The Experts below are selected from a list of 657 Experts worldwide ranked by ideXlab platform
Masaya Baba - One of the best experts on this subject based on the ideXlab platform.
-
Folliculin interacting protein 1 maintains metabolic homeostasis during b cell development by modulating ampk mtorc1 and tfe3
Journal of Immunology, 2019Co-Authors: Julita A Ramirez, Masaya Baba, Heon Park, Terri Iwata, Mark Tsang, Janella Kang, Katy Cui, Winnie Kwong, Richard G James, Laura S. SchmidtAbstract:Folliculin interacting protein 1 (Fnip1) is a cytoplasmic protein originally discovered through its interaction with the master metabolic sensor 5' AMP-activated protein kinase (AMPK) and Folliculin, a protein mutated in individuals with Birt-Hogg-Dube Syndrome. In response to low energy, AMPK stimulates catabolic pathways such as autophagy to enhance energy production while inhibiting anabolic pathways regulated by the mechanistic target of rapamycin complex 1 (mTORC1). We previously found that constitutive disruption of Fnip1 in mice resulted in a lack of peripheral B cells because of a block in B cell development at the pre-B cell stage. Both AMPK and mTORC1 were activated in Fnip1-deficient B cell progenitors. In this study, we found inappropriate mTOR localization at the lysosome under nutrient-depleted conditions. Ex vivo lysine or arginine depletion resulted in increased apoptosis. Genetic inhibition of AMPK, inhibition of mTORC1, or restoration of cell viability with a Bcl-xL transgene failed to rescue B cell development in Fnip1-deficient mice. Fnip1-deficient B cell progenitors exhibited increased nuclear localization of transcription factor binding to IgHM enhancer 3 (TFE3) in developing B cells, which correlated with an increased expression of TFE3-target genes, increased lysosome numbers and function, and increased autophagic flux. These results indicate that Fnip1 modulates autophagy and energy response pathways in part through the regulation of AMPK, mTORC1, and TFE3 in B cell progenitors.
-
Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation.
Journal of Bone and Mineral Research, 2018Co-Authors: Masaya Baba, Hisashi Hasumi, Mitsuhiro Endoh, Wenjuan Ma, Hirofumi Toyama, Akiyoshi Hirayama, Keizo Nishikawa, Keiyo Takubo, Hiroyuki Hano, Terumasa UmemotoAbstract:: Osteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast differentiation. However, the upstream regulatory mechanisms that drive these metabolic changes in osteoclastogenesis remain to be elucidated. Here, we demonstrate that induced deletion of a tumor suppressor gene, Folliculin (Flcn), in mouse osteoclast precursors causes severe osteoporosis in 3 weeks through excess osteoclastogenesis. Flcn-deficient osteoclast precursors reveal cell autonomous accelerated osteoclastogenesis with increased sensitivity to receptor activator of NF-κB ligand (RANKL). We demonstrate that Flcn regulates oxidative phosphorylation and purine metabolism through suppression of nuclear localization of the transcription factor Tfe3, thereby inhibiting expression of its target gene Pgc1. Metabolome studies revealed that Flcn-deficient osteoclast precursors exhibit significant augmentation of oxidative phosphorylation and nucleotide production, resulting in an enhanced purinergic signaling loop that is composed of controlled ATP release and autocrine/paracrine purinergic receptor stimulation. Inhibition of this purinergic signaling loop efficiently blocks accelerated osteoclastogenesis in Flcn-deficient osteoclast precursors. Here, we demonstrate an essential and novel role of the Flcn-Tfe3-Pgc1 axis in osteoclastogenesis through the metabolic reprogramming of oxidative phosphorylation and purine metabolism. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
-
Folliculin flcn inactivation leads to murine cardiac hypertrophy through mtorc1 deregulation
Human Molecular Genetics, 2014Co-Authors: Yukiko Hasumi, Masaya Baba, Hisashi Hasumi, Diana C Haines, Ying Huang, Martin Lang, Rachel Reindorf, Sebastiano Sciarretta, Kunio Nagashima, Michael D SchneiderAbstract:Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss ofFlcn, a novel AMPK–mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased inFlcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism underFlcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased inFlcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size ofFlcn/Ppargc1a doubly inactivated hearts, further supporting the idea thatPpargc1a is the critical element leading to deregulation of the AMPK–mTOR-axis and resulting in cardiac hypertrophy underFlcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model.
-
the Folliculin fnip1 pathway deleted in human birt hogg dube syndrome is required for murine b cell development
Blood, 2012Co-Authors: Masaya Baba, Hisashi Hasumi, Yukiko Hasumi, Jonathan R Keller, Hongwei Sun, Wolfgang Resch, Stefan Kuchen, Hyung Chan Suh, Kyongrim Kiefferkwon, Carme Gallego GonzalezAbstract:Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in Folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized Folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1−/− mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1−/− mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways.
-
tumor suppressor flcn inhibits tumorigenesis of a flcn null renal cancer cell line and regulates expression of key molecules in tgf β signaling
Molecular Cancer, 2010Co-Authors: Seungbeom Hong, Masaya Baba, Hyoungbin Oh, Vladimir Valera, Jaime Stull, Maria Merino, Marston W Linehan, Laura S. SchmidtAbstract:Background Germline mutations in the FLCN gene are responsible for the development of fibrofolliculomas, lung cysts and renal neoplasia in Birt-Hogg-Dube' (BHD) syndrome. The encoded protein Folliculin (FLCN) is conserved across species but contains no classic motifs or domains and its function remains unknown. Somatic mutations or loss of heterozygosity in the remaining wild type copy of the FLCN gene have been found in renal tumors from BHD patients suggesting that FLCN is a classic tumor suppressor gene.
Eamonn R Maher - One of the best experts on this subject based on the ideXlab platform.
-
expression and knockdown of zebrafish Folliculin suggests requirement for embryonic brain morphogenesis
BMC Developmental Biology, 2016Co-Authors: Maurice A M Van Steensel, Eamonn R Maher, Emma J Kenyon, Monique N H Luijten, Harmeet Gill, Matthew Rawlings, James C Bull, Yavor Hadzhiev, Ferenc MuellerAbstract:Birt-Hogg-Dube syndrome (BHD) is a dominantly inherited familial cancer syndrome characterised by the development of benign skin fibrofolliculomas, multiple lung and kidney cysts, spontaneous pneumothorax and susceptibility to renal cell carcinoma. BHD is caused by mutations in the gene encoding Folliculin (FLCN). Little is known about what FLCN does in a healthy individual and how best to treat those with BHD. As a first approach to developing a vertebrate model for BHD we aimed to identify the temporal and spatial expression of flcn transcripts in the developing zebrafish embryo. To gain insights into the function of flcn in a whole organism system we generated a loss of function model of flcn by the use of morpholino knockdown in zebrafish. flcn is expressed broadly and upregulated in the fin bud, somites, eye and proliferative regions of the brain of the Long-pec stage zebrafish embryos. Together with knockdown phenotypes, expression analysis suggest involvement of flcn in zebrafish embryonic brain development. We have utilised the zFucci system, an in vivo, whole organism cell cycle assay to study the potential role of flcn in brain development. We found that at the 18 somite stage there was a significant drop in cells in the S-M phase of the cell cycle in flcn morpholino injected embryos with a corresponding increase of cells in the G1 phase. This was particularly evident in the brain, retina and somites of the embryo. Timelapse analysis of the head region of flcn morpholino injected and mismatch control embryos shows the temporal dynamics of cell cycle misregulation during development. In conclusion we show that zebrafish flcn is expressed in a non-uniform manner and is likely required for the maintenance of correct cell cycle regulation during embryonic development. We demonstrate the utilisation of the zFucci system in testing the role of flcn in cell proliferation and suggest a function for flcn in regulating cell proliferation in vertebrate embryonic brain development.
-
Folliculin interacts with p0071 plakophilin 4 and deficiency is associated with disordered rhoa signalling epithelial polarization and cytokinesis
Human Molecular Genetics, 2012Co-Authors: Michael S Nahorski, Laurence Seabra, Ania Straatmaniwanowska, Aileen Wingenfeld, Anne Reiman, Jeff Klomp, Bin Tean Teh, Mechthild Hatzfeld, Paul Gissen, Eamonn R MaherAbstract:Inherited mutations in the Folliculin (FLCN) gene cause the Birt-Hogg-Dube syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though Folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterized. We identified plakophilin-4 (p0071) as a potential novel Folliculin interacting protein by yeast two-hybrid analysis. We confirmed the interaction of Folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to the regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell Folliculin status on p0071-related functions. Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that Folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of Folliculin-deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in Folliculin-deficient cells. Deficiency of Folliculin and of p0071 resulted in tight junction defects and mislocalization of E-cadherin in mouse inner medullary collecting duct-3 renal tubular cells. These findings suggest that aspects of Folliculin tumour suppressor function are linked to interaction with p0071 and the regulation of RhoA signalling.
-
gene expression and protein array studies of Folliculin regulated pathways
Anticancer Research, 2012Co-Authors: Anne Reiman, Michael S Nahorski, Laurence Seabra, Uncaar Boora, Wenbin Wei, Eamonn R MaherAbstract:The familial cancer syndrome Birt-Hogg-Dube syndrome is characterised by the development of skin (fibrofolliculomas) and renal tumours (and lung cysts) and is caused by mutations in the FLCN tumour suppressor gene. Though the FLCN gene product (Folliculin) has been linked to the regulation of a variety of signalling pathways (e.g. the mTOR, AMPK, TGFbeta and hyoxia-responsive genes) the precise function of the Folliculin protein is not well-defined. In order to identify potential novel pathways linked to Folliculin function we analysed paired isogenic Folliculin-deficient and Folliculin-expressing cell lines by gene expression and protein (Kinexus) arrays. Gene expression microarray analysis in the Folliculin +/- non-renal cancer line (FTC133), revealed 708 differentially expressed targets (fold change >2 and p<0.001) with enrichment of genes in the cadherin and Wnt signalling pathways. Comparison of the differentially expressed genes in the FTC133 datasets and previously reported gene expression data for a Folliculin-deficient renal tumour and the UOK257 renal cell carcinoma cell line, revealed that RAB27B was dysregulated in all three datasets (increased expression in Folliculin-deficient cells). The Kinexus protein array analysis suggested 73 candidate, differentially expressed, proteins and further investigation by western blot analysis of 5 candidates that were also differentially expressed in the FTC133 gene expression microarray data, revealed that EIF2AK2 (PKR) and CASP1 were reduced and PLCG2 was increased in Folliculin-deficient FTC133 cells and in a BHD renal tumour. In view of the role of CASP1 in apoptosis we investigated whether other apoptosis-related proteins might be regulated by Folliculin and found increased levels of SMAC/Diablo and HtrA2 in Folliculin-expressing FTC133 cells. These findings identify novel pathways and targets linked to Folliculin tumour suppressor activity.
-
abstract lb 145 Folliculin interacts with p0071 plakophilin 4 and deficiency is associated with disordered rhoa signalling epithelial polarization and cytokinesis
Cancer Research, 2012Co-Authors: Michael S Nahorski, Laurence Seabra, Ania Straatmaniwanowska, Aileen Wingenfeld, Anne Reiman, Mechthild Hatzfeld, Paul Gissen, Eamonn R MaherAbstract:Inherited mutations in the Folliculin gene (FLCN) cause the Birt-Hogg-Dube syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though Folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterised. We identified plakophilin-4 (PKP4, p0071) as a potential novel Folliculin interacting protein by yeast-2-hybrid analysis. We confirmed the interaction of Folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell Folliculin status on p0071-related functions. Folliculin and p0071 partially colocalised at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that Folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of Folliculin deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in Folliculin deficient cells. Deficiency of Folliculin and of p0071 resulted in tight junction defects and mislocalisation of E-cadherin in IMCD-3 renal tubular cells. These findings suggest that aspects of Folliculin tumour suppressor function are linked to interaction with p0071 and regulation of RhoA signalling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-145. doi:1538-7445.AM2012-LB-145
Michael S Nahorski - One of the best experts on this subject based on the ideXlab platform.
-
Folliculin interacts with p0071 plakophilin 4 and deficiency is associated with disordered rhoa signalling epithelial polarization and cytokinesis
Human Molecular Genetics, 2012Co-Authors: Michael S Nahorski, Laurence Seabra, Ania Straatmaniwanowska, Aileen Wingenfeld, Anne Reiman, Jeff Klomp, Bin Tean Teh, Mechthild Hatzfeld, Paul Gissen, Eamonn R MaherAbstract:Inherited mutations in the Folliculin (FLCN) gene cause the Birt-Hogg-Dube syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though Folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterized. We identified plakophilin-4 (p0071) as a potential novel Folliculin interacting protein by yeast two-hybrid analysis. We confirmed the interaction of Folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to the regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell Folliculin status on p0071-related functions. Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that Folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of Folliculin-deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in Folliculin-deficient cells. Deficiency of Folliculin and of p0071 resulted in tight junction defects and mislocalization of E-cadherin in mouse inner medullary collecting duct-3 renal tubular cells. These findings suggest that aspects of Folliculin tumour suppressor function are linked to interaction with p0071 and the regulation of RhoA signalling.
-
gene expression and protein array studies of Folliculin regulated pathways
Anticancer Research, 2012Co-Authors: Anne Reiman, Michael S Nahorski, Laurence Seabra, Uncaar Boora, Wenbin Wei, Eamonn R MaherAbstract:The familial cancer syndrome Birt-Hogg-Dube syndrome is characterised by the development of skin (fibrofolliculomas) and renal tumours (and lung cysts) and is caused by mutations in the FLCN tumour suppressor gene. Though the FLCN gene product (Folliculin) has been linked to the regulation of a variety of signalling pathways (e.g. the mTOR, AMPK, TGFbeta and hyoxia-responsive genes) the precise function of the Folliculin protein is not well-defined. In order to identify potential novel pathways linked to Folliculin function we analysed paired isogenic Folliculin-deficient and Folliculin-expressing cell lines by gene expression and protein (Kinexus) arrays. Gene expression microarray analysis in the Folliculin +/- non-renal cancer line (FTC133), revealed 708 differentially expressed targets (fold change >2 and p<0.001) with enrichment of genes in the cadherin and Wnt signalling pathways. Comparison of the differentially expressed genes in the FTC133 datasets and previously reported gene expression data for a Folliculin-deficient renal tumour and the UOK257 renal cell carcinoma cell line, revealed that RAB27B was dysregulated in all three datasets (increased expression in Folliculin-deficient cells). The Kinexus protein array analysis suggested 73 candidate, differentially expressed, proteins and further investigation by western blot analysis of 5 candidates that were also differentially expressed in the FTC133 gene expression microarray data, revealed that EIF2AK2 (PKR) and CASP1 were reduced and PLCG2 was increased in Folliculin-deficient FTC133 cells and in a BHD renal tumour. In view of the role of CASP1 in apoptosis we investigated whether other apoptosis-related proteins might be regulated by Folliculin and found increased levels of SMAC/Diablo and HtrA2 in Folliculin-expressing FTC133 cells. These findings identify novel pathways and targets linked to Folliculin tumour suppressor activity.
-
abstract lb 145 Folliculin interacts with p0071 plakophilin 4 and deficiency is associated with disordered rhoa signalling epithelial polarization and cytokinesis
Cancer Research, 2012Co-Authors: Michael S Nahorski, Laurence Seabra, Ania Straatmaniwanowska, Aileen Wingenfeld, Anne Reiman, Mechthild Hatzfeld, Paul Gissen, Eamonn R MaherAbstract:Inherited mutations in the Folliculin gene (FLCN) cause the Birt-Hogg-Dube syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though Folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterised. We identified plakophilin-4 (PKP4, p0071) as a potential novel Folliculin interacting protein by yeast-2-hybrid analysis. We confirmed the interaction of Folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell Folliculin status on p0071-related functions. Folliculin and p0071 partially colocalised at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that Folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of Folliculin deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in Folliculin deficient cells. Deficiency of Folliculin and of p0071 resulted in tight junction defects and mislocalisation of E-cadherin in IMCD-3 renal tubular cells. These findings suggest that aspects of Folliculin tumour suppressor function are linked to interaction with p0071 and regulation of RhoA signalling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-145. doi:1538-7445.AM2012-LB-145
-
abstract 1848 Folliculin flcn sequence variants involved in birt hogg dube syndrome
Cancer Research, 2010Co-Authors: Derek Lim, Michel Van Geel, Pauline K Rehal, Michael S Nahorski, Fiona Macdonald, Tijs Claessens, Lieke Gijezen, Johan J P Gille, Sophie Giraud, Stephane RichardAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Birt-Hogg-Dube (BHD) syndrome is an autosomal dominantly inherited familial cancer syndrome characterized most commonly by the development of facial fibrofolliculomas, pulmonary cysts (predisposing to spontaneous pneumothorax) and renal cancer. Germline mutations in FLCN on 17p11.2 have been reported in patients with BHD and also in patients with isolated familial primary spontaneous pneumothorax and familial clear cell renal cell carcinoma without other features of BHD. The function of the FLCN gene product, Folliculin, is not well characterized but recent studies have suggested that it may be implicated in the regulation of several key signalling pathways including the AMPK-mTOR route. Methods: We previously established an online locus-specific database (LSDB) for FLCN sequence variants at www.lovd.nl/flcn. Variants in the database have been curated from the published literature and novel unpublished sequence variants submitted to the database from diagnostic and research laboratories working on BHD syndrome. The entries in the database were analyzed looking at the variant type and distribution and associated phenotype. Results: The database currently contains a total of 115 unique sequence variants (including 70 pathogenic, 7 probably pathogenic, 1 variant of unknown significance and 37 single nucleotide polymorphisms) in FLCN. The majority of pathogenic mutations results in protein truncation whilst a minority are splice-site alterations. An up to date summary of the variants and their associated phenotype will be presented. Conclusion: Pathogenic mutations are found throughout the coding regions (exons 4-14) and there are no apparent genotype-phenotype correlations. The FLCN mutation database available at www.lovd.nl/flcn offers a valuable resource and tool for clinicians involved in the management of BHD patients, clinical geneticists and researchers. Researchers can directly submit new sequence variants online to the database or by e-mailing the author. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1848.
-
a new locus specific database lsdb for mutations in the Folliculin flcn gene
Human Mutation, 2010Co-Authors: Derek Lim, Michel Van Geel, Pauline K Rehal, Michael S Nahorski, Fiona Macdonald, Tijs Claessens, Lieke Gijezen, Johan J P Gille, Sophie Giraud, Stephane RichardAbstract:Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant condition characterised by the presence of facial fibrofolliculomas, pulmonary cysts which may be associated with spontaneous pneumothorax and renal tumours. Germline mutations in the gene Folliculin (FLCN) were first identified in BHD patients in 2002. In addition FLCN mutations have also been described in families with isolated primary spontaneous pneumothorax (PSP) and also familial clear cell renal carcinomas (FcRCC). We have established a locus-specific database based on the Leiden Open (source) Variation Database (LOVD) software. The version of the database contains 60 previously published mutations and 10 previously unpublished novel germline FLCN mutations. The mutations are comprised of deletions (44.3%), substitutions (35.7%), duplications (14.3%) and deletion/insertions (5.7%). The database is accessible online at http://www.lovd.nl/flcn.
Laura S. Schmidt - One of the best experts on this subject based on the ideXlab platform.
-
Folliculin interacting protein 1 maintains metabolic homeostasis during b cell development by modulating ampk mtorc1 and tfe3
Journal of Immunology, 2019Co-Authors: Julita A Ramirez, Masaya Baba, Heon Park, Terri Iwata, Mark Tsang, Janella Kang, Katy Cui, Winnie Kwong, Richard G James, Laura S. SchmidtAbstract:Folliculin interacting protein 1 (Fnip1) is a cytoplasmic protein originally discovered through its interaction with the master metabolic sensor 5' AMP-activated protein kinase (AMPK) and Folliculin, a protein mutated in individuals with Birt-Hogg-Dube Syndrome. In response to low energy, AMPK stimulates catabolic pathways such as autophagy to enhance energy production while inhibiting anabolic pathways regulated by the mechanistic target of rapamycin complex 1 (mTORC1). We previously found that constitutive disruption of Fnip1 in mice resulted in a lack of peripheral B cells because of a block in B cell development at the pre-B cell stage. Both AMPK and mTORC1 were activated in Fnip1-deficient B cell progenitors. In this study, we found inappropriate mTOR localization at the lysosome under nutrient-depleted conditions. Ex vivo lysine or arginine depletion resulted in increased apoptosis. Genetic inhibition of AMPK, inhibition of mTORC1, or restoration of cell viability with a Bcl-xL transgene failed to rescue B cell development in Fnip1-deficient mice. Fnip1-deficient B cell progenitors exhibited increased nuclear localization of transcription factor binding to IgHM enhancer 3 (TFE3) in developing B cells, which correlated with an increased expression of TFE3-target genes, increased lysosome numbers and function, and increased autophagic flux. These results indicate that Fnip1 modulates autophagy and energy response pathways in part through the regulation of AMPK, mTORC1, and TFE3 in B cell progenitors.
-
tumor suppressor flcn inhibits tumorigenesis of a flcn null renal cancer cell line and regulates expression of key molecules in tgf β signaling
Molecular Cancer, 2010Co-Authors: Seungbeom Hong, Masaya Baba, Hyoungbin Oh, Vladimir Valera, Jaime Stull, Maria Merino, Marston W Linehan, Laura S. SchmidtAbstract:Background Germline mutations in the FLCN gene are responsible for the development of fibrofolliculomas, lung cysts and renal neoplasia in Birt-Hogg-Dube' (BHD) syndrome. The encoded protein Folliculin (FLCN) is conserved across species but contains no classic motifs or domains and its function remains unknown. Somatic mutations or loss of heterozygosity in the remaining wild type copy of the FLCN gene have been found in renal tumors from BHD patients suggesting that FLCN is a classic tumor suppressor gene.
-
identification and characterization of a novel Folliculin interacting protein fnip2
Gene, 2008Co-Authors: Hisashi Hasumi, Masaya Baba, Seungbeom Hong, Laura S. Schmidt, Vladimir Valera, Marston W Linehan, Yukiko Hasumi, Ying Huang, Masahiro YaoAbstract:Birt-Hogg-Dube' syndrome characterized by increased risk for renal neoplasia is caused by germline mutations in the BHD/FLCN gene encoding a novel tumor suppressor protein, Folliculin(FLCN), which interacts with FNIP1 and 5'-AMP-activated protein kinase(AMPK). Here we report the identification and characterization of a novel FNIP1 homolog FNIP2 that also interacts with FLCN and AMPK. C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. These data taken together with our previous results that demonstrated FNIP1 binding to the C-terminus of FLCN suggest that FLCN tumor suppressor function may be facilitated by interactions with both FNIP1 and FNIP2 through its C-terminus. Furthermore, we demonstrate that FNIP1 and FNIP2 are able to form homo- or heteromeric multimers suggesting that they may function independently or cooperatively with FLCN. Differential expression of FNIP1 and FNIP2 transcripts in some normal tissues may indicate tissue specificity for these homologs. Interestingly FNIP1 and FNIP2 were oppositely expressed in human clear cell renal cell carcinoma (RCC), and coordinately expressed in chromophobe RCC and oncocytoma, suggesting their differential function in different histologic variants of RCC.
Seungbeom Hong - One of the best experts on this subject based on the ideXlab platform.
-
tumor suppressor flcn inhibits tumorigenesis of a flcn null renal cancer cell line and regulates expression of key molecules in tgf β signaling
Molecular Cancer, 2010Co-Authors: Seungbeom Hong, Masaya Baba, Hyoungbin Oh, Vladimir Valera, Jaime Stull, Maria Merino, Marston W Linehan, Laura S. SchmidtAbstract:Background Germline mutations in the FLCN gene are responsible for the development of fibrofolliculomas, lung cysts and renal neoplasia in Birt-Hogg-Dube' (BHD) syndrome. The encoded protein Folliculin (FLCN) is conserved across species but contains no classic motifs or domains and its function remains unknown. Somatic mutations or loss of heterozygosity in the remaining wild type copy of the FLCN gene have been found in renal tumors from BHD patients suggesting that FLCN is a classic tumor suppressor gene.
-
homozygous loss of bhd causes early embryonic lethality and kidney tumor development with activation of mtorc1 and mtorc2
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Yukiko Hasumi, Masaya Baba, Seungbeom Hong, Hisashi Hasumi, Vladimir Valera, Rieko Ajima, Mara E Klein, Diana C Haines, Maria J Merino, Terry P YamaguchiAbstract:Germline mutations in the BHD/FLCN tumor suppressor gene predispose patients to develop renal tumors in the hamartoma syndrome, Birt-Hogg-Dube (BHD). BHD encodes Folliculin, a protein with unknown function that may interact with the energy- and nutrient-sensing AMPK-mTOR signaling pathways. To clarify BHD function in the mouse, we generated a BHD knockout mouse model. BHD homozygous null (BHDd/d) mice displayed early embryonic lethality at E5.5–E6.5, showing defects in the visceral endoderm. BHD heterozygous knockout (BHDd/+) mice appeared normal at birth but developed kidney cysts and solid tumors as they aged (median kidney-lesion-free survival = 23 months, median tumor-free survival = 25 months). As observed in human BHD kidney tumors, three different histologic types of kidney tumors developed in BHDd/+ mice including oncocytic hybrid, oncocytoma, and clear cell with concomitant loss of heterozygosity (LOH), supporting a tumor suppressor function for BHD in the mouse. The PI3K-AKT pathway was activated in both human BHD renal tumors and kidney tumors in BHDd/+ mice. Interestingly, total AKT protein was elevated in kidney tumors compared to normal kidney tissue, but without increased levels of AKT mRNA, suggesting that AKT may be regulated by Folliculin through post translational or post-transcriptional modification. Finally, BHD inactivation led to both mTORC1 and mTORC2 activation in kidney tumors from BHDd/+ mice and human BHD patients. These data support a role for PI3K-AKT pathway activation in kidney tumor formation caused by loss of BHD and suggest that inhibitors of both mTORC1 and mTORC2 may be effective as potential therapeutic agents for BHD-associated kidney cancer.
-
identification and characterization of a novel Folliculin interacting protein fnip2
Gene, 2008Co-Authors: Hisashi Hasumi, Masaya Baba, Seungbeom Hong, Laura S. Schmidt, Vladimir Valera, Marston W Linehan, Yukiko Hasumi, Ying Huang, Masahiro YaoAbstract:Birt-Hogg-Dube' syndrome characterized by increased risk for renal neoplasia is caused by germline mutations in the BHD/FLCN gene encoding a novel tumor suppressor protein, Folliculin(FLCN), which interacts with FNIP1 and 5'-AMP-activated protein kinase(AMPK). Here we report the identification and characterization of a novel FNIP1 homolog FNIP2 that also interacts with FLCN and AMPK. C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. These data taken together with our previous results that demonstrated FNIP1 binding to the C-terminus of FLCN suggest that FLCN tumor suppressor function may be facilitated by interactions with both FNIP1 and FNIP2 through its C-terminus. Furthermore, we demonstrate that FNIP1 and FNIP2 are able to form homo- or heteromeric multimers suggesting that they may function independently or cooperatively with FLCN. Differential expression of FNIP1 and FNIP2 transcripts in some normal tissues may indicate tissue specificity for these homologs. Interestingly FNIP1 and FNIP2 were oppositely expressed in human clear cell renal cell carcinoma (RCC), and coordinately expressed in chromophobe RCC and oncocytoma, suggesting their differential function in different histologic variants of RCC.
-
kidney targeted birt hogg dube gene inactivation in a mouse model erk1 2 and akt mtor activation cell hyperproliferation and polycystic kidneys
Journal of the National Cancer Institute, 2008Co-Authors: Masaya Baba, Seungbeom Hong, Diana C Haines, Mutsuo Furihata, Lino Tessarollo, Eileen Southon, Vishal Patel, Peter IgarashiAbstract:Birt-Hogg-Dube (BHD) syndrome is an inherited kidney cancer syndrome that is characterized by benign hair follicle tumors, lung cysts, spontaneous pneumothorax, and an increased risk of renal neoplasia (1-3). We previously identified germline mutations in the BHD gene, which is located at chromosome 17p11.2, in BHD patients (4). Nearly all BHD mutations are frameshift or nonsense mutations that are predicted to prematurely truncate the BHD protein, Folliculin (FLCN) (4-7). BHD patients most frequently develop bilateral multifocal chromophobe renal tumors and renal oncocytic hybrid tumors with features of chromophobe renal carcinoma and renal oncocytoma (8-10). Somatic mutations in the remaining wild-type copy of BHD and loss of heterozygosity at chromosome 17p11.2 have been identified in BHD-associated renal tumors, supporting the Knudson “two-hit” hypothesis and a tumor suppressor role for BHD (11). Folliculin is a novel 64-kDa protein with no known functional domains (4). We recently identified FNIP1, the first Folliculin-interacting protein, which also interacts with 5′-AMP-activated protein kinase (AMPK (12)), an important energy sensor in cells that negatively regulates mammalian target of rapamycin (mTOR), the master switch for cell growth and proliferation (13). We demonstrated that FLCN and FNIP1 could serve as substrates for AMPK in vitro and in vivo and that inhibition of AMPK activity resulted in reduced phosphorylation and decreased expression of these proteins. Phospho-Folliculin levels were reduced by inhibition of mTOR activity. Under serum-starved conditions, the level of mTOR signaling was somewhat higher in BHD-null renal tumor cells than in BHD-restored cells (12). These results suggest that FLCN may play a role in cellular energy and nutrient sensing through interactions with the AMPK-mTOR signaling pathway. Mutations in several other tumor suppressor genes, including LKB1 (14), PTEN (15), and TSC1/2 (16), have been shown to lead to dysregulation of mTOR signaling and to the development of other hamartoma syndromes. Intriguingly, recent studies in yeast have suggested that Bhd activates Tor2 in opposition to the role of Tsc1/2 , which inhibits Tor2 in this model organism (17). Animal models of human cancer provide valuable research tools for dissecting the biochemical pathways responsible for neoplasia and for testing new therapeutic agents. Renal cystadenocarcinoma nodular dermatofibrosis (RCND) in dogs (18,19) and renal tumors in the Nihon rat (20,21) occur in animals that inherit a germline mutation in the corresponding BHD homolog. However, these naturally-occurring animal models may harbor additional genetic changes that could confound studies of the functional consequences of BHD inactivation. A genetically engineered mouse model provides a “clean” system with which to pursue FLCN functional studies. Here we report the generation of a conditionally targeted BHD allele and kidney-directed BHD inactivation in the mouse using the cadherin16 (KSP)-Cre transgene (22). We compared BHD-knockout and control kidneys by histology, cell proliferation measurements, immunostaining to evaluate activation of Raf-Erk1/2 and Akt-mTOR pathways, and evaluated the therapeutic effects of rapamycin treatment, an inhibitor of mTOR, on the BHD-knockout kidney phenotype.