Rhebbing up mTOR: New insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis

Cancer Biology and Therapy

Volumn 2, Issue 5, 2003, Pages 471-476

  Kwiatkowski, David J ^a  

^a NONE

Author keywords

Hamartoma; mTOR; Rapamycin; Rheb; TSC; TSC1; TSC2; Tuberous sclerosis

Indexed keywords

DROSOPHILA PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MONOMERIC GUANINE NUCLEOTIDE BINDING PROTEIN; NEUROPEPTIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN; PROTEIN KINASE; REPRESSOR PROTEIN; RHEB PROTEIN, DROSOPHILA; RHEB PROTEIN, HUMAN; S6 KINASE; TUBERIN; TUBEROUS SCLEROSIS COMPLEX 1 PROTEIN; TUMOR SUPPRESSOR PROTEIN;

HUMAN; METABOLISM; PATHOLOGY; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION; TUBEROUS SCLEROSIS;

1-PHOSPHATIDYLINOSITOL 3-KINASE; DROSOPHILA PROTEINS; HUMANS; MONOMERIC GTP-BINDING PROTEINS; NEUROPEPTIDES; PROTEIN KINASES; PROTEINS; REPRESSOR PROTEINS; RIBOSOMAL PROTEIN S6 KINASES; SIGNAL TRANSDUCTION; TUBEROUS SCLEROSIS; TUMOR SUPPRESSOR PROTEINS;

EID: 1542577673     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.2.5.446     Document Type: Review

References (71)

1. Gomez M, Sampson J, Whittemore V. The tuberous sclerosis complex. Oxford, England: Oxford University Press, 1999.
2. Al-Saleem T, Wessner LL, Scheithauer BW, Patterson K, Roach ES, Dreyer SJ et al. Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 1998; 83:2208-16. (Pubitemid 28525404)
3. Crino PB, Henske EP. New developments in the neurobiology of the tuberous sclerosis complex. Neurology 1999; 53:1384-90. (Pubitemid 29491925)
4. The European chromosome 16 tuberous sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75:1305-15.
5. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277:805-8.
6. Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ. Molecular genetic advances in tuberous sclerosis. Hum Genet 2000; 107:97-114.
7. Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 1999; 64:1305-1315. (Pubitemid 30468748)
8. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001; 68:64-80. (Pubitemid 32048362)
9. Henske EP, Scheithauer BW, Short MP, Wollmann R, Nahmias J, Hornigold N, et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 1996; 59:400-6. (Pubitemid 26266356)
10. Au KS, Hebert AA, Roach ES, Northrup H. Complete inactivation of the TSC2 gene leads to formation of hamartomas. Am J Hum Genet 1999; 65:1790-5. (Pubitemid 30468695)
11. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000; 97:6085-90. (Pubitemid 30367527)
12. Niida Y, Stemmer-Rachamimov AO, Logrip M, Tapon D, Perez R, Kwiatkowski DJ, et al. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am J Hum Genet 2001; 69:493-503. (Pubitemid 32777689)
13. Onda H, Lueck A, Marks PW, Warren HB, Kwiatkowski DJ. Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest 1999; 104:687-95. (Pubitemid 29536354)
14. Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O, Noda T. Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 1999; 59:1206-11. (Pubitemid 29136248)
15. Kobayashi T, Minowa O, Sugitani Y, Takai S, Mitani H, Kobayashi E, et al. A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc Natl Acad Sci USA 2001; 98:8762-7. (Pubitemid 32678101)
16. Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T, Knowles MA. Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene 1999; 18:2657-61. (Pubitemid 29216689)
17. Parry L, Maynard JH, Patel A, Hodges AK, von Deimling A, Sampson JR, et al. Molecular analysis of the TSC1 and TSC2 tumour suppressor genes in sporadic glial and glioneuronal tumours. Hum Genet 2000; 107:350-6.
18. Parry L, Maynard JH, Patel A, Clifford SC, Morrissey C, Maher ER, et al. Analysis of the TSC1 and TSC2 genes in sporadic renal cell carcinomas. Br J Cancer 2001; 85:1226-30. (Pubitemid 33052325)
19. Gao X, Pan D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 2001; 15:1383-92. (Pubitemid 32524645)
20. Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 2001; 105:357-68. (Pubitemid 32455342)
21. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001; 105:345-55. (Pubitemid 32455341)
22. Ito N, Rubin GM. gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 1999; 96:529-39. (Pubitemid 29106840)
23. Plank TL, Yeung RS, Henske EP. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res 1998; 58:4766-70. (Pubitemid 28503664)
24. van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Human Mol Genet 1998; 7:1053-1058.
25. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002; 4:699-704.
26. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002; 4:658-65. (Pubitemid 34993701)
27. Radimerski T, Montagne J, Hemmings-Mieszczak M, Thomas G. Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev 2002; 16:2627-32.
28. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia 2003; 17:590-603. (Pubitemid 36395654)
29. Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003; 4:117-26.
30. Huang S, Bjornsti M, Houghton PJ. Rapamycins: Mechanism of action and cellular resistance. Cancer Biol Ther 2003; 2:222-232.
31. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177-89.
32. Kim DH, Sarbassov dos D, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163-75.
33. Kim DH, Sarbassov dos D, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient- sensitive interaction between raptor and mTOR. Mol Cell 2003; 11:895-904.
34. Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 2002; 11:525-34.
35. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002; 277:30958-67. (Pubitemid 34970798)
36. Onda H, Crino PB, Zhang H, Murphey RD, Rastelli L, Gould Rothberg BE, et al. Tsc2 Null Murine Neuroepithelial Cells Are a Model for Human Tuber Giant Cells, and Show Activation of an mTOR Pathway. Mol Cell Neurosci 2002; 21:561-74. (Pubitemid 36062714)
37. Jaeschke A, Hartkamp J, Saitoh M, Roworth W, Nobukuni T, Hodges A, et al. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide- 3-OH kinase is mTOR independent. J Cell Biol 2002; 159:217-24. (Pubitemid 35283391)
38. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4:648-57. (Pubitemid 34993700)
39. Zhang H, Cicchetti G, Onda H, Koon HB, Ascrican K, Bajraszewski N, et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signalling through downregulation of PDGFR. J Clin Inv 2003; in press.
40. El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 2003; 361:1348-9. (Pubitemid 36514870)
41. Karbowniczek M, Yu J, Henske EP. Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and nonneoplastic vascular structures. Am J Pathol 2003; 162:491-500. (Pubitemid 36267856)
42. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Yeung RS, et al. PI3K/AKT pathway regulates TSC tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2002; 277:35364-70.
43. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10:151-62. (Pubitemid 34876569)
44. Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous Sclerosis Complex-1 and 2 gene products function together to inhibit mammalian toarget of Rapamycin- (mTOR) mediated downstream signalling. Proc Natl Acad Sci USA 2002; 99:13571-6. (Pubitemid 35215423)
45. Mach KE, Furge KA, Albright CF. Loss of Rhb1, a Rheb-related GTPase in fission yeast, causes growth arrest with a terminal phenotype similar to that caused by nitrogen starvation. Genetics 2000; 155:611-22. (Pubitemid 30397114)
46. Yamagata K, Sanders LK, Kaufmann WE, Yee W, Barnes CA, Nathans D, et al. rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J Biol Chem 1994; 269:16333-9. (Pubitemid 24209331)
47. Im E, von Lintig FC, Chen J, Zhuang S, Qui W, Chowdhury S, et al. Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 2002; 21:6356-65.
48. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 2003; 5:566-71.
49. Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 2003; 5:559-65. (Pubitemid 36781091)
50. Patel PH, Thapar N, Guo L, Martinez M, Maris J, Gau CL, et al. Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J Cell Sci 2003; 116:3601-10. (Pubitemid 37063403)
51. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 2003; 5:578-81. (Pubitemid 36781094)
52. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003; 11:1457-66. (Pubitemid 36776533)
53. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17:1829-34. (Pubitemid 36944560)
54. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb. Curr Biol 2003; 13:1259-68.
55. Tabancay Jr AP, Gau CL, Machado IM, Uhlmann EJ, Gutmann DH, Guo L, et al. Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J Biol Chem 2003; in press.
56. Castro AF, Rebhun JF, Clark GG, Quilliam LA. Rheb binds TSC2 and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem 2003; 278:32493-6. (Pubitemid 37055685)
57. Radimerski T, Montagne J, Rintelen F, Stocker H, van der Kaay J, Downes CP, et al. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nat Cell Biol 2002; 4:251-5.
58. Li Y, Inoki K, Vacrasis P, Guan KL. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 (TSC2) gene product, and enhances its interaction with 14-3-3. J Biol Chem 2003; 278:13663-71. (Pubitemid 36799902)
59. Shumway SD, Li Y, Xiong Y. 14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. J Biol Chem 2003; 278:2089-92. (Pubitemid 36801271)
60. Lamb RF, Roy C, Diefenbach TJ, Vinters HV, Johnson MW, Jay DG, et al. The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2000; 2:281-287.
61. Kleymenova E, Ibraghimov-Beskrovnaya O, Kugoh H, Everitt J, Xu H, Kiguchi K, et al. Tuberin-dependent membrane localization of polycystin-1: A functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol Cell 2001; 7:823-32. (Pubitemid 32436442)
62. Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS. The tuberin-hamartin complex negatively regulates Beta -catenin signaling activity. J Biol Chem 2003; 278:5947-51. (Pubitemid 36800842)
63. Kenerson HL, Aicher LD, True LD, Yeung RS. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res 2002; 62:5645-50. (Pubitemid 35204715)
64. El-Hashemite N, Walker V, Zhang H, Kwiatkowski DJ. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Research 2003; in press.
65. Hino H, Kobayashi T, Mitani H. Prevention of hereditary carcinogenesis. Proc Japan Acad 2002; 78:30-32.
66. Dabora SL, Roberts P, Nieto A, Perez R, Jozwiak S, Franz D, et al. Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients. Am J Hum Genet 2002; 71:750-8. (Pubitemid 135750509)
67. White R, Hua Y, Scheithauer B, Lynch DR, Henske EP, Crino PB. Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers. Ann Neurol 2001; 49:67-78. (Pubitemid 32163007)
68. Khan A, Pepio AM, Sossin WS. Serotonin activates S6 kinase in a rapamycin-sensitive manner in Aplysia synaptosomes. J Neurosci 2001; 21:382-91. (Pubitemid 32107429)
69. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc Natl Acad Sci USA 1999; 96:4438-42. (Pubitemid 29190354)
70. Liu MY, Poellinger L, Walker CL. Up-regulation of hypoxia-inducible factor 2alpha in renal cell carcinoma associated with loss of Tsc-2 tumor suppressor gene. Cancer Res 2003; 63:2657-80.
71. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cander Cell 2003; 4:147-58. (Pubitemid 37045363)