse Dio2-expressing cell types, that is, cortical astrocytes and hypothalamic tanycytes, establishing the anatomical basis for a potential in vivo interaction of Dio2 mRNA and MSl1. Indeed, increased D2 expression was observed in the cortex of mice lacking MSI1 protein. Furthermore, MSI1 knockdown-induced D2 expression slowed down cell proliferation by 56% in primary cultures of mouse cortical astrocytes, establishing the functionality of the MSI1-D2-T3 pathway. In summary, Dio2 mRNA is a target of MSI1 and the MSI1-D2-T3 pathway is a novel regulatory mechanism of astrocyte proliferation with the potential to regulate the pathogenesis of human glioblastoma. Competing Interests: Conflict of interest Antonio C. Bianco received consultant fees from AbbVie, Synthonics, Sention, Thyron, and Accella. The other authors declare that they have no conflicts of interests with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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