Cellular and Molecular Life Sciences

, Volume 71, Issue 13, pp 2483–2497 | Cite as

Novel roles for the MiTF/TFE family of transcription factors in organelle biogenesis, nutrient sensing, and energy homeostasis

  • José A. Martina
  • Heba I. Diab
  • Huiqing Li
  • Rosa PuertollanoEmail author


The MiTF/TFE family of basic helix–loop–helix leucine zipper transcription factors includes MITF, TFEB, TFE3, and TFEC. The involvement of some family members in the development and proliferation of specific cell types, such as mast cells, osteoclasts, and melanocytes, is well established. Notably, recent evidence suggests that the MiTF/TFE family plays a critical role in organelle biogenesis, nutrient sensing, and energy metabolism. The MiTF/TFE family is also implicated in human disease. Mutations or aberrant expression of most MiTF/TFE family members has been linked to different types of cancer. At the same time, they have recently emerged as novel and very promising targets for the treatment of neurological and lysosomal diseases. The characterization of this fascinating family of transcription factors is greatly expanding our understanding of how cells synchronize environmental signals, such as nutrient availability, with gene expression, energy production, and cellular homeostasis.


MITF TFE3 TFEB Autophagy Lysosomes Nutrients Transcription Disease 



v-akt murine thymoma viral oncogene


Retinal pigmented epithelium cell line


Alveolar soft part sarcoma chromosome region, candidate 1


Alveolar soft part sarcoma


Activating transcription factor 1


unc-51-like autophagy activating kinase 1


Autophagy-related 13


Autophagy-related 16-like (S. cerevisiae)


Autophagy-related 9B


ATPase, H+ transporting, lysosomal


B-cell CLL/lymphoma 2


Basic/helix–loop–helix/leucine zipper


Receptor tyrosine kinase

C. elegans

Caenorhabditis elegans


Clear cell sarcoma


Cyclin-dependent kinase 2


Coordinated lysosomal expression and regulation


Clathrin, heavy chain (Hc)


Mitogen-activated protein kinase 1


Forkhead box O3




Solute carrier family 2 (facilitated glucose transporter, member 4)


Glycogen synthase kinase 3 beta


Glycogen synthase


Huntington’s disease


Hypoxia inducible factor 1


Hexokinase 2


Caenorhabditis elegans TFEB orthologue


Hermansky–Pudlak syndrome 4


Interferon regulatory factor 3


Interferon regulatory factor 7


Insulin receptor substrate 2


Interferon-stimulated genes


Lysosomal-associated membrane protein 1


Lysosome-related organelles


Lysosomal storage disorders


Lysosomal trafficking regulator


Microtubule-associated protein 1 light chain 3 beta


MYC-associated factor X


Mucolipin 1


Microphthalmia-associated transcription factor


Mucopolysaccharidosis type IIIA


Multiple sulfatase deficiency


Mechanistic target of rapamycin (serine/threonine kinase) complex 1


v-myc avian myelocytomatosis viral oncogene homolog


Non-POU domain-containing, octamer-binding


Neuronal stem cells


Cyclin-dependent kinase inhibitor 2A


Cyclin-dependent kinase inhibitor 1A (p21, Cip1)


Parkinson’s disease


Renal cell carcinoma


Phosphatidylinositol-4,5-bisphosphate 3-kinase


Peroxisome proliferator-activated receptor alpha


Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha


Papillary renal cell carcinoma (translocation-associated)


Protein kinase C, beta


Presenilin 2 (Alzheimer disease 4)


Splicing factor proline/glutamine-rich


Tumor necrosis factor (ligand) superfamily, member 11


Ras homolog enriched in brain


SREBF chaperone


Single nucleotide polymorphism


Sequestosome 1


Sterol regulatory element-binding protein


Stimulator of interferon genes


TANK-binding kinase 1


Transcription factor binding to IGHM enhancer 3


Transcription factor EB


Transcription factor EC


Tumor protein p53


Translocation renal cell carcinoma


Three prime repair exonuclease 1


Tuberous sclerosis 2


Upstream transcription factor


UV radiation resistance associated


Vacuolar protein sorting 11 homolog (S. cerevisiae)


Vacuolar protein sorting 18 homolog (S. cerevisiae)


WD repeat domain, phosphoinositide interacting 1


Zinc finger with KRAB and SCAN domains 3



This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI).


  1. 1.
    Carr CS, Sharp PA (1990) A helix-loop-helix protein related to the immunoglobulin E box-binding proteins. Mol Cell Biol 10(8):4384–4388PubMedCentralPubMedGoogle Scholar
  2. 2.
    Hodgkinson CA, Moore KJ, Nakayama A, Steingrimsson E, Copeland NG, Jenkins NA, Arnheiter H (1993) Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 74(2):395–404PubMedGoogle Scholar
  3. 3.
    Hughes MJ, Lingrel JB, Krakowsky JM, Anderson KP (1993) A helix-loop-helix transcription factor-like gene is located at the mi locus. J Biol Chem 268(28):20687–20690PubMedGoogle Scholar
  4. 4.
    Steingrimsson E, Copeland NG, Jenkins NA (2004) Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet 38:365–411. doi: 10.1146/annurev.genet.38.072902.092717 PubMedGoogle Scholar
  5. 5.
    Zhao GQ, Zhao Q, Zhou X, Mattei MG, de Crombrugghe B (1993) TFEC, a basic helix-loop-helix protein, forms heterodimers with TFE3 and inhibits TFE3-dependent transcription activation. Mol Cell Biol 13(8):4505–4512PubMedCentralPubMedGoogle Scholar
  6. 6.
    Hemesath TJ, Steingrimsson E, McGill G, Hansen MJ, Vaught J, Hodgkinson CA, Arnheiter H, Copeland NG, Jenkins NA, Fisher DE (1994) Microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev 8(22):2770–2780PubMedGoogle Scholar
  7. 7.
    Pogenberg V, Ogmundsdottir MH, Bergsteinsdottir K, Schepsky A, Phung B, Deineko V, Milewski M, Steingrimsson E, Wilmanns M (2012) Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF. Genes Dev 26(23):2647–2658. doi: 10.1101/gad.198192.112 PubMedCentralPubMedGoogle Scholar
  8. 8.
    Aksan I, Goding CR (1998) Targeting the microphthalmia basic helix-loop-helix-leucine zipper transcription factor to a subset of E-box elements in vitro and in vivo. Mol Cell Biol 18(12):6930–6938PubMedCentralPubMedGoogle Scholar
  9. 9.
    Rehli M, Lichanska A, Cassady AI, Ostrowski MC, Hume DA (1999) TFEC is a macrophage-restricted member of the microphthalmia-TFE subfamily of basic helix-loop-helix leucine zipper transcription factors. J Immunol 162(3):1559–1565PubMedGoogle Scholar
  10. 10.
    Beckmann H, Su LK, Kadesch T (1990) TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev 4(2):167–179PubMedGoogle Scholar
  11. 11.
    Steingrimsson E, Tessarollo L, Reid SW, Jenkins NA, Copeland NG (1998) The bHLH-Zip transcription factor Tfeb is essential for placental vascularization. Development 125(23):4607–4616PubMedGoogle Scholar
  12. 12.
    Bharti K, Liu W, Csermely T, Bertuzzi S, Arnheiter H (2008) Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF. Development 135(6):1169–1178. doi: 10.1242/dev.014142 PubMedCentralPubMedGoogle Scholar
  13. 13.
    Steingrimsson E (2008) All for one, one for all: alternative promoters and Mitf. Pigment Cell Melanoma Res 21(4):412–414. doi: 10.1111/j.1755-148X.2008.00473.x PubMedGoogle Scholar
  14. 14.
    Kuiper RP, Schepens M, Thijssen J, Schoenmakers EF, van Kessel AG (2004) Regulation of the MiTF/TFE bHLH-LZ transcription factors through restricted spatial expression and alternative splicing of functional domains. Nucleic Acids Res 32(8):2315–2322. doi: 10.1093/nar/gkh571 PubMedCentralPubMedGoogle Scholar
  15. 15.
    Levy C, Khaled M, Fisher DE (2006) MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 12(9):406–414. doi: 10.1016/j.molmed.2006.07.008 PubMedGoogle Scholar
  16. 16.
    Hershey CL, Fisher DE (2004) Mitf and Tfe3: members of a b-HLH-ZIP transcription factor family essential for osteoclast development and function. Bone 34(4):689–696. doi: 10.1016/j.bone.2003.08.014 PubMedGoogle Scholar
  17. 17.
    Steingrimsson E, Tessarollo L, Pathak B, Hou L, Arnheiter H, Copeland NG, Jenkins NA (2002) Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development. Proc Natl Acad Sci USA 99(7):4477–4482. doi: 10.1073/pnas.072071099 PubMedCentralPubMedGoogle Scholar
  18. 18.
    Kitamura Y, Oboki K, Ito A (2006) Molecular mechanisms of mast cell development. Immunol Allergy Clin North Am 26(3):387–405; v. doi: 10.1016/j.iac.2006.05.004 Google Scholar
  19. 19.
    Yagil Z, Hadad Erlich T, Ofir-Birin Y, Tshori S, Kay G, Yekhtin Z, Fisher DE, Cheng C, Wong WS, Hartmann K, Razin E, Nechushtan H (2012) Transcription factor E3, a major regulator of mast cell-mediated allergic response. J Allergy Clin Immunol 129 (5):1357–1366 e1355. doi: 10.1016/j.jaci.2011.11.051 Google Scholar
  20. 20.
    Huan C, Kelly ML, Steele R, Shapira I, Gottesman SR, Roman CA (2006) Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity. Nat Immunol 7(10):1082–1091. doi: 10.1038/ni1378 PubMedCentralPubMedGoogle Scholar
  21. 21.
    Read AP, Newton VE (1997) Waardenburg syndrome. J Med Genet 34(8):656–665PubMedCentralPubMedGoogle Scholar
  22. 22.
    Saftig P, Klumperman J (2009) Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10(9):623–635. doi: 10.1038/nrm2745 PubMedGoogle Scholar
  23. 23.
    Luzio JP, Pryor PR, Bright NA (2007) Lysosomes: fusion and function. Nat Rev Mol Cell Biol 8(8):622–632. doi: 10.1038/nrm2217 PubMedGoogle Scholar
  24. 24.
    Helip-Wooley A, Thoene JG (2004) Sucrose-induced vacuolation results in increased expression of cholesterol biosynthesis and lysosomal genes. Exp Cell Res 292(1):89–100PubMedGoogle Scholar
  25. 25.
    Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, Banfi S, Parenti G, Cattaneo E, Ballabio A (2009) A gene network regulating lysosomal biogenesis and function. Science 325(5939):473–477. doi: 10.1126/science.1174447 PubMedGoogle Scholar
  26. 26.
    Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, Ballabio A (2011) Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet 20(19):3852–3866. doi: 10.1093/hmg/ddr306 PubMedGoogle Scholar
  27. 27.
    Singh R, Cuervo AM (2011) Autophagy in the cellular energetic balance. Cell Metab 13(5):495–504. doi: 10.1016/j.cmet.2011.04.004 PubMedCentralPubMedGoogle Scholar
  28. 28.
    Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A (2011) TFEB links autophagy to lysosomal biogenesis. Science 332(6036):1429–1433. doi: 10.1126/science.1204592 PubMedCentralPubMedGoogle Scholar
  29. 29.
    Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29(10):2570–2581. doi: 10.1128/MCB.00166-09 PubMedCentralPubMedGoogle Scholar
  30. 30.
    Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126(1):121–134. doi: 10.1016/j.cell.2006.05.034 PubMedGoogle Scholar
  31. 31.
    Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6(6):458–471. doi: 10.1016/j.cmet.2007.11.001 PubMedGoogle Scholar
  32. 32.
    Chauhan S, Goodwin JG, Manyam G, Wang J, Kamat AM, Boyd DD (2013) ZKSCAN3 is a master transcriptional repressor of autophagy. Mol Cell 50(1):16–28. doi: 10.1016/j.molcel.2013.01.024 PubMedCentralPubMedGoogle Scholar
  33. 33.
    Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ, Wollenberg AC, Di Bernardo D, Chan L, Irazoqui JE, Ballabio A (2013) TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol 15(8):1016. doi: 10.1038/ncb2814 Google Scholar
  34. 34.
    Martina JA, Chen Y, Gucek M, Puertollano R (2012) MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8(6):903–914. doi: 10.4161/auto.19653 PubMedCentralPubMedGoogle Scholar
  35. 35.
    Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM (2012) The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 5(228):ra42. doi: 10.1126/scisignal.2002790 PubMedCentralPubMedGoogle Scholar
  36. 36.
    Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, Facchinetti V, Sabatini DM, Ballabio A (2012) A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 31(5):1095–1108. doi: 10.1038/emboj.2012.32 PubMedCentralPubMedGoogle Scholar
  37. 37.
    Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35. doi: 10.1038/nrm3025 PubMedCentralPubMedGoogle Scholar
  38. 38.
    Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM (2012) Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150(6):1196–1208. doi: 10.1016/j.cell.2012.07.032 PubMedCentralPubMedGoogle Scholar
  39. 39.
    Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141(2):290–303. doi: 10.1016/j.cell.2010.02.024 PubMedCentralPubMedGoogle Scholar
  40. 40.
    Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320(5882):1496–1501. doi: 10.1126/science.1157535 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334(6056):678–683. doi: 10.1126/science.1207056 PubMedCentralPubMedGoogle Scholar
  42. 42.
    Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5(6):566–571. doi: 10.1038/ncb996 PubMedGoogle Scholar
  43. 43.
    Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G, Hafen E (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5(6):559–565. doi: 10.1038/ncb995 PubMedGoogle Scholar
  44. 44.
    Martina JA, Puertollano R (2013) Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J Cell Biol 200(4):475–491. doi: 10.1083/jcb.201209135 PubMedCentralPubMedGoogle Scholar
  45. 45.
    Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20(7):1981–1991. doi: 10.1091/mbc.E08-12-1248 PubMedCentralPubMedGoogle Scholar
  46. 46.
    Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N (2009) Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5(7):973–979PubMedGoogle Scholar
  47. 47.
    Ferron M, Settembre C, Shimazu J, Lacombe J, Kato S, Rawlings DJ, Ballabio A, Karsenty G (2013) A RANKL-PKCbeta-TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts. Genes Dev 27(8):955–969. doi: 10.1101/gad.213827.113 PubMedCentralPubMedGoogle Scholar
  48. 48.
    Pena-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff NC, Tran TA, Zou L, Xie XJ, Corey DR, Brugarolas J (2011) Regulation of TFEB and V-ATPases by mTORC1. EMBO J 30(16):3242–3258. doi: 10.1038/emboj.2011.257 PubMedCentralPubMedGoogle Scholar
  49. 49.
    Platt FM, Boland B, van der Spoel AC (2012) The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J Cell Biol 199(5):723–734. doi: 10.1083/jcb.201208152 PubMedCentralPubMedGoogle Scholar
  50. 50.
    Hasan M, Koch J, Rakheja D, Pattnaik AK, Brugarolas J, Dozmorov I, Levine B, Wakeland EK, Lee-Kirsch MA, Yan N (2013) Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes. Nat Immunol 14(1):61–71. doi: 10.1038/ni.2475 PubMedCentralPubMedGoogle Scholar
  51. 51.
    Martina JA, Diab HI, Lishu L, Jeong-A L, Patange S, Raben N, Puertollano R (2014) TFE3 activates in response to nutrient deprivation and promotes autophagy, lysosomal biogenesis and cellular clearance. Sci Signal 7(309). doi: 10.1126/scisignal.2004754
  52. 52.
    Nakagawa Y, Shimano H, Yoshikawa T, Ide T, Tamura M, Furusawa M, Yamamoto T, Inoue N, Matsuzaka T, Takahashi A, Hasty AH, Suzuki H, Sone H, Toyoshima H, Yahagi N, Yamada N (2006) TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes. Nat Med 12(1):107–113. doi: 10.1038/nm1334 PubMedGoogle Scholar
  53. 53.
    Iwasaki H, Naka A, Iida KT, Nakagawa Y, Matsuzaka T, Ishii KA, Kobayashi K, Takahashi A, Yatoh S, Yahagi N, Sone H, Suzuki H, Yamada N, Shimano H (2012) TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice. Am J Physiol Endocrinol Metab 302(7):E896–E902. doi: 10.1152/ajpendo.00204.2011 PubMedGoogle Scholar
  54. 54.
    Shimano H (2007) SREBP-1c and TFE3, energy transcription factors that regulate hepatic insulin signaling. J Mol Med 85(5):437–444. doi: 10.1007/s00109-007-0158-5 PubMedGoogle Scholar
  55. 55.
    Fujimoto Y, Nakagawa Y, Satoh A, Okuda K, Shingyouchi A, Naka A, Matsuzaka T, Iwasaki H, Kobayashi K, Yahagi N, Shimada M, Yatoh S, Suzuki H, Yogosawa S, Izumi T, Sone H, Urayama O, Yamada N, Shimano H (2013) TFE3 controls lipid metabolism in adipose tissue of male mice by suppressing lipolysis and thermogenesis. Endocrinology. doi: 10.1210/en.2013-1203 PubMedGoogle Scholar
  56. 56.
    Merrell K, Wells S, Henderson A, Gorman J, Alt F, Stall A, Calame K (1997) The absence of the transcription activator TFE3 impairs activation of B cells in vivo. Mol Cell Biol 17(6):3335–3344PubMedCentralPubMedGoogle Scholar
  57. 57.
    Cheli Y, Ohanna M, Ballotti R, Bertolotto C (2010) Fifteen-year quest for microphthalmia-associated transcription factor target genes. Pigment Cell Melanoma Res 23(1):27–40. doi: 10.1111/j.1755-148X.2009.00653.x PubMedGoogle Scholar
  58. 58.
    Bertolotto C, Abbe P, Hemesath TJ, Bille K, Fisher DE, Ortonne JP, Ballotti R (1998) Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. J Cell Biol 142(3):827–835PubMedCentralPubMedGoogle Scholar
  59. 59.
    Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (2008) Novel MITF targets identified using a two-step DNA microarray strategy. Pigment Cell Melanoma Res 21(6):665–676. doi: 10.1111/j.1755-148X.2008.00505.x PubMedGoogle Scholar
  60. 60.
    Ho H, Kapadia R, Al-Tahan S, Ahmad S, Ganesan AK (2011) WIPI1 coordinates melanogenic gene transcription and melanosome formation via TORC1 inhibition. J Biol Chem 286(14):12509–12523. doi: 10.1074/jbc.M110.200543 PubMedCentralPubMedGoogle Scholar
  61. 61.
    Hah YS, Cho HY, Lim TY, Park DH, Kim HM, Yoon J, Kim JG, Kim CY, Yoon TJ (2012) Induction of melanogenesis by rapamycin in human MNT-1 melanoma cells. Ann Dermatol 24(2):151–157. doi: 10.5021/ad.2012.24.2.151 PubMedCentralPubMedGoogle Scholar
  62. 62.
    Bennicelli JL, Barr FG (2002) Chromosomal translocations and sarcomas. Curr Opin Oncol 14(4):412–419PubMedGoogle Scholar
  63. 63.
    Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Storkel S, van den Berg E, Zbar B (1997) The Heidelberg classification of renal cell tumours. J Pathol 183(2):131–133. doi: 10.1002/(SICI)1096-9896(199710)183:2<131:AID-PATH931>3.0.CO;2-G PubMedGoogle Scholar
  64. 64.
    Linehan WM, Ricketts CJ (2013) The metabolic basis of kidney cancer. Semin Cancer Biol 23(1):46–55. doi: 10.1016/j.semcancer.2012.06.002 PubMedCentralPubMedGoogle Scholar
  65. 65.
    Komai Y, Fujiwara M, Fujii Y, Mukai H, Yonese J, Kawakami S, Yamamoto S, Migita T, Ishikawa Y, Kurata M, Nakamura T, Fukui I (2009) Adult Xp11 translocation renal cell carcinoma diagnosed by cytogenetics and immunohistochemistry. Clin Cancer Res 15(4):1170–1176. doi: 10.1158/1078-0432.CCR-08-1183 PubMedGoogle Scholar
  66. 66.
    Nambiar M, Kari V, Raghavan SC (2008) Chromosomal translocations in cancer. Biochim Biophys Acta 1786(2):139–152. doi: 10.1016/j.bbcan.2008.07.005 PubMedGoogle Scholar
  67. 67.
    Davis IJ, Hsi BL, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez-Atayde AR, Argani P, Ladanyi M, Fletcher JA, Fisher DE (2003) Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. Proc Natl Acad Sci USA 100(10):6051–6056. doi: 10.1073/pnas.0931430100 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Kuiper RP, Schepens M, Thijssen J, van Asseldonk M, van den Berg E, Bridge J, Schuuring E, Schoenmakers EF, van Kessel AG (2003) Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Hum Mol Genet 12(14):1661–1669PubMedGoogle Scholar
  69. 69.
    Guru SC, Olufemi SE, Manickam P, Cummings C, Gieser LM, Pike BL, Bittner ML, Jiang Y, Chinault AC, Nowak NJ, Brzozowska A, Crabtree JS, Wang Y, Roe BA, Weisemann JM, Boguski MS, Agarwal SK, Burns AL, Spiegel AM, Marx SJ, Flejter WL, de Jong PJ, Collins FS, Chandrasekharappa SC (1997) A 2.8-Mb clone contig of the multiple endocrine neoplasia type 1 (MEN1) region at 11q13. Genomics 42(3):436–445. doi: 10.1006/geno.1997.4783 PubMedGoogle Scholar
  70. 70.
    van Asseldonk M, Schepens M, de Bruijn D, Janssen B, Merkx G, Geurts van Kessel A (2000) Construction of a 350-kb sequence-ready 11q13 cosmid contig encompassing the markers D11S4933 and D11S546: mapping of 11 genes and 3 tumor-associated translocation breakpoints. Genomics 66(1):35–42. doi: 10.1006/geno.2000.6194 PubMedGoogle Scholar
  71. 71.
    Pecciarini L, Cangi MG, Lo Cunsolo C, Macri E, Dal Cin E, Martignoni G, Doglioni C (2007) Characterization of t(6;11)(p21;q12) in a renal-cell carcinoma of an adult patient. Genes Chromosomes Cancer 46(5):419–426. doi: 10.1002/gcc.20422 PubMedGoogle Scholar
  72. 72.
    Argani P, Lui MY, Couturier J, Bouvier R, Fournet JC, Ladanyi M (2003) A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 22(34):5374–5378. doi: 10.1038/sj.onc.1206686 PubMedGoogle Scholar
  73. 73.
    Clark J, Lu YJ, Sidhar SK, Parker C, Gill S, Smedley D, Hamoudi R, Linehan WM, Shipley J, Cooper CS (1997) Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Oncogene 15(18):2233–2239. doi: 10.1038/sj.onc.1201394 PubMedGoogle Scholar
  74. 74.
    Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PH, Mertens F, Mandahl N, van den Berghe H, Sciot R, Dal Cin P, Bridge J (2001) The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 20(1):48–57. doi: 10.1038/sj.onc.1204074 PubMedGoogle Scholar
  75. 75.
    Gao CF, Vande Woude GF (2005) HGF/SF-Met signaling in tumor progression. Cell Res 15(1):49–51. doi: 10.1038/ PubMedGoogle Scholar
  76. 76.
    Tsuda M, Davis IJ, Argani P, Shukla N, McGill GG, Nagai M, Saito T, Lae M, Fisher DE, Ladanyi M (2007) TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res 67(3):919–929. doi: 10.1158/0008-5472.CAN-06-2855 PubMedGoogle Scholar
  77. 77.
    Reis H, Hager T, Wohlschlaeger J, Bauer S, Katenkamp K, Katenkamp D, Baba HA (2013) Mammalian target of rapamycin pathway activity in alveolar soft part sarcoma. Hum Pathol. doi: 10.1016/j.humpath.2013.04.018 Google Scholar
  78. 78.
    Weterman MA, van Groningen JJ, Tertoolen L, van Kessel AG (2001) Impairment of MAD2B-PRCC interaction in mitotic checkpoint defective t(X;1)-positive renal cell carcinomas. Proc Natl Acad Sci USA 98(24):13808–13813. doi: 10.1073/pnas.241304198 PubMedCentralPubMedGoogle Scholar
  79. 79.
    Medendorp K, van Groningen JJ, Vreede L, Hetterschijt L, Brugmans L, van den Hurk WH, van Kessel AG (2009) The renal cell carcinoma-associated oncogenic fusion protein PRCCTFE3 provokes p21 WAF1/CIP1-mediated cell cycle delay. Exp Cell Res 315(14):2399–2409. doi: 10.1016/j.yexcr.2009.04.022 PubMedGoogle Scholar
  80. 80.
    Muller-Hocker J, Babaryka G, Schmid I, Jung A (2008) Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion. Pathol Res Pract 204(8):589–597. doi: 10.1016/j.prp.2008.01.010 PubMedGoogle Scholar
  81. 81.
    Flaherty KT, Hodi FS, Fisher DE (2012) From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer 12(5):349–361. doi: 10.1038/nrc3218 PubMedGoogle Scholar
  82. 82.
    Cheli Y, Giuliano S, Botton T, Rocchi S, Hofman V, Hofman P, Bahadoran P, Bertolotto C, Ballotti R (2011) Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny. Oncogene 30(20):2307–2318. doi: 10.1038/onc.2010.598 PubMedGoogle Scholar
  83. 83.
    Cheli Y, Giuliano S, Fenouille N, Allegra M, Hofman V, Hofman P, Bahadoran P, Lacour JP, Tartare-Deckert S, Bertolotto C, Ballotti R (2012) Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells. Oncogene 31(19):2461–2470. doi: 10.1038/onc.2011.425 PubMedGoogle Scholar
  84. 84.
    Hoek KS, Eichhoff OM, Schlegel NC, Dobbeling U, Kobert N, Schaerer L, Hemmi S, Dummer R (2008) In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res 68(3):650–656. doi: 10.1158/0008-5472.CAN-07-2491 PubMedGoogle Scholar
  85. 85.
    Wellbrock C, Marais R (2005) Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation. J Cell Biol 170(5):703–708. doi: 10.1083/jcb.200505059 PubMedCentralPubMedGoogle Scholar
  86. 86.
    Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR (2005) Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436(7047):117–122. doi: 10.1038/nature03664 PubMedGoogle Scholar
  87. 87.
    Carreira S, Goodall J, Aksan I, La Rocca SA, Galibert MD, Denat L, Larue L, Goding CR (2005) Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. Nature 433(7027):764–769. doi: 10.1038/nature03269 PubMedGoogle Scholar
  88. 88.
    Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK, Golub TR, Fisher DE (2004) Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6(6):565–576. doi: 10.1016/j.ccr.2004.10.014 PubMedGoogle Scholar
  89. 89.
    Loercher AE, Tank EM, Delston RB, Harbour JW (2005) MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. J Cell Biol 168(1):35–40. doi: 10.1083/jcb.200410115 PubMedCentralPubMedGoogle Scholar
  90. 90.
    McGill GG, Haq R, Nishimura EK, Fisher DE (2006) c-Met expression is regulated by Mitf in the melanocyte lineage. J Biol Chem 281(15):10365–10373. doi: 10.1074/jbc.M513094200 PubMedGoogle Scholar
  91. 91.
    McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE (2002) Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109(6):707–718PubMedGoogle Scholar
  92. 92.
    Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P, Hoek KS, Testori A, Larue L, Goding CR (2006) Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev 20(24):3426–3439. doi: 10.1101/gad.406406 PubMedCentralPubMedGoogle Scholar
  93. 93.
    Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, Dessen P, d’Hayer B, Mohamdi H, Remenieras A, Maubec E, de la Fouchardiere A, Molinie V, Vabres P, Dalle S, Poulalhon N, Martin-Denavit T, Thomas L, Andry-Benzaquen P, Dupin N, Boitier F, Rossi A, Perrot JL, Labeille B, Robert C, Escudier B, Caron O, Brugieres L, Saule S, Gardie B, Gad S, Richard S, Couturier J, Teh BT, Ghiorzo P, Pastorino L, Puig S, Badenas C, Olsson H, Ingvar C, Rouleau E, Lidereau R, Bahadoran P, Vielh P, Corda E, Blanche H, Zelenika D, Galan P, French Familial Melanoma Study Group, Aubin F, Bachollet B, Becuwe C, Berthet P, Bignon YJ, Bonadona V, Bonafe JL, Bonnet-Dupeyron MN, Cambazard F, Chevrant-Breton J, Coupier I, Dalac S, Demange L, d’Incan M, Dugast C, Faivre L, Vincent-Fetita L, Gauthier-Villars M, Gilbert B, Grange F, Grob JJ, Humbert P, Janin N, Joly P, Kerob D, Lasset C, Leroux D, Levang J, Limacher JM, Livideanu C, Longy M, Lortholary A, Stoppa-Lyonnet D, Mansard S, Mansuy L, Marrou K, Mateus C, Maugard C, Meyer N, Nogues C, Souteyrand P, Venat-Bouvet L, Zattara H, Chaudru V, Lenoir GM, Lathrop M, Davidson I, Avril MF, Demenais F, Ballotti R, Bressac-de Paillerets B (2011) A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480(7375):94–98. doi: 10.1038/nature10539 PubMedGoogle Scholar
  94. 94.
    Davis IJ, Kim JJ, Ozsolak F, Widlund HR, Rozenblatt-Rosen O, Granter SR, Du J, Fletcher JA, Denny CT, Lessnick SL, Linehan WM, Kung AL, Fisher DE (2006) Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. Cancer Cell 9(6):473–484. doi: 10.1016/j.ccr.2006.04.021 PubMedGoogle Scholar
  95. 95.
    Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, Vila M (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 30(37):12535–12544. doi: 10.1523/JNEUROSCI.1920-10.2010 PubMedGoogle Scholar
  96. 96.
    Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A (2013) TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proc Natl Acad Sci USA 110(19):E1817–E1826. doi: 10.1073/pnas.1305623110 PubMedCentralPubMedGoogle Scholar
  97. 97.
    Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA, Masliah E, La Spada AR (2012) PGC-1alpha rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med 4(142):142ra197. doi: 10.1126/scitranslmed.3003799 Google Scholar
  98. 98.
    Pastore N, Blomenkamp K, Annunziata F, Piccolo P, Mithbaokar P, Maria Sepe R, Vetrini F, Palmer D, Ng P, Polishchuk E, Iacobacci S, Polishchuk R, Teckman J, Ballabio A, Brunetti-Pierri N (2013) Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency. EMBO Mol Med 5(3):397–412. doi: 10.1002/emmm.201202046 PubMedCentralPubMedGoogle Scholar
  99. 99.
    Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5(7):554–565. doi: 10.1038/nrm1423 PubMedGoogle Scholar
  100. 100.
    Platt FM, Walkley SU (2004) Lysosomal disorders of brain: recent advances in molecular and cellular pathogenesis and treatment. Oxford University Press, OxfordGoogle Scholar
  101. 101.
    Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G, Spampanato C, Puri C, Pignata A, Martina JA, Sardiello M, Palmieri M, Polishchuk R, Puertollano R, Ballabio A (2011) Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell 21(3):421–430. doi: 10.1016/j.devcel.2011.07.016 PubMedCentralPubMedGoogle Scholar
  102. 102.
    Spampanato C, Feeney E, Li L, Cardone M, Lim JA, Annunziata F, Zare H, Polishchuk R, Puertollano R, Parenti G, Ballabio A, Raben N (2013) Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol Med 5(5):691–706. doi: 10.1002/emmm.201202176 PubMedCentralPubMedGoogle Scholar
  103. 103.
    Abe K, Puertollano R (2011) Role of TRP channels in the regulation of the endosomal pathway. Physiology 26(1):14–22. doi: 10.1152/physiol.00048.2010 PubMedCentralPubMedGoogle Scholar
  104. 104.
    Vergarajauregui S, Puertollano R (2006) Two di-leucine motifs regulate trafficking of mucolipin-1 to lysosomes. Traffic 7(3):337–353. doi: 10.1111/j.1600-0854.2006.00387.x PubMedCentralPubMedGoogle Scholar
  105. 105.
    Song W, Wang F, Savini M, Ake A, di Ronza A, Sardiello M, Segatori L (2013) TFEB regulates lysosomal proteostasis. Hum Mol Genet 22(10):1994–2009. doi: 10.1093/hmg/ddt052 PubMedGoogle Scholar
  106. 106.
    McClive P, Pall G, Newton K, Lee M, Mullins J, Forrester L (1998) Gene trap integrations expressed in the developing heart: insertion site affects splicing of the PT1-ATG vector. Dev Dyn 212(2):267–276. doi: 10.1002/(SICI)1097-0177(199806)212:2<267:AID-AJA11>3.0.CO;2-1 PubMedGoogle Scholar
  107. 107.
    Grove CA, De Masi F, Barrasa MI, Newburger DE, Alkema MJ, Bulyk ML, Walhout AJ (2009) A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell 138(2):314–327. doi: 10.1016/j.cell.2009.04.058 PubMedCentralPubMedGoogle Scholar
  108. 108.
    O’Rourke EJ, Ruvkun G (2013) MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat Cell Biol 15(6):668–676. doi: 10.1038/ncb2741 PubMedCentralPubMedGoogle Scholar
  109. 109.
    Lapierre LR, De Magalhaes Filho CD, McQuary PR, Chu CC, Visvikis O, Chang JT, Gelino S, Ong B, Davis AE, Irazoqui JE, Dillin A, Hansen M (2013) The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun 4:2267. doi: 10.1038/ncomms3267 PubMedGoogle Scholar
  110. 110.
    Lister JA, Lane BM, Nguyen A, Lunney K (2011) Embryonic expression of zebrafish MiT family genes tfe3b, tfeb, and tfec. Dev Dyn 240(11):2529–2538. doi: 10.1002/dvdy.22743 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Basel (outside the USA) 2014

Authors and Affiliations

  • José A. Martina
    • 1
  • Heba I. Diab
    • 1
  • Huiqing Li
    • 1
  • Rosa Puertollano
    • 1
    Email author
  1. 1.Cell Biology and Physiology Center, National Heart, Lung, and Blood InstituteNational Institutes of HealthBethesdaUSA

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