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Folliculin

This article was updated by an external expert under a dual publication model. The corresponding peer-reviewed article was published in the journal Gene. Click to view.
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Not to be confused with Estrogen or Estrone.
FLCN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFLCN, BHD, FLCL, Folliculin, DENND8B
External IDsOMIM: 607273; MGI: 2442184; HomoloGene: 14583; GeneCards: FLCN; OMA:FLCN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

201163

216805

Ensembl

ENSG00000154803

ENSMUSG00000032633

UniProt

Q8NFG4

Q8QZS3

RefSeq (mRNA)

NM_144606
NM_144997
NM_001353229
NM_001353230
NM_001353231

NM_001271356
NM_001271357
NM_146018

RefSeq (protein)

NP_653207
NP_659434
NP_001340158
NP_001340159
NP_001340160

NP_001258285
NP_001258286
NP_666130

Location (UCSC)Chr 17: 17.21 – 17.24 MbChr 11: 59.68 – 59.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect.[5] Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts (often associated with pneumothorax), and kidney tumors.[6]

Gene

Structure

The FLCN gene consists of 14 exons.[7]

Location

Cytogenetic location: The FLCN gene is located on the short (p) arm of chromosome 17 at position 11.2. (17p11.2).[8]

Molecular location on chromosome 17: base pairs 17,056,252 to 17,081,230 (NCI Build 36.1)

Clinical significance

Germline mutations in the FLCN gene cause Birt–Hogg–Dubé syndrome (BHD), an autosomal dominant disease that predisposes individuals to develop benign tumors of the hair follicle called fibrofolliculomas, lung cysts, spontaneous pneumothorax, and an increased risk for kidney tumors.[7] FLCN mutations have also been found in the germline of patients with inherited spontaneous pneumothorax and no other clinical manifestations.[9][10]

In a risk assessment performed in affected and unaffected members of BHD families, the odds ratio for developing kidney tumors in a person affected with BHD was 6.9 times greater than his unaffected siblings. The odds ratio for spontaneous pneumothorax in BHD affected individuals, when adjusted for age, was 50.3 times greater than unaffected family members.[11]

Discovery

Birt–Hogg–Dubé syndrome was originally described by three Canadian physicians in a family in which 15 of 70 members over 3 generations exhibited a triad of dermatological lesions (fibrofolliculomas, trichodiscomas and acrochordons).[12] Subsequently, cosegregation of kidney neoplasms with BHD cutaneous lesions was observed in 3 families with a family history of kidney tumors,[13] suggesting that kidney tumors may be part of the BHD syndrome phenotype. In order to identify the genetic locus for BHD syndrome, genetic linkage analysis was performed in families recruited on the basis of BHD cutaneous lesions.[14][15] A region spanning chromosome 17p11 was identified and mutations in a novel gene, FLCN, were subsequently found in the germline of individuals affected with BHD syndrome.[7]

Genetics

The FLCN gene encodes a 64 kDa protein, FLCN, which is highly conserved across species. The majority of germline FLCN mutations identified in BHD patients are loss-of-function mutations including frameshift mutations (insertion/deletion), nonsense mutations, and splice site mutations that are predicted to inactivate the FLCN protein, although some missense mutations have been reported that exchange one nucleotide for another and consequently result in a different amino acid at the mutation site.[16] Most mutations are identified by DNA sequencing. With the advent of multiplex ligation-dependent probe amplification (MLPA) technology, partial deletions of the FLCN gene have also been identified[17][18] permitting a FLCN mutation detection rate in BHD cohorts that approaches 90%.[16] Very few FLCN mutations have been found in association with sporadic kidney tumors indicating that FLCN mutation may play only a minor role in non-inherited kidney cancer.[19][20][21]

Experimental evidence supports a role for FLCN as a tumor suppressor gene. In BHD-associated kidney tumors, the inherited FLCN gene with a germline mutation is present in all cells, but the remaining wild type copy is inactivated in the tumor cells through somatic mutation or loss of heterozygosity.[22] Naturally-occurring dog and rat models with germline Flcn mutations develop kidney tumors that retain only the mutant copy of the gene.[23][24] Homozygous inactivation of Flcn in these animal models is lethal to the embryo. Tumors develop in mice injected with FLCN-deficient kidney cancer cells from BHD-associated human tumors but when wild type FLCN is restored in these cells, tumor development is inhibited.[25] Additionally, injection of kidney tumor cells from the adenocarcinoma cell line ACHN with FLCN inactivation into immunocompromised mice resulted in the growth of significantly larger tumors, further underscoring a tumor suppressor role for FLCN.[26] Based on the presence of FLCN staining by immunohistochemistry, haploinsufficiency, that is mutation of one copy of FLCN with retention of the wild type copy, may be sufficient for the development of fibrofolliculomas[27] and lung cysts.[28]

Function

Interactions

FLCN has been shown to interact through its C-terminus with two new co-chaperones folliculin interacting protein 1 (FNIP1)[29][30] and folliculin interacting protein 2 (FNIP2/FNIPL),[31][30][29] and indirectly through FNIP1 and FNIP2 with AMP-activated protein kinase (AMPK).[30][31] AMPK is an important energy sensor in cells and negative regulator of mechanistic target of rapamycin (mTOR)[32] suggesting that FLCN and FNIP1 may play a role in modulating mTOR activity through energy- or nutrient-sensing pathways. Coimmunoprecipitation experiments with FNIPL/FNIP2 and FLCN expressed in Cos7 cells have shown that the C-termini of FLCN and FNIPL/FNIP2 are required for optimal FLCN-FNIPL binding.[31] In the absence of either FNIP1 or FNIPL/FNIP2 expression, FLCN localizes to the nucleus, while co-expressed FLCN and FNIPL colocalize to the cytoplasm in a reticular pattern.[31]

FLCN phosphorylation

FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR and AMPK signaling. FNIP1 was phosphorylated by AMPK and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression.[30] FLCN has multiple phosphorylation sites including serine 62, which are differentially affected by FNIP1 binding and by inhibitors of mTOR and AMPK.[30][33] The significance of this modification, however, is unknown.

Functions of FLCN

Folliculin (FLCN) functions as a binding partner and uncompetitive inhibitor of Lactate Dehydrogenase-A (LDHA). A flexible loop within the amino-terminus of FLCN controls movement of the LDHA active site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. The glycolytic shift of cancer cells seems to be the result of FLCN inactivation or dissociation from LDHA. FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.

Several pathways in which FLCN plays a role as a tumor suppressor have been identified, but it remains to be determined which of these pathways, when dysregulated, leads to the cutaneous, lung and kidney phenotypes associated with Birt-Hogg-Dubé syndrome.

Regulation of the AKT-mTOR pathway

Work with Flcn-deficient mouse models suggests a role for FLCN in regulating the AKT-mechanistic target of rapamycin (mTOR) signaling pathway, but the results are conflicting. mTOR activation was seen in the highly cystic kidneys that developed in mice with kidney-targeted inactivation of Flcn.[34][35] Elevated AKT and phospho-AKT proteins, and activation of mTORC1 and mTORC2 were observed in late-onset tumors that developed in aged Flcn heterozygous mice subsequent to loss of the remaining Flcn wild type allele, and in FLCN-deficient kidney tumors from BHD patients.[36] On the other hand, mTOR inhibition was demonstrated in smaller cysts (although mTOR activation was seen in larger cysts) that developed in Flcn heterozygous knockout mice generated with a gene trapping approach.[26] N-ethyl-N-nitrosourea (ENU) mutagenesis of another Flcn heterozygous mouse model produced tumors with reduced mTOR activity.[37] Evidence from studies in yeast suggests that the FLCN ortholog Bhd activates the mTOR ortholog Tor2.[38] These opposing effects of FLCN deficiency on the mTOR pathway have led to the hypothesis that FLCN regulation of mTOR activity may be context or cell-type dependent.

mTORC1 activation on the lysosome

Resolution of the crystal structure of the FLCN carboxy-terminal protein domain revealed a structural similarity to the differentially expressed in normal cells and neoplasia (DENN) domain of DENN1B suggesting that they are distantly related proteins. The DENN domain family of proteins are guanine nucleotide exchange factors (GEFs) for Rab proteins, members of the Ras superfamily of G proteins that are involved in vesicular transport suggesting that FLCN may have a similar function.[39]

FLCN acts as a GTPase-activating protein (GAP) toward Rag C/D GTPases, members of another Ras-related GTP-binding protein family, which are necessary for amino acid-dependent mTORC1 activation at the lysosomal membrane.[40] The heterodimeric Rag GTPases (RagA or B in complex with RagC or D) in a lysosome-associated complex with Ragulator and vacuolar adenosine triphosphatase (v-ATPase) interact with mTORC1 in response to amino acids from the lysosomal lumen to promote translocation of mTORC1 to the lysosomal surface for activation by the small GTPase Ras-homolog enriched in brain (Rheb). GTP-loading of RagA/B is a requirement for amino acid signaling to mTORC1.[41] In recent studies, FLCN was shown to localize to the lysosome surface under amino acid starved conditions, where with its binding partners FNIP1/FNIP2, FLCN acts as a GAP to facilitate GDP-loading of Rag C/D, clarifying the role of this Rag GTPase in amino acid-dependent mTORC1 activation.[40] Another report demonstrated that FLCN in association with FNIP1 preferentially binds to GDP-bound /nucleotide free Rag A/B under amino acid deprived conditions suggesting a potential role for FLCN as a GEF for RagA/B.[42] Recently the heterodimeric Lst4-Lst7 complex in yeast, orthologous to the mammalian FLCN-FNIP1 complex, was found to function as a GAP for Gtr2, the yeast ortholog of Rag C/D, and cluster at the vacuolar membrane in amino acid starved cells. Refeeding of amino acids stimulated Lst4-Lst7 binding to and GAP activity towards Gtr2 resulting in mTORC1 activation and demonstrating conservation of a GAP function for FLCN in lower organisms.[43]

Control of TFE3/TFEB transcriptional activation

TFE3 and TFEB are members of the microphthalmia-associated transcription factor (MiTF) family, which also includes MiTF and TFEC. Gene fusions of TFE3 with a number of different gene partners can arise sporadically and are responsible for Xp11.2 translocation renal cell carcinoma.[44] FLCN-deficient BHD associated renal tumors and tumors that develop in mouse models with Flcn inactivation were found to have elevated expression of transmembrane glycoprotein NMB (GPNMB), a transcriptional target of TFE3.[45] Subsequently, FLCN was shown to regulate TFE3 activity by sequestering TFE3 in the cytoplasm where it is transcriptionally inactive; however, loss of FLCN expression results in localization of TFE3 to the nucleus driving transcriptional activation of its target genes including GPNMB.[45] Another study investigating genes required for mouse embryonic stem cell (ESC) progression from pluripotency to cell lineage differentiation revealed that Flcn in complex with Fnip1/2 was necessary for ESC exit from pluripotency through cytoplasmic sequestering of Tfe3, thereby abrogating expression of its gene target, estrogen-related receptor beta(Esrrb), the core pluripotency factor.[46]

Regulation of PGC-1α and mitochondrial biogenesis

Chromophobe renal carcinoma and hybrid oncocytic tumors with features of chromophobe renal carcinoma and renal oncocytoma, which are the most common renal tumor histologic subtypes associated with BHD, contain large numbers of mitochondria. Comparative gene expression profiling of BHD-associated renal tumors and sporadic counterpart tumors revealed distinct gene expression patterns and cytogenetic differences between the groups. BHD-associated tumors displayed high expression of mitochondrial- and oxidative phosphorylation-associated genes reflecting deregulation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha / mitochondrial transcription factor A (PGC-1α/TFAM) signaling axis.[47] FLCN expression was inversely correlated with PGC-1α activation, which drives mitochondrial biogenesis. In support of these data, FLCN inactivation was correlated with PGC-1α activation and upregulation of its target genes in BHD-associated renal tumors, and kidney, heart and muscle tissues from genetically engineered mouse models with Flcn inactivation targeted to the respective tissues.[48][49]

Maintenance of cell-cell adhesions and regulation of RhoA signaling

Yeast two-hybrid screening performed by two independent groups identified p0071 (plakophilin-4) as a FLCN interacting protein.[50][51] p0071 binds E-cadherin at adherens junctions, which are important for maintenance of cell architecture in epithelial tissues, and regulates RhoA activity. Loss of FLCN function leads to a disruptive effect on cell-cell adhesions and cell polarity, and dysregulation of RhoA signaling. Additional supporting evidence includes reduction in E-cadherin expression and increased alveolar apoptosis in lungs from lung-targeted Flcn-deficient mice,[52] and increased cell-cell adhesions in FLCN-deficient lung cell lines.[53] These studies suggest a potential function of FLCN in maintaining proper cell-cell adhesions for lung cell integrity and support the "stretch hypothesis" as a mechanism of pulmonary cyst pathogenesis in BHD.[54]

Ciliogenesis and cilia-dependent flow sensory mechanisms

Individuals affected with the inherited kidney cancer syndromes von Hippel–Lindau syndrome and tuberous sclerosis complex can develop kidney cysts in addition to kidney tumors, which have been shown to result from defects in primary cilia function.[55][56] BHD patients also may present with kidney cysts, which led researchers to investigate a potential role for FLCN in regulating primary cilia development and/or function. FLCN protein was found to localize on primary cilia, the basal body and centrosome in different cell types. FLCN siRNA knockdown in nutrient starved kidney cells resulted in delayed cilia development. Both overexpression of FLCN in FLCN-expressing kidney cells and knockdown of FLCN resulted in reduced numbers of cilia and aberrant cell divisions, suggesting that levels of FLCN must be tightly regulated for proper ciliogenesis.[57] Primary cilia play a role in inhibiting the canonical Wnt signaling pathway ( Wnt/β-catenin signaling pathway) by sequestering β-catenin in the basal body, and dysregulated Wnt/β-catenin signaling has been linked to kidney cyst formation. In Flcn-deficient mouse inner medullary collecting duct cells, levels of unphosphorylated (active) β-catenin and its down stream targets were elevated suggesting that improper activation of the canonical Wnt/β-catenin signaling pathway through defective ciliogenesis may lead to kidney, and potentially lung, cyst development in BHD syndrome.[57]

Additional experimental evidence that FLCN may be involved in primary cilium function was obtained from a yeast two-hybrid screening that identified KIF3A as a FLCN interacting protein.[58] Intraflagellar transport, which is required for primary cilium assembly and maintenance, is driven by kinesin-2 motor made up of subunits KIF3A and KIF3B. Researchers have shown that FLCN could interact with both subunits in a cilium-dependent manner and localize to cilia in FLCN-expressing but not FLCN-deficient cells.[58] Cilia have been shown to act as flow sensors and suppress mTOR signaling by activating the serine/threonine kinase LKB1 located in the basal body of resting cells in response to flow stimuli. LKB1 in turn phosphorylates and activates AMPK, a negative regulator of mTOR activation.[59] Flow stress was able to suppress mTOR signaling in FLCN-expressing human kidney cells but not under FLCN deficient conditions, and required intact cilia. FLCN was shown to recruit LKB1 and facilitate its interaction with AMPK in the basal body in a flow stress-dependent manner.[58] These findings suggest a role for FLCN in the mechanosensory signaling machinery of the cell that controls the cilia-dependent regulation of the LKB1-AMPK-mTOR signaling axis.

Other potential functions

Additional potential roles for FLCN in autophagy,[60][61][62] TGF β signaling,[63][25] regulation of AMPK activity,[60][64][65] and regulation of HIF-1α transcriptional activity[66][64] have been described.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000154803 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032633 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Woodford MR, Baker-Williams AJ, Sager RA, Backe SJ, Blanden AR, Hashmi F, et al. (August 2021). "The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect". Nature Structural & Molecular Biology. 28 (8): 662–670. doi:10.1038/s41594-021-00633-2. PMC 9278990. PMID 34381247.
  6. ^ Linehan WM, Schmidt LS, Crooks DR, Wei D, Srinivasan R, Lang M, Ricketts CJ (August 2019). "The Metabolic Basis of Kidney Cancer". Cancer Discovery. 9 (8): 1006–1021. doi:10.1158/2159-8290.CD-18-1354. PMC 3563773. PMID 31088840.
  7. ^ a b c Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. (August 2002). "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome". Cancer Cell. 2 (2): 157–64. doi:10.1016/S1535-6108(02)00104-6. PMID 12204536.
  8. ^ "Folliculin". Genetics Home Reference. National Library of Medicine, U.S. Department of Health and Human Services.
  9. ^ Ren HZ, Zhu CC, Yang C, Chen SL, Xie J, Hou YY, et al. (August 2008). "Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax". Clinical Genetics. 74 (2): 178–83. doi:10.1111/j.1399-0004.2008.01030.x. PMID 18505456. S2CID 8393765.
  10. ^ Graham RB, Nolasco M, Peterlin B, Garcia CK (July 2005). "Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults". American Journal of Respiratory and Critical Care Medicine. 172 (1): 39–44. doi:10.1164/rccm.200501-143OC. PMID 15805188. S2CID 29807063.
  11. ^ Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, et al. (April 2002). "Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome". Cancer Epidemiology, Biomarkers & Prevention. 11 (4): 393–400. PMID 11927500.
  12. ^ Birt AR, Hogg GR, Dubé WJ (December 1977). "Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons". Archives of Dermatology. 113 (12): 1674–7. doi:10.1001/archderm.113.12.1674. PMID 596896.
  13. ^ Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, Linehan M, Turner ML (October 1999). "Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia". Archives of Dermatology. 135 (10): 1195–202. doi:10.1001/archderm.135.10.1195. PMID 10522666.
  14. ^ Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR, et al. (October 2001). "Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2". American Journal of Human Genetics. 69 (4): 876–82. doi:10.1086/323744. PMC 1226073. PMID 11533913.
  15. ^ Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjöld M, Teh BT (August 2001). "Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2". Oncogene. 20 (37): 5239–42. doi:10.1038/sj.onc.1204703. PMID 11526515. S2CID 9672228.
  16. ^ a b Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, et al. (June 2008). "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports". Journal of Medical Genetics. 45 (6): 321–31. doi:10.1136/jmg.2007.054304. PMC 2564862. PMID 18234728.
  17. ^ Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, et al. (June 2011). "Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome". Genes, Chromosomes & Cancer. 50 (6): 466–77. doi:10.1002/gcc.20872. PMC 3075348. PMID 21412933.
  18. ^ Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, et al. (April 2010). "Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature". Journal of Medical Genetics. 47 (4): 281–7. doi:10.1136/jmg.2009.070565. PMC 2981024. PMID 20413710.
  19. ^ Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, et al. (August 2003). "Inactivation of BHD in sporadic renal tumors". Cancer Research. 63 (15): 4583–7. PMID 12907635.
  20. ^ Murakami T, Sano F, Huang Y, Komiya A, Baba M, Osada Y, et al. (April 2007). "Identification and characterization of Birt-Hogg-Dubé associated renal carcinoma". The Journal of Pathology. 211 (5): 524–31. doi:10.1002/path.2139. PMID 17323425. S2CID 44617711.
  21. ^ Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, et al. (September 2014). "The somatic genomic landscape of chromophobe renal cell carcinoma". Cancer Cell. 26 (3): 319–30. doi:10.1016/j.ccr.2014.07.014. PMC 4160352. PMID 25155756.
  22. ^ Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, et al. (June 2005). "High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors". Journal of the National Cancer Institute. 97 (12): 931–5. doi:10.1093/jnci/dji154. PMID 15956655.
  23. ^ Lingaas F, Comstock KE, Kirkness EF, Sørensen A, Aarskaug T, Hitte C, et al. (December 2003). "A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog". Human Molecular Genetics. 12 (23): 3043–53. doi:10.1093/hmg/ddg336. PMID 14532326.
  24. ^ Okimoto K, Sakurai J, Kobayashi T, Mitani H, Hirayama Y, Nickerson ML, et al. (February 2004). "A germ-line insertion in the Birt-Hogg-Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer". Proceedings of the National Academy of Sciences of the United States of America. 101 (7): 2023–7. Bibcode:2004PNAS..101.2023O. doi:10.1073/pnas.0308071100. PMC 357045. PMID 14769940.
  25. ^ a b Hong SB, Oh H, Valera VA, Stull J, Ngo DT, Baba M, Merino MJ, Linehan WM, Schmidt LS (June 2010). "Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling". Molecular Cancer. 9: 160. doi:10.1186/1476-4598-9-160. PMC 2907329. PMID 20573232.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ a b Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, Paquet M, et al. (March 2010). "Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin". Journal of Medical Genetics. 47 (3): 182–9. doi:10.1136/jmg.2009.072009. PMID 19843504. S2CID 24687473.
  27. ^ van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutiérrez P, Marcus-Soekarman D, et al. (March 2007). "Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients". The Journal of Investigative Dermatology. 127 (3): 588–93. doi:10.1038/sj.jid.5700592. PMID 17124507.
  28. ^ Koga S, Furuya M, Takahashi Y, Tanaka R, Yamaguchi A, Yasufuku K, et al. (October 2009). "Lung cysts in Birt-Hogg-Dubé syndrome: histopathological characteristics and aberrant sequence repeats". Pathology International. 59 (10): 720–8. doi:10.1111/j.1440-1827.2009.02434.x. PMID 19788617. S2CID 20769705.
  29. ^ a b Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, et al. (June 2016). "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding". Nature Communications. 7: 12037. Bibcode:2016NatCo...712037W. doi:10.1038/ncomms12037. PMC 4931344. PMID 27353360.
  30. ^ a b c d e Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, et al. (October 2006). "Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling". Proceedings of the National Academy of Sciences of the United States of America. 103 (42): 15552–15557. Bibcode:2006PNAS..10315552B. doi:10.1073/pnas.0603781103. PMC 1592464. PMID 17028174.
  31. ^ a b c d Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, et al. (September 2008). "Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein". Oncogene. 27 (40): 5339–5347. doi:10.1038/onc.2008.261. PMID 18663353. S2CID 9965195.
  32. ^ Shackelford DB, Shaw RJ (August 2009). "The LKB1-AMPK pathway: metabolism and growth control in tumour suppression". Nature Reviews. Cancer. 9 (8): 563–575. doi:10.1038/nrc2676. PMC 2756045. PMID 19629071.
  33. ^ Wang L, Kobayashi T, Piao X, Shiono M, Takagi Y, Mineki R, et al. (January 2010). "Serine 62 is a phosphorylation site in folliculin, the Birt-Hogg-Dubé gene product". FEBS Letters. 584 (1): 39–43. doi:10.1016/j.febslet.2009.11.033. PMID 19914239. S2CID 20383948.
  34. ^ Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, Southon E, et al. (January 2008). "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. 100 (2): 140–54. doi:10.1093/jnci/djm288. PMC 2704336. PMID 18182616.
  35. ^ Chen J, Futami K, Petillo D, Peng J, Wang P, Knol J, et al. (2008). "Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia". PLOS ONE. 3 (10): e3581. Bibcode:2008PLoSO...3.3581C. doi:10.1371/journal.pone.0003581. PMC 2570491. PMID 18974783.
  36. ^ Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, Klein ME, Haines DC, Merino MJ, Hong SB, Yamaguchi TP, Schmidt LS, Linehan WM (November 2009). "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. 106 (44): 18722–7. Bibcode:2009PNAS..10618722H. doi:10.1073/pnas.0908853106. PMC 2765925. PMID 19850877.
  37. ^ Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, Simon MC, Henske EP (April 2009). "The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis". Oncogene. 28 (13): 1594–604. doi:10.1038/onc.2009.14. PMC 2664853. PMID 19234517.
  38. ^ van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, Henske EP (August 2007). "The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe". The Journal of Biological Chemistry. 282 (34): 24583–90. doi:10.1074/jbc.M700857200. PMID 17556368. S2CID 34442960.
  39. ^ Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson JC, Blaszczyk BK, et al. (August 2012). "Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer". Open Biology. 2 (8): 120071. doi:10.1098/rsob.120071. PMC 3438538. PMID 22977732.
  40. ^ a b Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, Sabatini DM (November 2013). "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1". Molecular Cell. 52 (4): 495–505. doi:10.1016/j.molcel.2013.09.016. PMC 3867817. PMID 24095279.
  41. ^ Bar-Peled L, Sabatini DM (July 2014). "Regulation of mTORC1 by amino acids". Trends in Cell Biology. 24 (7): 400–6. doi:10.1016/j.tcb.2014.03.003. PMC 4074565. PMID 24698685.
  42. ^ Petit CS, Roczniak-Ferguson A, Ferguson SM (September 2013). "Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases". The Journal of Cell Biology. 202 (7): 1107–22. doi:10.1083/jcb.201307084. PMC 3787382. PMID 24081491.
  43. ^ Péli-Gulli MP, Sardu A, Panchaud N, Raucci S, De Virgilio C (October 2015). "Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2". Cell Reports. 13 (1): 1–7. doi:10.1016/j.celrep.2015.08.059. PMID 26387955.
  44. ^ Armah HB, Parwani AV (January 2010). "Xp11.2 translocation renal cell carcinoma". Archives of Pathology & Laboratory Medicine. 134 (1): 124–9. doi:10.5858/2008-0391-RSR.1. PMID 20073616.
  45. ^ a b Hong SB, Oh H, Valera VA, Baba M, Schmidt LS, Linehan WM (December 2010). "Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization". PLOS ONE. 5 (12): e15793. Bibcode:2010PLoSO...515793H. doi:10.1371/journal.pone.0015793. PMC 3012117. PMID 21209915.
  46. ^ Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, Smith A (April 2013). "Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3". Cell. 153 (2): 335–47. doi:10.1016/j.cell.2013.03.012. PMC 3661979. PMID 23582324.
  47. ^ Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, et al. (December 2010). "Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression". BMC Medical Genomics. 3: 59. doi:10.1186/1755-8794-3-59. PMC 3012009. PMID 21162720.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  48. ^ Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, et al. (November 2012). "Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN". Journal of the National Cancer Institute. 104 (22): 1750–64. doi:10.1093/jnci/djs418. PMC 3502196. PMID 23150719.
  49. ^ Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, et al. (November 2014). "Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation". Human Molecular Genetics. 23 (21): 5706–19. doi:10.1093/hmg/ddu286. PMC 4189904. PMID 24908670.
  50. ^ Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, Henske EP (2012). "Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion". PLOS ONE. 7 (11): e47842. Bibcode:2012PLoSO...747842M. doi:10.1371/journal.pone.0047842. PMC 3490959. PMID 23139756.
  51. ^ Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, et al. (December 2012). "Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis". Human Molecular Genetics. 21 (24): 5268–79. doi:10.1093/hmg/dds378. PMC 3755511. PMID 22965878.
  52. ^ Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, et al. (April 2014). "Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK". Cell Reports. 7 (2): 412–23. doi:10.1016/j.celrep.2014.03.025. PMC 4034569. PMID 24726356.
  53. ^ Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, et al. (August 2014). "Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells". Physiological Reports. 2 (8): e12107. doi:10.14814/phy2.12107. PMC 4246594. PMID 25121506.
  54. ^ Kennedy JC, Khabibullin D, Henske EP (April 2016). "Mechanisms of pulmonary cyst pathogenesis in Birt-Hogg-Dube syndrome: The stretch hypothesis". Seminars in Cell & Developmental Biology. 52: 47–52. doi:10.1016/j.semcdb.2016.02.014. PMID 26877139.
  55. ^ Esteban MA, Harten SK, Tran MG, Maxwell PH (July 2006). "Formation of primary cilia in the renal epithelium is regulated by the von Hippel–Lindau tumor suppressor protein". Journal of the American Society of Nephrology. 17 (7): 1801–6. doi:10.1681/ASN.2006020181. PMID 16775032.
  56. ^ Hartman TR, Liu D, Zilfou JT, Robb V, Morrison T, Watnick T, Henske EP (January 2009). "The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway". Human Molecular Genetics. 18 (1): 151–63. doi:10.1093/hmg/ddn325. PMC 2644647. PMID 18845692.
  57. ^ a b Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles RH, Coull BJ, van Steensel MA (November 2013). "Birt-Hogg-Dube syndrome is a novel ciliopathy". Human Molecular Genetics. 22 (21): 4383–97. doi:10.1093/hmg/ddt288. PMC 3792695. PMID 23784378.
  58. ^ a b c Zhong M, Zhao X, Li J, Yuan W, Yan G, Tong M, Guo S, Zhu Y, Jiang Y, Liu Y, Jiang Y (May 2016). "Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia". The Journal of Biological Chemistry. 291 (22): 11689–97. doi:10.1074/jbc.M116.719997. PMC 4882437. PMID 27072130.
  59. ^ Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, et al. (November 2010). "Primary cilia regulate mTORC1 activity and cell size through Lkb1". Nature Cell Biology. 12 (11): 1115–22. doi:10.1038/ncb2117. PMC 3390256. PMID 20972424.
  60. ^ a b Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, Pause A (April 2014). "Folliculin regulates ampk-dependent autophagy and metabolic stress survival". PLOS Genetics. 10 (4): e1004273. doi:10.1371/journal.pgen.1004273. PMC 3998892. PMID 24763318.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  61. ^ Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, et al. (October 2014). "FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation". Autophagy. 10 (10): 1749–60. doi:10.4161/auto.29640. PMC 4198360. PMID 25126726.
  62. ^ Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, Czyzyk-Krzeska MF (2013). "Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy". PLOS ONE. 8 (7): e70030. Bibcode:2013PLoSO...870030B. doi:10.1371/journal.pone.0070030. PMC 3726479. PMID 23922894.
  63. ^ Cash TP, Gruber JJ, Hartman TR, Henske EP, Simon MC (June 2011). "Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated transcription". Oncogene. 30 (22): 2534–46. doi:10.1038/onc.2010.628. PMC 3109270. PMID 21258407.
  64. ^ a b Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, et al. (June 2014). "The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation". The Journal of Clinical Investigation. 124 (6): 2640–50. doi:10.1172/JCI71749. PMC 4038567. PMID 24762438.
  65. ^ Yan M, Audet-Walsh É, Manteghi S, Dufour CR, Walker B, Baba M, St-Pierre J, Giguère V, Pause A (May 2016). "Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα". Genes & Development. 30 (9): 1034–46. doi:10.1101/gad.281410.116. PMC 4863735. PMID 27151976.
  66. ^ Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, et al. (March 2011). "Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility". Oncogene. 30 (10): 1159–73. doi:10.1038/onc.2010.497. PMC 3787473. PMID 21057536.

Further reading

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