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000270813 1001_ $$00000-0002-0247-3819$$aBrunialti, Electra$$b0
000270813 245__ $$aDesign and validation of a reporter mouse to study the dynamic regulation of TFEB and TFE3 activity through in vivo imaging techniques.
000270813 260__ $$aAbingdon, Oxon$$bTaylor & Francis$$c2024
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000270813 520__ $$aTFEB and TFE3 belong to the MiT/TFE family of transcription factors that bind identical DNA responsive elements in the regulatory regions of target genes. They are involved in regulating lysosomal biogenesis, function, exocytosis, autophagy, and lipid catabolism. Precise control of TFEB and TFE3 activity is crucial for processes such as senescence, stress response, energy metabolism, and cellular catabolism. Dysregulation of these factors is implicated in various diseases, thus researchers have explored pharmacological approaches to modulate MiT/TFE activity, considering these transcription factors as potential therapeutic targets. However, the physiological complexity of their functions and the lack of suitable in vivo tools have limited the development of selective MiT/TFE modulating agents. Here, we have created a reporter-based biosensor, named CLEARoptimized, facilitating the pharmacological profiling of TFEB- and TFE3-mediated transcription. This innovative tool enables the measurement of TFEB and TFE3 activity in living cells and mice through imaging and biochemical techniques. CLEARoptimized consists of a promoter with six coordinated lysosomal expression and regulation motifs identified through an in-depth bioinformatic analysis of the promoters of 128 TFEB-target genes. The biosensor drives the expression of luciferase and tdTomato reporter genes, allowing the quantification of TFEB and TFE3 activity in cells and in animals through optical imaging and biochemical assays. The biosensor's validity was confirmed by modulating MiT/TFE activity in both cell culture and reporter mice using physiological and pharmacological stimuli. Overall, this study introduces an innovative tool for studying autophagy and lysosomal pathway modulation at various biological levels, from individual cells to the entire organism.Abbreviations: CLEAR: coordinated lysosomal expression and regulation; MAR: matrix attachment regions; MiT: microphthalmia-associated transcription factor; ROI: region of interest; TBS: tris-buffered saline; TF: transcription factor; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TH: tyrosine hydroxylase; TK: thymidine kinase; TSS: transcription start site.
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000270813 650_7 $$2Other$$aAutophagy
000270813 650_7 $$2Other$$adrug discovery
000270813 650_7 $$2Other$$aluciferase
000270813 650_7 $$2Other$$alysosomal pathway
000270813 650_7 $$2Other$$anon-invasive study of TFEB and TFE3
000270813 650_7 $$2Other$$aoptical imaging
000270813 650_7 $$2NLM Chemicals$$aBasic Helix-Loop-Helix Leucine Zipper Transcription Factors
000270813 650_7 $$2NLM Chemicals$$aTcfeb protein, mouse
000270813 650_7 $$0136896-33-8$$2NLM Chemicals$$aTcfe3 protein, mouse
000270813 650_7 $$2NLM Chemicals$$aTFE3 protein, human
000270813 650_7 $$2NLM Chemicals$$aTFEB protein, human
000270813 650_2 $$2MeSH$$aAnimals
000270813 650_2 $$2MeSH$$aBasic Helix-Loop-Helix Leucine Zipper Transcription Factors: metabolism
000270813 650_2 $$2MeSH$$aMice
000270813 650_2 $$2MeSH$$aLysosomes: metabolism
000270813 650_2 $$2MeSH$$aGenes, Reporter
000270813 650_2 $$2MeSH$$aHumans
000270813 650_2 $$2MeSH$$aPromoter Regions, Genetic: genetics
000270813 650_2 $$2MeSH$$aAutophagy
000270813 650_2 $$2MeSH$$aBiosensing Techniques: methods
000270813 650_2 $$2MeSH$$aGene Expression Regulation: drug effects
000270813 7001_ $$00000-0001-7075-2759$$aRizzi, Nicoletta$$b1
000270813 7001_ $$0P:(DE-2719)9001609$$aPinto-Costa, Rita$$b2$$udzne
000270813 7001_ $$00000-0002-7445-916X$$aVilla, Alessandro$$b3
000270813 7001_ $$00009-0001-5142-2698$$aPanzeri, Alessia$$b4
000270813 7001_ $$00000-0003-3524-2010$$aMeda, Clara$$b5
000270813 7001_ $$aRebecchi, Monica$$b6
000270813 7001_ $$0P:(DE-2719)2481741$$aDi Monte, Donato A$$b7
000270813 7001_ $$00000-0001-5771-5638$$aCiana, Paolo$$b8
000270813 773__ $$0PERI:(DE-600)2262043-6$$a10.1080/15548627.2024.2334111$$gVol. 20, no. 8, p. 1879 - 1894$$n8$$p1879 - 1894$$tAutophagy$$v20$$x1554-8627$$y2024
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