Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival


The FLCN gene is responsible for the hereditary human tumor disease called Birt-Hogg-Dube syndrome (BHD). Patients that inherit an inactivating mutation in the FLCN gene develop lung collapse as well as tumors in the kidney, colon, and skin. It is not clear yet what the exact function of this protein is in the cell or an organism. In this study, we used a simple model organism (the round worm C. elegans) to study the function of FLCN. We found that it is involved in the regulation of energy metabolism in the cell. FLCN normally binds and blocks the action of another protein (AMPK), which is involved in the maintenance of energy levels. When energy levels fall, AMPK is activated and drives a recycling pathway called autophagy, where cellular components are recycled producing energy. In the absence of FLCN in worms and mammalian cells, like in tumors of BHD patients, AMPK and autophagy are chronically activated leading to an increased energy level, which makes the cells/organism very resistant to many stresses that would normally kill them, which in the end could lead to progression of tumorigenesis.


Vyšlo v časopise: Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival. PLoS Genet 10(4): e32767. doi:10.1371/journal.pgen.1004273
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004273

Souhrn

The FLCN gene is responsible for the hereditary human tumor disease called Birt-Hogg-Dube syndrome (BHD). Patients that inherit an inactivating mutation in the FLCN gene develop lung collapse as well as tumors in the kidney, colon, and skin. It is not clear yet what the exact function of this protein is in the cell or an organism. In this study, we used a simple model organism (the round worm C. elegans) to study the function of FLCN. We found that it is involved in the regulation of energy metabolism in the cell. FLCN normally binds and blocks the action of another protein (AMPK), which is involved in the maintenance of energy levels. When energy levels fall, AMPK is activated and drives a recycling pathway called autophagy, where cellular components are recycled producing energy. In the absence of FLCN in worms and mammalian cells, like in tumors of BHD patients, AMPK and autophagy are chronically activated leading to an increased energy level, which makes the cells/organism very resistant to many stresses that would normally kill them, which in the end could lead to progression of tumorigenesis.


Zdroje

1. HornsteinOP, KnickenbergM (1975) Perifollicular fibromatosis cutis with polyps of the colon–a cutaneo-intestinal syndrome sui generis. Arch Dermatol Res 253: 161–175.

2. BirtAR, HoggGR, DubeWJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113: 1674–1677.

3. ToroJR, GlennG, DurayP, DarlingT, WeirichG, et al. (1999) Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135: 1195–1202.

4. PavlovichCP, WaltherMM, EylerRA, HewittSM, ZbarB, et al. (2002) Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol 26: 1542–1552.

5. ZbarB, AlvordWG, GlennG, TurnerM, PavlovichCP, et al. (2002) Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev 11: 393–400.

6. TobinoK, GunjiY, KuriharaM, KunogiM, KoikeK, et al. (2011) Characteristics of pulmonary cysts in Birt-Hogg-Dube syndrome: thin-section CT findings of the chest in 12 patients. Eur J Radiol 77: 403–409.

7. GuptaP, EshaghiN, KambaTT, GholeV, Garcia-MoralesF (2007) Radiological findings in Birt-Hogg-Dube syndrome: a rare differential for pulmonary cysts and renal tumors. Clin Imaging 31: 40–43.

8. KupresKA, KrivdaSJ, TurianskyGW (2003) Numerous asymptomatic facial papules and multiple pulmonary cysts: a case of Birt-Hogg-Dube syndrome. Cutis 72: 127–131.

9. FuruyaM, TanakaR, KogaS, YatabeY, GotodaH, et al. (2012) Pulmonary cysts of Birt-Hogg-Dube syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol 36: 589–600.

10. Van DenhoveA, Guillot-PougetI, GiraudS, IsaacS, FreymondN, et al. (2011) [Multiple spontaneous pneumothoraces revealing Birt-Hogg-Dube syndrome]. Rev Mal Respir 28: 355–359.

11. PeterssonF, GatalicaZ, GrossmannP, Perez MontielMD, Alvarado CabreroI, et al. (2010) Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases. Virchows Arch 456: 355–365.

12. KogaS, FuruyaM, TakahashiY, TanakaR, YamaguchiA, et al. (2009) Lung cysts in Birt-Hogg-Dube syndrome: histopathological characteristics and aberrant sequence repeats. Pathol Int 59: 720–728.

13. ToroJR, WeiMH, GlennGM, WeinreichM, ToureO, et al. (2008) BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports. J Med Genet 45: 321–331.

14. NickersonML, WarrenMB, ToroJR, MatrosovaV, GlennG, et al. (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-Dube syndrome. Cancer Cell 2: 157–164.

15. KhooSK, BradleyM, WongFK, HedbladMA, NordenskjoldM, et al. (2001) Birt-Hogg-Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene 20: 5239–5242.

16. SchmidtLS, WarrenMB, NickersonML, WeirichG, MatrosovaV, et al. (2001) Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 69: 876–882.

17. WarrenMB, Torres-CabalaCA, TurnerML, MerinoMJ, MatrosovaVY, et al. (2004) Expression of Birt-Hogg-Dube gene mRNA in normal and neoplastic human tissues. Mod Pathol 17: 998–1011.

18. LinehanWM, SrinivasanR, SchmidtLS (2010) The genetic basis of kidney cancer: a metabolic disease. Nature Reviews Urology 7: 277–285.

19. VockeCD, YangY, PavlovichCP, SchmidtLS, NickersonML, et al. (2005) High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal tumors. J Natl Cancer Inst 97: 931–935.

20. KouchiM, OkimotoK, MatsumotoI, TanakaK, YasubaM, et al. (2006) Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt-Hogg-Dube syndrome. Virchows Arch 448: 463–471.

21. TogashiY, KobayashiT, MomoseS, UedaM, OkimotoK, et al. (2006) Transgenic rescue from embryonic lethality and renal carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene. Oncogene 25: 2885–2889.

22. BonsdorffTB, JansenJH, LingaasF (2008) Second hits in the FLCN gene in a hereditary renal cancer syndrome in dogs. Mamm Genome 19: 121–126.

23. BonsdorffTB, JansenJH, ThomassenRF, LingaasF (2009) Loss of heterozygosity at the FLCN locus in early renal cystic lesions in dogs with renal cystadenocarcinoma and nodular dermatofibrosis. Mamm Genome 20: 315–320.

24. HudonV, SabourinS, DydensborgAB, KottisV, GhaziA, et al. (2010) Renal tumour suppressor function of the Birt-Hogg-Dube syndrome gene product folliculin. J Med Genet 47: 182–189.

25. HasumiY, BabaM, AjimaR, HasumiH, ValeraVA, et al. (2009) Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 106: 18722–18727.

26. HongSB, OhH, ValeraVA, StullJ, NgoDT, et al. (2010) Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Mol Cancer 9: 160.

27. HasumiH, BabaM, HongSB, HasumiY, HuangY, et al. (2008) Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene 415: 60–67.

28. BabaM, HongSB, SharmaN, WarrenMB, NickersonML, et al. (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 103: 15552–15557.

29. TakagiY, KobayashiT, ShionoM, WangL, PiaoX, et al. (2008) Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene 27: 5339–5347.

30. ParkH, StaehlingK, TsangM, ApplebyMW, BrunkowME, et al. (2012) Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity 36: 769–781.

31. BabaM, KellerJR, SunHW, ReschW, KuchenS, et al. (2012) The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dube syndrome is required for murine B-cell development. Blood 120: 1254–1261.

32. LimTH, FujikaneR, SanoS, SakagamiR, NakatsuY, et al. (2012) Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated base mismatch in DNA. DNA Repair (Amst) 11: 259–266.

33. BetschingerJ, NicholsJ, DietmannS, CorrinPD, PaddisonPJ, et al. (2013) Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3. Cell 153: 335–347.

34. WangL, KobayashiT, PiaoX, ShionoM, TakagiY, et al. (2010) Serine 62 is a phosphorylation site in folliculin, the Birt-Hogg-Dube gene product. FEBS Lett 584: 39–43.

35. SanoS, SakagamiR, SekiguchiM, HidakaM (2013) Stabilization of MAPO1 by specific binding with folliculin and AMP-activated protein kinase in O(6)-methylguanine-induced apoptosis. Biochem Biophys Res Commun 430: 810–815.

36. BehrendsC, SowaME, GygiSP, HarperJW (2010) Network organization of the human autophagy system. Nature 466: 68–76.

37. PrestonRS, PhilpA, ClaessensT, GijezenL, DydensborgAB, et al. (2011) Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene 30: 1159–1173.

38. KlompJA, PetilloD, NiemiNM, DykemaKJ, ChenJ, et al. (2010) Birt-Hogg-Dube renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. BMC Med Genomics 3: 59.

39. HasumiH, BabaM, HasumiY, HuangY, OhH, et al. (2012) Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. J Natl Cancer Inst 104: 1750–1764.

40. HardieDG, RossFA, HawleySA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13: 251–262.

41. CarlingD, ThorntonC, WoodsA, SandersMJ (2012) AMP-activated protein kinase: new regulation, new roles? Biochem J 445: 11–27.

42. MihaylovaMM, ShawRJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13: 1016–1023.

43. XiaoB, SandersMJ, UnderwoodE, HeathR, MayerFV, et al. (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472: 230–233.

44. OakhillJS, SteelR, ChenZP, ScottJW, LingN, et al. (2011) AMPK is a direct adenylate charge-regulated protein kinase. Science 332: 1433–1435.

45. HardieDG (2011) AMPK and autophagy get connected. EMBO J 30: 634–635.

46. EganDF, ShackelfordDB, MihaylovaMM, GelinoS, KohnzRA, et al. (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331: 456–461.

47. KimJ, KunduM, ViolletB, GuanKL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13: 132–141.

48. KimJ, KimYC, FangC, RussellRC, KimJH, et al. (2013) Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152: 290–303.

49. MairW, MorantteI, RodriguesAP, ManningG, MontminyM, et al. (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470: 404–408.

50. ApfeldJ, O'ConnorG, McDonaghT, DiStefanoPS, CurtisR (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18: 3004–3009.

51. SchulzTJ, ZarseK, VoigtA, UrbanN, BirringerM, et al. (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6: 280–293.

52. GreerEL, DowlatshahiD, BankoMR, VillenJ, HoangK, et al. (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17: 1646–1656.

53. NarbonneP, RoyR (2009) Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 457: 210–214.

54. LeeH, ChoJS, LambacherN, LeeJ, LeeSJ, et al. (2008) The Caenorhabditis elegans AMP-activated protein kinase AAK-2 is phosphorylated by LKB1 and is required for resistance to oxidative stress and for normal motility and foraging behavior. J Biol Chem 283: 14988–14993.

55. FukuyamaM, SakumaK, ParkR, KasugaH, NagayaR, et al. (2012) C. elegans AMPKs promote survival and arrest germline development during nutrient stress. Biol Open 1: 929–936.

56. CurtisR, O'ConnorG, DiStefanoPS (2006) Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5: 119–126.

57. LaRueBL, PadillaPA (2011) Environmental and genetic preconditioning for long-term anoxia responses requires AMPK in Caenorhabditis elegans. PLoS One 6: e16790.

58. ChenY, AzadMB, GibsonSB (2009) Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16: 1040–1052.

59. BaumeisterR, SchaffitzelE, HertweckM (2006) Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. J Endocrinol 190: 191–202.

60. Robida-StubbsS, Glover-CutterK, LammingDW, MizunumaM, NarasimhanSD, et al. (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15: 713–724.

61. LapierreLR, HansenM (2012) Lessons from C. elegans: signaling pathways for longevity. Trends Endocrinol Metab

62. FinkelT, HolbrookNJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408: 239–247.

63. MooreMN (2008) Autophagy as a second level protective process in conferring resistance to environmentally-induced oxidative stress. Autophagy 4: 254–256.

64. MelendezA, TalloczyZ, SeamanM, EskelinenEL, HallDH, et al. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301: 1387–1391.

65. HansenM, ChandraA, MiticLL, OnkenB, DriscollM, et al. (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4: e24.

66. KangC, YouYJ, AveryL (2007) Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation. Genes Dev 21: 2161–2171.

67. GutierrezMG, SakaHA, ChinenI, ZoppinoFC, YoshimoriT, et al. (2007) Protective role of autophagy against Vibrio cholerae cytolysin, a pore-forming toxin from V. cholerae. Proc Natl Acad Sci U S A 104: 1829–1834.

68. HosokawaN, HaraY, MizushimaN (2006) Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett 580: 2623–2629.

69. ShintaniT, KlionskyDJ (2004) Cargo proteins facilitate the formation of transport vesicles in the cytoplasm to vacuole targeting pathway. J Biol Chem 279: 29889–29894.

70. DjeddiA, MicheletX, CulettoE, AlbertiA, BaroisN, et al. (2012) Induction of autophagy in ESCRT mutants is an adaptive response for cell survival in C. elegans. J Cell Sci 125: 685–694.

71. JiaK, ThomasC, AkbarM, SunQ, Adams-HuetB, et al. (2009) Autophagy genes protect against Salmonella typhimurium infection and mediate insulin signaling-regulated pathogen resistance. Proc Natl Acad Sci U S A 106: 14564–14569.

72. SamokhvalovV, ScottBA, CrowderCM (2008) Autophagy protects against hypoxic injury in C. elegans. Autophagy 4: 1034–1041.

73. NoguchiN, YamamotoH, MisawaS (1993) Effects of paraquat on Mg(2+)-ATPase activity in rat liver. Arch Environ Contam Toxicol 24: 483–486.

74. YuQ, WangT, ZhouX, WuJ, ChenX, et al. (2011) Wld(S) reduces paraquat-induced cytotoxicity via SIRT1 in non-neuronal cells by attenuating the depletion of NAD. PLoS One 6: e21770.

75. YangW, ChenL, DingY, ZhuangX, KangUJ (2007) Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice. Hum Mol Genet 16: 2900–2910.

76. PadillaPA, NystulTG, ZagerRA, JohnsonAC, RothMB (2002) Dephosphorylation of cell cycle-regulated proteins correlates with anoxia-induced suspended animation in Caenorhabditis elegans. Mol Biol Cell 13: 1473–1483.

77. AltmanBJ, RathmellJC (2012) Metabolic stress in autophagy and cell death pathways. Cold Spring Harb Perspect Biol 4: a008763.

78. SamaraC, TavernarakisN (2008) Autophagy and cell death in Caenorhabditis elegans. Curr Pharm Des 14: 97–115.

79. Takacs-VellaiK, VellaiT, PuotiA, PassannanteM, WickyC, et al. (2005) Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans. Curr Biol 15: 1513–1517.

80. GartnerA, BoagPR, BlackwellTK (2008) Germline survival and apoptosis. WormBook 1–20.

81. JudyME, NakamuraA, HuangA, GrantH, McCurdyH, et al. (2013) A shift to organismal stress resistance in programmed cell death mutants. PLoS Genet 9: e1003714.

82. HundeshagenP, Hamacher-BradyA, EilsR, BradyNR (2011) Concurrent detection of autolysosome formation and lysosomal degradation by flow cytometry in a high-content screen for inducers of autophagy. BMC Biol 9: 38.

83. AtkinsonDE, WaltonGM (1967) Adenosine triphosphate conservation in metabolic regulation. Rat liver citrate cleavage enzyme. J Biol Chem 242: 3239–3241.

84. LeeI, HendrixA, KimJ, YoshimotoJ, YouYJ (2012) Metabolic rate regulates L1 longevity in C. elegans. PLoS One 7: e44720.

85. NathN, McCartneyRR, SchmidtMC (2003) Yeast Pak1 kinase associates with and activates Snf1. Mol Cell Biol 23: 3909–3917.

86. WoodsA, DickersonK, HeathR, HongSP, MomcilovicM, et al. (2005) Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2: 21–33.

87. HongSP, LeiperFC, WoodsA, CarlingD, CarlsonM (2003) Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci U S A 100: 8839–8843.

88. TaoL, XieQ, DingYH, LiST, PengS, et al. (2013) CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16. Elife 2: e00518.

89. ZarseK, SchmeisserS, GrothM, PriebeS, BeusterG, et al. (2012) Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab 15: 451–465.

90. BungardD, FuerthBJ, ZengPY, FaubertB, MaasNL, et al. (2010) Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation. Science 329: 1201–1205.

91. GharbiH, FabrettiF, BharillP, RinschenM, BrinkkotterS, et al. (2013) Loss of the Birt-Hogg-Dube gene product Folliculin induces longevity in a hypoxia-inducible factor dependent manner. Aging Cell

92. DaviesSK, LeroiAM, BundyJG (2012) Fluorodeoxyuridine affects the identification of metabolic responses to daf-2 status in Caenorhabditis elegans. Mech Ageing Dev 133: 46–49.

93. Van RaamsdonkJM, HekimiS (2011) FUdR causes a twofold increase in the lifespan of the mitochondrial mutant gas-1. Mech Ageing Dev 132: 519–521.

94. AitlhadjL, SturzenbaumSR (2010) The use of FUdR can cause prolonged longevity in mutant nematodes. Mech Ageing Dev 131: 364–365.

95. WangL, BrautiganDL (2013) alpha-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKalpha in vitro. Nat Commun 4: 1559.

96. SuzukiT, BridgesD, NakadaD, SkiniotisG, MorrisonSJ, et al. (2013) Inhibition of AMPK catabolic action by GSK3. Mol Cell 50: 407–419.

97. LiangJ, MillsGB (2013) AMPK: A Contextual Oncogene or Tumor Suppressor? Cancer Res

98. FaubertB, BoilyG, IzreigS, GrissT, SamborskaB, et al. (2013) AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo. Cell Metab 17: 113–124.

99. JeonSM, ChandelNS, HayN (2012) AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485: 661–665.

100. LevineB (2007) Cell biology - Autophagy and cancer. Nature 446: 745–747.

101. YangS, WangX, ContinoG, LiesaM, SahinE, et al. (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25: 717–729.

102. Karantza-WadsworthV, WhiteE (2007) Role of autophagy in breast cancer. Autophagy 3: 610–613.

103. ShintaniT, KlionskyDJ (2004) Autophagy in health and disease: a double-edged sword. Science 306: 990–995.

104. MikhaylovaO, StrattonY, HallD, KellnerE, EhmerB, et al. (2012) VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer Cell 21: 532–546.

105. FolkmanJ (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6: 273–286.

106. LiuL, UlbrichJ, MullerJ, WustefeldT, AeberhardL, et al. (2012) Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483: 608–612.

107. LeprivierG, RemkeM, RotblatB, DubucA, MateoAR, et al. (2013) The eEF2 Kinase Confers Resistance to Nutrient Deprivation by Blocking Translation Elongation. Cell 153: 1064–1079.

108. TennakoonJB, ShiY, HanJJ, TsoukoE, WhiteMA, et al. (2013) Androgens regulate prostate cancer cell growth via an AMPK-PGC-1alpha-mediated metabolic switch. Oncogene

109. DupuyF, GrissT, BlagihJ, BridonG, AvizonisD, et al. (2013) LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer. Cancer Metab 1: 18.

110. CashTP, GruberJJ, HartmanTR, HenskeEP, SimonMC (2011) Loss of the Birt-Hogg-Dube tumor suppressor results in apoptotic resistance due to aberrant TGFbeta-mediated transcription. Oncogene 30: 2534–2546.

111. GaurK, LiJ, WangD, DuttaP, YanSJ, et al. (2013) The Birt-Hogg-Dube tumor suppressor Folliculin negatively regulates ribosomal RNA synthesis. Hum Mol Genet 22: 284–299.

112. NahorskiMS, SeabraL, Straatman-IwanowskaA, WingenfeldA, ReimanA, et al. (2012) Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Hum Mol Genet 21: 5268–5279.

113. MedvetzDA, KhabibullinD, HariharanV, OngusahaPP, GoncharovaEA, et al. (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: e47842.

114. TsunZY, Bar-PeledL, ChantranupongL, ZoncuR, WangT, et al. (2013) The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1. Mol Cell 52: 495–505.

115. PetitCS, Roczniak-FergusonA, FergusonSM (2013) Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol 202: 1107–1122.

116. HanahanD, WeinbergRA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–674.

117. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.

118. KamathRS, Martinez-CamposM, ZipperlenP, FraserAG, AhringerJ (2001) Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biology 2.

119. KenyonC, ChangJ, GenschE, RudnerA, TabtiangR (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366: 461–464.

120. HoogewijsD, HouthoofdK, MatthijssensF, VandesompeleJ, VanfleterenJR (2008) Selection and validation of a set of reliable reference genes for quantitative sod gene expression analysis in C-elegans. Bmc Molecular Biology 9.

121. MacIverNJ, BlagihJ, SaucilloDC, TonelliL, GrissT, et al. (2011) The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism. Journal of Immunology 187: 4187–4198.

122. HallDH (1995) Electron microscopy and three-dimensional image reconstruction. Methods in Cell Biology, Vol 48 48: 395–436.

123. KellyKO, DernburgAF, StanfieldGM, VilleneuveAM (2000) Caenorhabditis elegans msh-5 is required for both normal and radiation-induced meiotic crossing over but not for completion of meiosis. Genetics 156: 617–630.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 4
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa