Genetics and molecular biology of Tuberous Sclerosis Complex

Current Genomics

Volumn 9, Issue 7, 2008, Pages 475-487

  Napolioni, Valerio ^a   Curatolo, Paolo ^b  

^a UNIVERSITY OF CAMERINO   (Italy)

^b UNIVERSITY OF ROME TOR VERGATA   (Italy)

Author keywords

Genetics; Germ line mosaicism; Hamartin; Multifactorial disease; Mutations; Rapamycin; Tuberin; Tuberous sclerosis

Indexed keywords

GENE PRODUCT; HAMARTIN; INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN S6; PROTEIN TSC1; RAPAMYCIN; RHEB PROTEIN; S6 KINASE; TACROLIMUS; TUBERIN; UNCLASSIFIED DRUG;

AUTOSOMAL DOMINANT DISORDER; AUTOSOMAL DOMINANT INHERITANCE; BRAIN DISEASE; CARCINOGENESIS; CELL GROWTH; CLINICAL TRIAL; DISEASE MODEL; DROSOPHILA; DRUG ACTIVITY; DRUG EFFICACY; ENZYME ACTIVITY; EYE DISEASE; GENE MUTATION; GENETIC ANALYSIS; GENETIC POLYMORPHISM; HAMARTOMA; HEART DISEASE; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; KIDNEY DISEASE; KNOCKOUT MOUSE; LUNG DISEASE; MOLECULAR BIOLOGY; MOSAICISM; NONHUMAN; PHENOTYPE; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; REGULATORY MECHANISM; REVIEW; SCHIZOSACCHAROMYCES POMBE; SIGNAL TRANSDUCTION; SKIN DISEASE; TUBEROUS SCLEROSIS COMPLEX;

MAMMALIA;

EID: 60849130177     PISSN: 13892029     EISSN: None     Source Type: Journal    
DOI: 10.2174/138920208786241243     Document Type: Review

References (125)

1. Curatolo, P. Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes. London: Mac Keith Press, 2003.
2. Narayanan, V. Tuberous sclerosis complex: Genetics to pathogenesis. Pediatr. Neurol. 2003, 29: 404-9.
3. Gomez, M.R., Sampson, J.R., Whittemore, V.H. Tuberous Sclerosis Complex. Oxford: Oxford University Press, 1999.
4. Curatolo, P., Verdecchia, M., Bombardieri, R. Tuberous sclerosis complex: a review of neurological aspects. Eur. J. Pediatr. Neurol. 2002, 6: 15-23.
5. Joinson, C., O'Callaghan, F.J., Osborne, J.P., Martyn, C., Harris, T., Bolton, P.F. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol. Med. 2003, 33: 335-44.
6. Curatolo, P., Seri, S., Verdecchia, M., Bombardieri, R. Infantile spasms in tuberous sclerosis complex. Brain Dev. 2001, 23: 502-7.
7. Fukushima, K., Inoue, Y., Fujiwara, T., Yagi, K. Long-term follow-up study of West syndrome associated with tuberous sclerosis. Brain Dev. 2001, 23: 698-704.
8. Gillberg, I.C., Gillberg, C., Ahlsen, G. Autistic behaviour and attention deficits in tuberous sclerosis: a population-based study. Dev. Med. Child. Neurol. 1994, 36: 50-6.
9. Shepherd, C.W., Houser, O.W., Gomez, M.R. MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. Am. J. Neuroradiol. 1995, 16: 149-55.
10. Bolton, P.F., Park, R.J., Higgins, J.N., Griffiths, P.D., Pickles, A. Neuroepileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 2002, 125: 1247-55.
11. O'Callaghan, F.J., Noakes, M.J., Martyns, C.N., Osborne, J.P. An epidemiological study of renal pathology in tuberous sclerosis complex. BJU Int. 2004, 94: 853-7.
12. Casper, K.A., Donnelly, L.F., Chen, B., Bissler, J.J. Tuberous sclerosis complex: renal imaging findings. Radiology 2002, 225: 451-6.
13. Watson, G.H. Cardiac rhabdomyomas in tuberous sclerosis. Ann. NY Acad. Sci. 1991, 615: 50-7.
14. Chorianopoulos, D., Stratakos, G. Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. Lung 2008
15. Rowley, S.A., O'Callaghan, F.J., Osborne, J.P. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br. J. Ophthalmol. 2001, 85: 420-3.
16. Zimmer-Galler, I.E., Robertson, D.M. Long-term observation of retinal lesions in tuberous sclerosis. Am. J. Ophthalmol. 1995, 119: 318-24.
17. Cheadle, J.P., Reeve, M.P., Sampson, J.R., Kwiatkowski, D.J. Molecular genetic advances in tuberous sclerosis. Hum. Genet. 2000, 107: 97-114.
18. Sampson, J.R., Scahill, S.J., Stephenson, J.B., Mann, L., Connor, J.M. Genetic aspects of tuberous sclerosis in the west of Scotland. J. Med. Genet. 1989, 26: 28-31.
19. Dabora, S.L., Jozwiak, S., Franz, D.N., Roberts, P.S., Nieto, A., Chung, J., Choy, Y.S., Reeve, M.P., Thiele, E., Egelhoff, J.C., Kasprzyk-Obara, J., Domanska-Pakiela, D., Kwiatkowski, D.J. 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.
20. Jones, A.C., Shyamsundar, M.M., Thomas, M.W., Maynard, J., Idziaszczyk, S., Tomkins, S., Sampson, J.R., Cheadle, J.P. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 1999, 64: 1305-15.
21. Sancak, O., Nellist, M., Goedbloed, M., Elfferich, P., Wouters, C., Maat-Kievit, A., Zonnenberg, B., Verhoef, S., Halley, D., van den Ouweland, A. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur. J. Hum. Genet. 2005, 13: 731-41.
22. Au, K.S., Hebert, A.A., Roach, E.S., Northrup, H. Complete inactivation of the TSC2 gene leads to formation of hamartomas. Am. J. Hum. Genet. 1999, 65: 1790-5.
23. Green, A.J., Smith, M., Yates, J.R. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat. Genet. 1994, 6: 193-6.
24. Henske, E.P., Scheithauer, B.W., Short, M.P., Wollmann, R., Nahmias, J., Hornigold, N., van Slegtenhorst, M., Welsh, C.T., Kwiatkowski, D.J. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am. J. Hum. Genet. 1996, 59: 400-6.
25. Niida, Y., Stemmer-Rachamimov, A.O., Logrip, M., Tapon, D., Perez, R., Kwiatkowski, D.J., Sims, K., MacCollin, M., Louis, D.N., Ramesh, V. 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.
26. Han, S., Santos, T.M., Puga, A., Roy, J., Thiele, E.A., McCollin, M., Stemmer-Rachamimov, A., Ramesh, V. Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer. Res. 2004, 64: 812-6.
27. van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., Woodward, K., Nahmias, J., Fox, M., Ekong, R., Osborne, J., Wolfe, J., Povey, S., Snell, R.G., Cheadle, J.P., Jones, A.C., Tachataki, M., Ravine, D., Sampson, J.R., Reeve, M.P., Richardson, P., Wilmer, F., Munro, C., Hawkins, T.L., Sepp, T., Ali, J.B., Ward, S., Green, A.J., Yates, J.R., Kwiatkowska, J., Henske, E.P., Short, M.P., Haines, J.H., Jozwiak, S., Kwiatkowski, D.J. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997, 277: 805-8.
28. Ali, M., Girimaji, S.C., Kumar, A. Identification of a core promoter and a novel isoform of the human TSC1 gene transcript and structural comparison with mouse homolog. Gene 2003, 320: 145-154.
29. Sampson, J.R. TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis. Biochem. Soc. Trans. 2003, 31: 592-6.
30. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993, 75: 1305-15.
31. Lamb, R.F., Roy, C., Diefenbach, T.J., Vinters, H.V., Johnson, M.W., Jay, D.G., Hall, A. The TSC1 tumor suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat. Cell. Biol. 2000, 2: 281-7.
32. Goncharova, E., Goncharov, D., Noonan, D., Krymskaya, V.P. TSC2 modulates actin cytoskelton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. J. Cell. Biol. 2004, 167: 1171-82.
33. Haddad, L.A., Smith, N., Bowser, M., Niida, Y., Murthy, V., Gonzalez-Agosti, C., Ramesh, V. The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskelton. J. Biol. Chem. 2002, 277: 44180-6.
34. Maheshwar, M.M., Cheadle, J.P., Jones, A.C., Myring, J., Fryer, A.E., Harris, P.C., Sampson, J.R. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum. Mol. Genet. 1997, 6: 1991-6.
35. York, B., Lou, D., Panettieri, R.A. Jr., Krymskaya, V.P., Vanaman, T.C., Noonan, D.J. Cross-talk between tuberin, calmodulin, and estrogen signalling pathways. FASEB J. 2005, 19: 1202-4.
36. Brook-Carter, P.T., Peral, B., Ward, C.J., Thompson, P., Hughes, J., Maheshwar, M.M., Nellist, M., Gamble, V., Harris, P.C., Sampson, J.R. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease - a contiguous gene syndrome. Nat. Genet. 1994, 8: 328-32.
37. Crino, P.B., Nathanson, K.L., Henske, E.P. The tuberous sclerosis complex. N. Engl. J. Med. 2006, 355: 1345-56.
38. Chong-Kopera, H., Inoki, K., Li, Y., Zhu, T., Garcia-Gonzalo, F.R., Luis Rosa, J., Guan, K.L. TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J. Biol. Chem. 2006, 281: 8313-6.
39. Lu, Z., Hu, X., Li, Y., Zheng, L., Zhou, Y., Jiang, H., Ning, T., Basang, Z., Zhang, C., Ke, Y. Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin. J. Biol. Chem. 2004, 279: 35664-70.
40. Gan, B., Melkoumian, Z.K., Wu, X., Guan, K.L., Guan, J.L. Identification of FIP200 interaction with the TSC1-TSC2 complex and its role in regulation of cell size control. J. Cell. Biol. 2005, 170: 379-89.
41. Nakashima, A., Yoshino, K., Miyamoto, T., Eguchi, S., Oshiro, N., Kikkawa, U., Yonezawa, K. Identification of TBC7 having TBC domain as a novel binding protein to TSC1-TSC2 complex. Biochem. Biophys. Res. Commun. 2007, 361: 218-23.
42. Nellist, M., Burgers, P.C., van den Ouweland, A.M., Halley, D.J., Luider, T.M. Phosphorylation and binding partner analysis of the TSC1-TSC2 complex. Biochem. Biophys. Res. Commun. 2005, 333: 818-26.
43. Astrinidis, A., Senapedis, W., Henske, E.P. Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum. Mol. Genet. 2006, 15: 287-97.
44. Rosner, M., Hanneder, M., Siegel, N., Valli, A., Hengstschläger, M. The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. Mutat. Res. 2008, 658: 234-46.
45. Jones, A.C., Daniells, C.E., Snell, R.G., Tachataki, M., Idziaszczyk, S.A., Krawczak, M., Sampson, J.R., Cheadle, J.P. Molecular genetic and phenotypic analysis reveals difference between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum. Mol. Genet. 1997, 6: 2155-61.
46. Niida, Y., Lawrence-Smith, N., Banwell, A., Hammer, E., Lewis, J., Beauchamp, R.L., Sims, K., Ramesh, V., Ozelius, L. Analysis of both TSC1 and TSC2 for germline mutations in 126 urelated patients with tuberous sclerosis. Hum. Mutat. 1999, 14: 412-22.
47. van Slegtenhorst, M., Verhoef, S., Tempelaars, A., Bakker, L., Wang, Q., Wessels, M., Bakker, R., Nellist, M., Lindhout, D., Halley, D., van den Ouweland, A. Mutational spectrum of TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. J. Med. Genet. 1999, 36: 285-9.
48. http://chromium.liacs.nl/lovd/index.php?select_db=TSC1 or _db=TSC2
49. Mayer, K., Ballhausen, W., Leistner, W., Rott, H. Three novelf types of splicing aberrations in the tuberous sclerosis TSC2 gene caused by mutations apart from splice consensus sequences. Biochim. Biophys. Acta. 2000, 1502: 495-507.
50. Nellist, M., Verhaaf, B., Goedbloed, M.A., Reuser, A.J., van den Ouweland, A.M., Halley, D.J. TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. Hum. Mol. Genet. 2001, 10: 2889-98.
51. Nellist, M., Sancak, O., Goedbloed, M.A., Rohe, C., van Netten, D., Mayer, K., Tucker-Williams, A., van den Ouweland, A.M., Halley, D.J. Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur. J. Hum. Genet. 2005, 13: 59-68.
52. Tee, A.R., Fingar, D.C., Manning, B.D., Kwiatkowski, D.J., Cantley, L.C., Blenis, J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl. Acad. Sci. USA 2002, 99: 13571-6.
53. Tee, A.R., Anjum, R., Blenis, J. Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase (PI3K)/Akt-dependent and -independent phosphorylation of tuberin. J. Biol. Chem. 2003, 278: 37288-96.
54. Nellist, M., Sancak, O., Goedbloed, M., Adriaans, A., Wessels, M., Maat-Kievit, A., Baars, M., Dommering, C., van den Ouweland, A., Halley, D. Functional characterisation of the TSC1-TSC2 complex to assess multiple TSC2 variants identified in single families affected by tuberous sclerosis complex. BMC Med. Genet. 2008, 9: 10.
55. Roberts, P.S., Ramesh, V., Dabora, S., Kwiatkowski, D.J. A 34 bp deletion within TSC2 is a rare polymorphism, not a pathogenic mutation. Ann. Hum. Genet. 2003, 67: 495-503.
56. Sampson, J.R., Maheshwar, M.M., Aspinwall, R., Thompson, P., Cheadle, J.P., Ravine, D., Roy, S., Haan, E., Bernstein, J., Harris, P.C. Renal cystic disease in tuberous sclerosis: Role of the polycystic kidney disease 1 gene. Am. J. Hum. Genet. 1997, 61: 843-51.
57. Kleymenova, E., Ibraghimov-Beskrovnaya, O., Kugoh, H., Everitt, J., Xu, H., Kiguchi, K., Landes, G., Harris, P., Walzer, C. 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.
58. Ariyurek, Y., Lantinga-van Leeuwen, I., Spruit, L., Ravine, D., Breuning, M.H., Peters, D.J. Large Deletions in the Polycystic Kidney Disease 1 (PKD1) Gene. Hum. Mutat. 2004, 23: 99.
59. The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 1994, 77: 881-94.
60. Thomas, R., Mc Connell, R., Whittacker, J., Kirkpatrick, P., Bradley, J., Sandford, R. Identification of mutations in the repeated part of the autosomal dominant polycystic kidney disease type 1 gene, PKD1, by long-range PCR. Am. J. Hum. Genet. 1999, 65: 39-49.
61. Lee, J.K., Sayers, T.J., Brooks, A.D., Back, T.C., Young, H.A., Komschlies, K.L., Wipsgginton, J.M., Wiltrout, R.H. IFN-g-dependent delay of in vivo tumor progression by Fas overexpression on murine renal cancer cells. J. Immunol. 2000, 164: 231-9.
62. Becker, C., Pohla, H., Frankenberger, B., Schüler, T., Assenmacher, M., Schendel, D.J., Blankenstein, T. Adoptive tumor therapy with T lymphocytes enriched through an IFN-g capture assay. Nat. Med. 2001, 7: 1159-62.
63. Dabora, S.L., Roberts, P., Nieto, A., Perez, R., Jozwiak, S., Franz, D., Bissler, J., Thiele, E.A., Sims, K., Kwiatkowski, D.J. Association between a high-expressing interferon-γ allele and a lower frequency of kidney angiomyolipomas in TSC2 Patients. Am. J. Hum. Genet. 2002, 71: 750-8.
64. Pravica, V., Asderakis, A., Perrey, C., Hajeer, A., Sinnott, P.J., Hutchinson, I.V. In vitro production of IFN-γ correlates with CA repeat polymorphism in the human IFN-γ gene. Eur. J. Immunogenet. 1999, 26: 1-3.
65. Habib, S.L., Danial, E., Nath, S., Schneider, J., Jenkinson, C.P., Duggirala, R., Abboud, H.E., Thameem, F. Genetic polymorphisms in OGG1 and their association with angiomyolipoma, a benign kidney tumor in patients with tuberous sclerosis. Cancer. Biol. Ther. 2007, 8: 7.
66. Fahsold, R., Rott, H.D., Lorenz, P. A third gene locus for tuberous sclerosis is closely linked to the phenylalanine hydroxylase gene locus. Hum. Genet. 1991, 88: 85-90.
67. Hall, J.G. Somatic mosaicism: observations related to clinical genetics. Am. J. Hum. Genet. 1988, 43: 355-63.
68. van der Meulen, M.A., van der Meulen, M.J., te Meerman, G.T. Recurrence risk for germinalmosaics revisited. J. Med. Genet. 1995, 32: 102-4.
69. Northrup, H., Wheless, J.W., Bertin, T.K., Lewis, R.A. Variability of expression in tuberous sclerosis. J. Med. Genet. 1993, 30: 41-3.
70. Ruggieri, M., Carbonare, C., Magro, G., Magone, N., Grasso, S., Tine, A., Pavone, L., Gomez, M.R. Tuberous sclerosis complex: neonatal deaths in three of four children of consanguineous, nonexpressing parents. J. Med. Genet. 1997, 34: 256-260.
71. Yates, J.R.W., van Bakel, I., Sepp, T., Payne, S.J., Webb, D.W., Nevin, N.C., Green, A.J. Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis. Hum. Mol. Genet. 1997, 6: 2265-9.
72. Rose, V.M., Au, K.S., Pollom, G., Roach, E.S., Prashner, H.R., Northrup, H. Germ-line mosaicism in tuberous sclerosis: how common? Am. J. Hum. Genet. 1999, 64: 986-92.
73. Kwiatkowski, D.J., Manning, B.D. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet. 2005, 14: 251-8.
74. Mak, B.C., Kenerson, H.L., Aicher, L.D., Barnes, E.A., Yeung, R.S. Aberrant b-Catenin Signaling in Tuberous Sclerosis. Am. J. Pathol. 2005, 167: 107-16.
75. Astrinidis, A., Senapedis, W., Coleman, T.R., Henske, E.P. Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. J. Biol. Chem. 2003, 278: 51372-9.
76. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., Pandolfi, P.P. Phosphorylation and functional inactivation of TSC2 by Erk: implications for tuberous sclerosis and cancer pathogenesis. Cell 2005, 121: 179-93.
77. Roux, P.P., Ballif, B.A., Anjum, R., Gygi, S.P., Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA 2004, 101: 13489-94.
78. Ballif, B.A., Roux, P.P., Gerber, S.A., MacKeigan, J.P., Blenis, J., Gygi, S.P. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc. Natl. Acad. Sci. USA 2005, 102: 667-72.
79. Li, Y., Inoki, K., Vacratsis, P., Guan, K.L. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. J. Biol. Chem. 2003, 278: 13663-71.
80. Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., Cantley, L.C. 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.
81. Inoki, K., Zhu, T., Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115: 577-90.
82. Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., Yang, Q., Bennett, C., Harada, Y., Stankunas, K., Wang, C.Y., He, X., MacDougald, O.A., You, M., Williams, B.O., Guan, K.L. TSC2 Integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006, 126: 955-68.
83. Yaffe, M.B., Cantley, L.C. Signal transduction. Grabbing phospho-proteins. Nature 1999, 402: 30-1.
84. Nellist, M., Goedbloed, M.A., Halley, D.J. Regulation of tuberous sclerosis complex (TSC) function by 14-3-3 proteins. Biochem. Soc. Trans. 2003, 31: 587-91.
85. Shumway, S.D., Li, Y., Xiong, Y. 14-3-3 binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. J. Biol. Chem. 2003, 278: 2089-92.
86. Yasui, S., Tsuzaki, K., Ninomiya, H., Floricel, F., Asano, Y., Maki, H., Takamura, A., Nanba, E., Higaki, K., Ohno, K. The TSC1 gene product hamartin interacts with NADE. Mol. Cell. Neurosci. 2007, 35: 100-8.
87. Mukai, J., Hachiya, T., Shoji-Hoshino, S., Kimura, M.T., Nadano, D., Suvanto, P., Hanaoka, T., Li, Y., Irie, S., Greene, L.A., Sato, T.A. NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR. J. Biol. Chem. 2000, 275: 17566-70.
88. Mukai, J., Shiji, S., Kimura, M.T., Okubo, S., Sano, H., Suvanto, P., Li, Y., Irie, S., Sato, T.A. Structure-function analysis of NADE. J. Biol. Chem. 2002, 227: 13973-82.
89. Wu, E.H.T., Wu, K.H.H., Wong, Y.H. Tuberin: a stimulus-regulated tumor suppressor protein controlled by a diverse array of receptor tyrosine kinases and G protein-coupled receptors. Neurosignals 2006, 15: 217-27.
90. Cao, Y., Kamioka, Y., Yokoi, N., Kobayashi, T., Hino, O., Onodera, M., Mochizuki, N., Nakae, J. Interaction of FOXO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway. J. Biol. Chem. 2006, 281: 40242-51.
91. Inoki, K., Corradetti, M.N., Guan, K.L. Dysregulation of the TSC-mTOR pathway in human disease. Nat. Genet. 2005, 37: 19-24.
92. Tee, A.R., Blenis, J. mTOR, translational control and human disease. Semin. Cell. Dev. Biol. 2005, 16: 29-37.
93. Rosner, M., Freilinger, A., Hengstschläger, M. Akt regulates nuclear/cytoplasmic localization of tuberin. Oncogene 2007, 26: 521-31.
94. Rosner, M., Freilinger, A., Hengstschläger, M. The tuberous sclerosis genes and regulation of the cyclin-dependent kinase inhibitor p27. Mutat. Res. 2006, 613: 10-6.
95. Carrano, A.C., Etan, E., Hershko, A., Pagano, M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat. Cell. Biol. 1999, 1: 193-9.
96. Sutterlüty, H., Chatelain, E., Marti, A., Wirbelauer, C., Senften, M., Müller, U., Krek, W. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat. Cell. Biol. 1999, 1: 207-14.
97. Rosner, M., Hengstschläger, M. Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2. J. Biol. Chem. 2004, 279: 48707-15.
98. Ozcan, U., Ozcan, L., Yilmaz, E., Düvel, K., Sahin, M., Manning, B.D., Hotamisligil, G.S. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 2008, 29: 541-51.
99. Habib, S.L., Simone, S., Barnes, J.J., Abboud, H.E. Tuberin haploinsufficiency is associated with the loss of OGG1 in rat kidney tumors. Mol. Cancer 2008, 7: 10.
100. Kobayashi, T., Mitani, H., Takahashi, R., Hirabayashi, M., Ueda, M., Tamura, H., Hino, O. Transgenic rescue from embryonic lethality and renal carcinogenesis in the Eker rat model by introduction of a wild-type Tsc2 gene. Proc. Natl. Acad. Sci. USA 1997, 94: 3990-3.
101. Rennebeck, G., Kleymenova, E.V., Anderson, R., Yeung, R.S., Artzt, K., Walker, C.L. Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc. Natl. Acad. Sci. USA 1998, 95: 15629-34.
102. Kwiatkowski, D.J., Zhang, H., Bandura, J.L., Heiberger, K.M., Glogauer, M., el-Hashemite, N., Onda, H. A mouse model of TSC1 reveals sexdependent lethality from liver hemangiomas, and upregulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 2002, 11: 525-34.
103. Kobayashi, T., Hirayama, Y., Kobayashi, E., Kubo, Y., Hino, O. A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat. Genet. 1995, 9: 70-4.
104. Yeung, R.S., Katsetos, C.D., Klein-Szanto, A. Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis. Am. J. Pathol. 1997, 151: 1477-86.
105. Kobayashi, T., Urakami, S., Hirayama, Y., Yamamoto, T., Nishizawa, M., Takahara, T., Kubo, Y., Hino, O. Intragenic Tsc2 somatic mutations as Knudson's second hit in spontaneous and chemically induced renal carcinomas in the Eker rat model. Jpn. J. Cancer Res. 1997, 88: 254-61.
106. Neufeld, T.P., de la Cruz, A.F., Johnston, L.A., Edgar, B.A. Coordination of growth and cell division in the Drosophila wing. Cell 1998, 93: 1183-93.
107. Leevers, S.J., Weinkove, D., MacDougall, L.K., Hafen, E., Water-field, M.D. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 1996, 15: 6584-94.
108. Böhni, R., Riesgo-Escovar, J., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B.F., Beckingham, K., Hafen, E. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 1999, 97: 865-75.
109. Verdu, J., Buratovich, M.A., Wilder, E.L., Birnbaum, M.J. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/ PKB. Nat. Cell. Biol. 1999, 1: 500-6.
110. Gao, X., Neufeld, T.P., Pan, D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways. Dev. Biol. 2000, 221: 404-18.
111. Cho, K.S., Lee, J.H., Kim, S., Kim, D., Koh, H., Lee, J., Kim, C., Kim, J., Chung, J. Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway. Proc. Natl. Acad. Sci. USA 2001, 98: 6144-9.
112. Montagne, J., Stewart, M.J., Stocker, H., Hafen, E., Kozma, S.C., Thomas, G. Drosophila S6 kinase: a regulator of cell size. Science 1999, 285: 2126-9.
113. Ito, N., Rubin, G.M. Gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 1999, 96: 529-39.
114. Gao, X., Pan, D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes. Dev. 2001, 15: 1383-92.
115. Tapon, N., Ito, N., Dickson, B.J., Treisman, J.E., Hariharan, I.K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001, 105: 345-55.
116. Matsumoto, S., Bandyopadhyay, A., Kwiatkowski, D.J., Maitra, U., Matsumoto, T. Role of the Tsc1-Tsc2 complex in signalling and transport across the cell membrane in the fission yeast Schizosaccharomyces pombe. Genetics 2002, 161: 1053-63.
117. Jozwiak, J., Jozwiak, S., Oldak, M. Molecular activity of sirolimus and its possible applications in tuberous sclerosis treatment. Med. Res. Rev. 2006, 26: 160-80.
118. Bierer, B.E., Mattila, P.S., Standaert, R.F., Herzenberg, L.A., Burakoff, S.J., Crabtree, G., Schreiber, S.L. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc. Natl. Acad. Sci. USA 1990, 87: 9231-5.
119. Edinger, A.L., Linardic, C.M., Chiang, G.G., Thompson, C.B., Abraham, R.T. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res. 2003, 63: 8451-60.
120. Brugarolas, J.B., Vazquez, F., Reddy, A., Sellers, W.R., Kaelin, W.G. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 2003, 4: 147-58.
121. Franz, D.N., Leonard, J., Tudor, C., Chuck, G., Care, M., Sethuraman, G., Dinopoulos, A., Thomas, G., Crone, K.R. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 2006, 59: 490-8.
122. Bissler, J.J., McCormack, F.X., Young, L.R., Elwing, J.M., Chuck, G., Leonard, J.M., Schmithorst, V.J., Laor, T., Brody, A.S., Bean, J., Salisbury, S., Franz, D.N. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 2008, 358: 140-51.
123. Rauktys, A., Lee, N., Lee, L., Dabora, S.L. Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model. BMC Dermatol. 2008, 8: 1.
124. Schwartz, R.A., Fernandez, G., Kotulska, K., Jozwiak, S. Tuberous sclerosis complex: advances in diagnosis, genetics and management. J. Am. Acad. Dermatol. 2007, 57: 189-202.
125. Zeng, L.H., Xu, L., Gutmann, D.H., Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 2008, 63: 444-53.