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The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation

Moskot, Marta and Montefusco, Sandro and Jakóbkiewicz-Banecka, Joanna and Mozolewski, Paweł and Węgrzyn, Alicja and Bernardo, Diego Di and Węgrzyn, Grzegorz and Medina, Diego and Ballabio, Andrea and Gabig-Cimińska, Magdalena (2014) The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. Journal of Biological Chemistry, 289 . pp. 17054-17069. ISSN 0021-9258

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Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) has been previously proposed as a potential drug for use in substrate reduction therapy for mucopolysaccharidoses, a group of inherited metabolic diseases caused by mutations leading to inefficient degradation of glycosaminoglycans (GAGs) in lysosomes. It was demonstrated that this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases. So far, no comprehensive genomic analyses have been performed to elucidate the molecular mechanisms underlying the effect elicited by genistein. Therefore, the aim of this work was to identify the genistein-modulated gene network regulating GAG biosynthesis and degradation, taking into consideration the entire lysosomal metabolism. Our analyses identified over 60 genes with known roles in lysosomal biogenesis and/or function whose expression was enhanced by genistein. Moreover, 19 genes whose products are involved in both GAG synthesis and degradation pathways were found to be remarkably differentially regulated by genistein treatment. We found a regulatory network linking genistein- mediated control of transcription factor EB (TFEB) gene expression, TFEB nuclear translocation, and activation of TFEB-dependent lysosome biogenesis to lysosomal metabolism. Our data indicate that the molecular mechanism of genistein action involves not only impairment of GAG synthesis but more importantly lysosomal enhancement via TFEB. These findings contribute to explaining the beneficial effects of genistein in lysosomal storage diseases as well as envisage new therapeutic approaches to treat these devastating diseases.

Item Type:Article
Subjects:Q Science > Q Science (General)
Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
Divisions:Laboratory of Molecular Biology (in Gdansk)
ID Code:1127
Deposited By: Prof. Magdalena Gabig-Cimińska
Deposited On:25 Jan 2016 08:28
Last Modified:25 Jan 2016 08:28

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