{"doi":"10.15252/emmm.202216877","title":"TFEB and TFE3 drive kidney cystogenesis and tumorigenesis","abstract":"Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.","journal":"EMBO Molecular Medicine","year":2023,"id":318781,"datarank":1.331328138782772,"base_score":4.127134385045092,"endowment":4.127134385045092,"self_citation_contribution":0.6190701577567639,"citation_network_contribution":0.7122579810260081,"self_endowment_contribution":0.6190701577567639,"citer_contribution":0.7122579810260081,"corpus_percentile":null,"corpus_rank":null,"citation_count":61,"citer_count":38,"citers_with_citation_signal":24,"citers_with_endowment":24,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE213063","GSE207649","GSE207650"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":233325,"name":"Angela Zampelli","orcid":"0000-0002-1600-1708","position":1,"is_corresponding":false},{"id":1027444,"name":"Letizia Granieri","orcid":null,"position":2,"is_corresponding":false},{"id":233329,"name":"Claudia Vilardo","orcid":"0000-0003-4713-5298","position":3,"is_corresponding":false},{"id":628610,"name":"Rossella De Cegli","orcid":"0000-0002-8526-8692","position":4,"is_corresponding":false},{"id":1026716,"name":"Laura Cinque","orcid":"0000-0002-8497-3939","position":5,"is_corresponding":false},{"id":234610,"name":"Edoardo Nusco","orcid":null,"position":6,"is_corresponding":false},{"id":233321,"name":"Salvatore Pece","orcid":"0000-0003-1764-3929","position":7,"is_corresponding":false},{"id":1026717,"name":"Daniela Tosoni","orcid":"0000-0003-4443-1059","position":8,"is_corresponding":false},{"id":1026718,"name":"Francesca Sanguedolce","orcid":"0000-0001-7459-3521","position":9,"is_corresponding":false},{"id":948347,"name":"Nicolina Cristina Sorrentino","orcid":"0000-0002-3426-5109","position":10,"is_corresponding":false},{"id":218403,"name":"Maria J. 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