Generic placeholder image

Current Topics in Medicinal Chemistry

Author(s): Nalini Natarajan and Vijay Thiruvenkatam*

DOI: 10.2174/1568026620666200825170355

DownloadDownload PDF Flyer Cite As
An Insight of Scientific Developments in TSC for Better Therapeutic Strategy

Page: [2080 - 2093] Pages: 14

  • * (Excluding Mailing and Handling)

Abstract

Tuberous sclerosis complex (TSC) is a rare genetic disease, which is characterized by noncancerous tumors in multi-organ systems in the body. Mutations in the TSC1 or TSC2 genes are known to cause the disease. The resultant mutant proteins TSC1 (hamartin) and TSC2 (tuberin) complex evade its normal tumor suppressor function, which leads to abnormal cell growth and proliferation. Both TSC1 and TSC2 are involved in several protein-protein interactions, which play a significant role in maintaining cellular homeostasis. The recent biochemical, genetic, structural biology, clinical and drug discovery advancements on TSC give a useful insight into the disease as well as the molecular aspects of TSC1 and TSC2. The complex nature of TSC disease, a wide range of manifestations, mosaicism and several other factors limits the treatment choices. This review is a compilation of the course of TSC, starting from its discovery to the current findings that would take us a step ahead in finding a cure for TSC.

Keywords: Tuberous sclerosis complex, Rapalogs treatment, mTOR inhibition, Crystal structure, Protein-protein interaction, Coiled-coil sequence, Disruptive mutation, Hypoxia, Heat shock proteins.

Graphical Abstract

[1]
Roach, E.S.; Smith, M.; Huttenlocher, P.; Bhat, M.; Alcorn, D.; Hawley, L. Diagnostic criteria: tuberous sclerosis complex. report of the diagnostic criteria committee of the national tuberous sclerosis association. J. Child Neurol., 1992, 7(2), 221-224.
[http://dx.doi.org/10.1177/088307389200700219] [PMID: 1573244]
[2]
Hyman, M.H.; Whittemore, V.H. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch. Neurol., 2000, 57(5), 662-665.
[http://dx.doi.org/10.1001/archneur.57.5.662] [PMID: 10815131]
[3]
Roach, E.S.; Williams, D.P.; Laster, D.W. Magnetic resonance imaging in tuberous sclerosis. Arch. Neurol., 1987, 44(3), 301-303.
[http://dx.doi.org/10.1001/archneur.1987.00520150047020] [PMID: 3827681]
[4]
Gomez, M.R. Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria. Ann. N. Y. Acad. Sci., 1991, 615, 1-7.
[http://dx.doi.org/10.1111/j.1749-6632.1991.tb37742.x] [PMID: 2039135]
[5]
Bongaarts, A.; Giannikou, K.; Reinten, R. J.; Anink, J. J.; Mills, J.D.; Jansen, F. E.; Spliet, G.; den Dunnen, W.; Coras, R.; Blümcke, I.; Paulus, W.; Scholl, T.; Feucht, M.; Kotulska, K.; Jozwiak, S.; Buccoliero, A. M.; Caporalini, C.; Giordano, F.; Genitori, L.; Söylemezoğlu, F. Subependymal giant cell astrocytomas in tuberous sclerosis complex have consistent tsc1/tsc2 biallelic inactivation, and no braf mutations. Oncotarget, 2017, 8(56), 95516–95529.
[6]
McCormack, F.X. Lymphangioleiomyomatosis and Pulmonary Disease in TSC; Tuberous Sclerosis Complex, 2017.
[7]
Northrup, H.; Krueger, D.A. International tuberous sclerosis complex consensus group. tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 iinternational tuberous sclerosis complex consensus conference. Pediatr. Neurol., 2013, 49(4), 243-254.
[http://dx.doi.org/10.1016/j.pediatrneurol.2013.08.001] [PMID: 24053982]
[8]
European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell, 1993, 75(7), 1305-1315.
[http://dx.doi.org/10.1016/0092-8674(93)90618-Z] [PMID: 8269512]
[9]
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(5327), 805-808.
[http://dx.doi.org/10.1126/science.277.5327.805] [PMID: 9242607]
[10]
Nellist, M.; van Slegtenhorst, M.A.; Goedbloed, M.; van den Ouweland, A.M.W.; Halley, D.J.J.; van der Sluijs, P. Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J. Biol. Chem., 1999, 274(50), 35647-35652.
[http://dx.doi.org/10.1074/jbc.274.50.35647] [PMID: 10585443]
[11]
van Slegtenhorst, M.; Nellist, M.; Nagelkerken, B.; Cheadle, J.; Snell, R.; van den Ouweland, A.; Reuser, A.; Sampson, J.; Halley, D.; van der Sluijs, P. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet., 1998, 7(6), 1053-1057.
[http://dx.doi.org/10.1093/hmg/7.6.1053] [PMID: 9580671]
[12]
Castro, A.F.; Rebhun, J.F.; Clark, G.J.; Quilliam, L.A. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem., 2003, 278(35), 32493-32496.
[http://dx.doi.org/10.1074/jbc.C300226200] [PMID: 12842888]
[13]
Gomez, M.R. The history of tuberous sclerosis complex. Brain Dev., 1995, 17(1), 55-57.
[14]
Vogt, P.D.D.H. On the pathology and pathological anatomy of the various forms of idiocy. Eur. Neurol., 1908, 24, 118-129.
[http://dx.doi.org/10.1159/000316471]
[15]
Kirpicznik, J. Ein Fall von tuberöser Sklerose und gleichzeitigen multiplen Nierengeschwülsten. Virchows Arch. Pathol. Anat. Physiol. Klin. Med., 1910, 202, 358-376.
[http://dx.doi.org/10.1007/BF01993975]
[16]
Moolten, S.E. Hamartial nature of the tuberous sclerosis complex and its bearing on the tumor problem: report of a case with tumor anomaly of the kidney and adenoma sebaceum. Arch. Intern. Med., 1942, 69, 589-623.
[http://dx.doi.org/10.1001/archinte.1942.00200160040005]
[17]
Fryer, A.E.; Chalmers, A.; Connor, J.M.; Fraser, I.; Povey, S.; Yates, A.D.; Yates, J.R.; Osborne, J.P. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet, 1987, 1(8534), 659-661.
[http://dx.doi.org/10.1016/S0140-6736(87)90416-8] [PMID: 2882085]
[18]
Kandt, R.S.; Haines, J.L.; Smith, M.; Northrup, H.; Gardner, R.J.; Short, M.P.; Dumars, K.; Roach, E.S.; Steingold, S.; Wall, S. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat. Genet., 1992, 2(1), 37-41.
[http://dx.doi.org/10.1038/ng0992-37] [PMID: 1303246]
[19]
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(21), 13571-13576.
[http://dx.doi.org/10.1073/pnas.202476899] [PMID: 12271141]
[20]
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(1), 151-162.
[http://dx.doi.org/10.1016/S1097-2765(02)00568-3] [PMID: 12150915]
[21]
Kenerson, H.; Dundon, T.A.; Yeung, R.S. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr. Res., 2005, 57(1), 67-75.
[http://dx.doi.org/10.1203/01.PDR.0000147727.78571.07] [PMID: 15557109]
[22]
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(3), 490-498.
[http://dx.doi.org/10.1002/ana.20784] [PMID: 16453317]
[23]
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(2), 140-151.
[http://dx.doi.org/10.1056/NEJMoa063564] [PMID: 18184959]
[24]
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(1), 218-223.
[http://dx.doi.org/10.1016/j.bbrc.2007.07.011] [PMID: 17658474]
[25]
Kwiatkowski, D.J. Tuberous sclerosis: from tubers to mTOR. Ann. Hum. Genet., 2003, 67(Pt 1), 87-96.
[http://dx.doi.org/10.1046/j.1469-1809.2003.00012.x] [PMID: 12556239]
[26]
Huang, J.; Manning, B.D. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J., 2008, 412(2), 179-190.
[http://dx.doi.org/10.1042/BJ20080281] [PMID: 18466115]
[27]
Tomasoni, R.; Mondino, A. The tuberous sclerosis complex: balancing proliferation and survival. Biochem. Soc. Trans., 2011, 39(2), 466-471.
[http://dx.doi.org/10.1042/BST0390466] [PMID: 21428921]
[28]
Demetriades, C.; Plescher, M.; Teleman, A.A. Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nat. Commun., 2016, 7, 10662.
[http://dx.doi.org/10.1038/ncomms10662] [PMID: 26868506]
[29]
Zacharek, S.J.; Xiong, Y.; Shumway, S.D. Negative regulation of TSC1-TSC2 by mammalian D-type cyclins. Cancer Res., 2005, 65(24), 11354-11360.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-2236] [PMID: 16357142]
[30]
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(51), 51372-51379.
[http://dx.doi.org/10.1074/jbc.M303956200] [PMID: 14551205]
[31]
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 cytoskeleton. J. Biol. Chem., 2002, 277(46), 44180-44186.
[http://dx.doi.org/10.1074/jbc.M207211200] [PMID: 12226091]
[32]
Woodford, M.R.; Sager, R.A.; Marris, E.; Dunn, D.M.; Blanden, A.R.; Murphy, R.L.; Rensing, N.; Shapiro, O.; Panaretou, B.; Prodromou, C.; Loh, S.N.; Gutmann, D.H.; Bourboulia, D.; Bratslavsky, G.; Wong, M.; Mollapour, M. Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO J., 2017, 36(24), 3650-3665.
[http://dx.doi.org/10.15252/embj.201796700] [PMID: 29127155]
[33]
Nellist, M.; Goedbloed, M.A.; de Winter, C.; Verhaaf, B.; Jankie, A.; Reuser, A.J.; van den Ouweland, A.M.; van der Sluijs, P.; Halley, D.J. Identification and characterization of the interaction between tuberin and 14-3-3zeta. J. Biol. Chem., 2002, 277(42), 39417-39424.
[http://dx.doi.org/10.1074/jbc.M204802200] [PMID: 12176984]
[34]
Li, Y.; Inoki, K.; Yeung, R.; Guan, K.L. Regulation of TSC2 by 14-3-3 binding. J. Biol. Chem., 2002, 277(47), 44593-44596.
[http://dx.doi.org/10.1074/jbc.C200510200] [PMID: 12364343]
[35]
Liu, M.Y.; Cai, S.; Espejo, A.; Bedford, M.T.; Walker, C.L. 14-3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site(s). Cancer Res., 2002, 62(22), 6475-6480.
[PMID: 12438239]
[36]
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(3), 234-246.
[http://dx.doi.org/10.1016/j.mrrev.2008.01.001] [PMID: 18291711]
[37]
Jozwiak, J. Hamartin and tuberin: working together for tumour suppression. Int. J. Cancer, 2006, 118(1), 1-5.
[http://dx.doi.org/10.1002/ijc.21542] [PMID: 16206276]
[38]
Momose, S.; Kobayashi, T.; Mitani, H.; Hirabayashi, M.; Ito, K.; Ueda, M.; Nabeshima, Y.; Hino, O. Identification of the coding sequences responsible for Tsc2-mediated tumor suppression using a transgenic rat system. Hum. Mol. Genet., 2002, 11(24), 2997-3006.
[http://dx.doi.org/10.1093/hmg/11.24.2997] [PMID: 12417521]
[39]
Zech, R.; Kiontke, S.; Mueller, U.; Oeckinghaus, A.; Kümmel, D. Structure of the tuberous sclerosis complex 2 (tsc2) n terminus provides insight into complex assembly and tuberous sclerosis pathogenesis. J. Biol. Chem., 2016, 291(38), 20008-20020.
[http://dx.doi.org/10.1074/jbc.M116.732446] [PMID: 27493206]
[40]
York, B.; Lou, D.; Panettieri, R.A., Jr; Krymskaya, V.P.; Vanaman, T.C.; Noonan, D.J. Cross-talk between tuberin, calmodulin, and estrogen signaling pathways. FASEB J., 2005, 19(9), 1202-1204.
[http://dx.doi.org/10.1096/fj.04-3142fje] [PMID: 15851513]
[41]
Plank, T.L.; Yeung, R.S.; Henske, E.P. 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(21), 4766-4770.
[PMID: 9809973]
[42]
Lamb, R.F.; Roy, C.; Diefenbach, T.J.; Vinters, H.V.; Johnson, M.W.; Jay, D.G.; Hall, A. The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat. Cell Biol., 2000, 2(5), 281-287.
[http://dx.doi.org/10.1038/35010550] [PMID: 10806479]
[43]
Santiago Lima, A.J.; Hoogeveen-Westerveld, M.; Nakashima, A.; Maat-Kievit, A.; van den Ouweland, A.; Halley, D.; Kikkawa, U.; Nellist, M. Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex. PLoS One, 2014, 9(4), e93940.
[http://dx.doi.org/10.1371/journal.pone.0093940] [PMID: 24714658]
[44]
Caban, C.; Khan, N.; Hasbani, D.M.; Crino, P.B. Genetics of tuberous sclerosis complex: implications for clinical practice. Appl. Clin. Genet., 2016, 10, 1-8.
[http://dx.doi.org/dx.doi:10.2147/TACG.S90262]
[45]
Mier, P.; Alanis-Lobato, G.; Andrade-Navarro, M.A. Protein-protein interactions can be predicted using coiled coil co-evolution patterns. J. Theor. Biol., 2017, 412, 198-203.
[http://dx.doi.org/10.1016/j.jtbi.2016.11.001] [PMID: 27832945]
[46]
Lupas, A.; Van Dyke, M.; Stock, J. Predicting coiled coils from protein sequences. Science, 1991, 252(5009), 1162-1164.
[http://dx.doi.org/10.1126/science.252.5009.1162] [PMID: 2031185]
[47]
Sun, W.; Zhu, Y.J.; Wang, Z.; Zhong, Q.; Gao, F.; Lou, J.; Gong, W.; Xu, W. Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations. Nat. Commun., 2013, 4, 2135.
[http://dx.doi.org/10.1038/ncomms3135] [PMID: 23857276]
[48]
Dibble, C.C.; Elis, W.; Menon, S.; Qin, W.; Klekota, J.; Asara, J.M.; Finan, P.M.; Kwiatkowski, D.J.; Murphy, L.O.; Manning, B.D. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell, 2012, 47(4), 535-546.
[http://dx.doi.org/10.1016/j.molcel.2012.06.009] [PMID: 22795129]
[49]
Sato, N.; Koinuma, J.; Ito, T.; Tsuchiya, E.; Kondo, S.; Nakamura, Y.; Daigo, Y. Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis. Genes Chromosomes Cancer, 2010, 49(4), 353-367.
[http://dx.doi.org/10.1002/gcc.20747] [PMID: 20095038]
[50]
Capo-Chichi, J.M.; Tcherkezian, J.; Hamdan, F.F.; Décarie, J.C.; Dobrzeniecka, S.; Patry, L.; Nadon, M.A.; Mucha, B.E.; Major, P.; Shevell, M.; Bencheikh, B.O.; Joober, R.; Samuels, M.E.; Rouleau, G.A.; Roux, P.P.; Michaud, J.L. Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. J. Med. Genet., 2013, 50(11), 740-744.
[http://dx.doi.org/10.1136/jmedgenet-2013-101680] [PMID: 23687350]
[51]
Frasa, M.A.; Koessmeier, K.T.; Ahmadian, M.R.; Braga, V.M. Illuminating the functional and structural repertoire of human TBC/RABGAPs. Nat. Rev. Mol. Cell Biol., 2012, 13(2), 67-73.
[http://dx.doi.org/10.1038/nrm3267] [PMID: 22251903]
[52]
Yoshimura, S.; Egerer, J.; Fuchs, E.; Haas, A.K.; Barr, F.A. Functional dissection of Rab GTPases involved in primary cilium formation. J. Cell Biol., 2007, 178(3), 363-369.
[http://dx.doi.org/10.1083/jcb.200703047] [PMID: 17646400]
[53]
Qin, J.; Wang, Z.; Hoogeveen-Westerveld, M.; Shen, G.; Gong, W.; Nellist, M.; Xu, W. Structural basis of the interaction between tuberous sclerosis complex 1 (TSC1) and Tre2-Bub2-Cdc16 domain family member 7 (TBC1D7). J. Biol. Chem., 2016, 291(16), 8591-8601.
[http://dx.doi.org/10.1074/jbc.M115.701870] [PMID: 26893383]
[54]
Gai, Z.; Chu, W.; Deng, W.; Li, W.; Li, H.; He, A.; Nellist, M.; Wu, G. Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region. J. Mol. Cell Biol., 2016, 8(5), 411-425.
[http://dx.doi.org/10.1093/jmcb/mjw001] [PMID: 26798146]
[55]
Inoue, H.; Ndong, M.; Suzuki, T.; Kazami, M.; Uyama, T.; Kobayashi, K.; Tadokoro, T.; Yamamoto, Y. Hamartin-Hsp70 interaction is necessary for Akt-dependent tuberin phosphorylation during heat shock. Biosci. Biotechnol. Biochem., 2009, 73(11), 2488-2493.
[http://dx.doi.org/10.1271/bbb.90489] [PMID: 19897899]
[56]
Natarajan, N.; Shaik, A.; Thiruvenkatam, V. Recombinant tumor suppressor TSC1 differentially interacts with Escherichia coli DnaK and human HSP70. ACS Omega, 2020, 5(30), 19131-19139.
[http://dx.doi.org/10.1021/acsomega.0c02480] [PMID: 32775915]
[57]
Stocker, H.; Radimerski, T.; Schindelholz, B.; Wittwer, F.; Belawat, P.; Daram, P.; Breuer, S.; Thomas, G.; Hafen, E. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol., 2003, 5(6), 559-565.
[http://dx.doi.org/10.1038/ncb995] [PMID: 12766775]
[58]
Saucedo, L.J.; Gao, X.; Chiarelli, D.A.; Li, L.; Pan, D.; Edgar, B.A. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol., 2003, 5(6), 566-571.
[http://dx.doi.org/10.1038/ncb996] [PMID: 12766776]
[59]
Garami, A.; Zwartkruis, F.J.T.; Nobukuni, T.; Joaquin, M.; Roccio, M.; Stocker, H.; Kozma, S.C.; Hafen, E.; Bos, J.L.; Thomas, G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell, 2003, 11(6), 1457-1466.
[http://dx.doi.org/10.1016/S1097-2765(03)00220-X] [PMID: 12820960]
[60]
Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol., 2002, 4(9), 648-657.
[http://dx.doi.org/10.1038/ncb839] [PMID: 12172553]
[61]
Hara, K.; Yonezawa, K.; Weng, Q-P.; Kozlowski, M.T.; Belham, C.; Avruch, J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem., 1998, 273(23), 14484-14494.
[http://dx.doi.org/10.1074/jbc.273.23.14484] [PMID: 9603962]
[62]
Yu, Y.; Li, S.; Xu, X.; Li, Y.; Guan, K.; Arnold, E.; Ding, J. Structural basis for the unique biological function of small GTPase RHEB. J. Biol. Chem., 2005, 280(17), 17093-17100.
[http://dx.doi.org/10.1074/jbc.M501253200] [PMID: 15728574]
[63]
Mizuki, N.; Kimura, M.; Ohno, S.; Miyata, S.; Sato, M.; Ando, H.; Ishihara, M.; Goto, K.; Watanabe, S.; Yamazaki, M.; Ono, A.; Taguchi, S.; Okumura, K.; Nogami, M.; Taguchi, T.; Ando, A.; Inoko, H. Isolation of cDNA and genomic clones of a human Ras-related GTP-binding protein gene and its chromosomal localization to the long arm of chromosome 7, 7q36. Genomics, 1996, 34(1), 114-118.
[http://dx.doi.org/10.1006/geno.1996.0248] [PMID: 8661031]
[64]
Yamagata, K.; Sanders, L.K.; Kaufmann, W.E.; Yee, W.; Barnes, C.A.; Nathans, D.; Worley, P.F. rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J. Biol. Chem., 1994, 269(23), 16333-16339.
[PMID: 8206940]
[65]
Aspuria, P-J.; Tamanoi, F. The Rheb family of GTP-binding proteins. Cell. Signal., 2004, 16(10), 1105-1112.
[http://dx.doi.org/10.1016/j.cellsig.2004.03.019] [PMID: 15240005]
[66]
Zhang, Y.; Gao, X.; Saucedo, L.J.; Ru, B.; Edgar, B.A.; Pan, D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol., 2003, 5(6), 578-581.
[http://dx.doi.org/10.1038/ncb999] [PMID: 12771962]
[67]
Inoki, K.; Li, Y.; Xu, T.; Guan, K.L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev., 2003, 17(15), 1829-1834.
[http://dx.doi.org/10.1101/gad.1110003] [PMID: 12869586]
[68]
Hsu, Y.C.; Chern, J.J.; Cai, Y.; Liu, M.; Choi, K.W. Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature, 2007, 445(7129), 785-788.
[http://dx.doi.org/10.1038/nature05528] [PMID: 17301792]
[69]
Dong, X.; Yang, B.; Li, Y.; Zhong, C.; Ding, J. Molecular basis of the acceleration of the GDP-GTP exchange of human ras homolog enriched in brain by human translationally controlled tumor protein. J. Biol. Chem., 2009, 284(35), 23754-23764.
[http://dx.doi.org/10.1074/jbc.M109.012823] [PMID: 19570981]
[70]
Wang, X.; Fonseca, B.D.; Tang, H.; Liu, R.; Elia, A.; Clemens, M.J.; Bommer, U.A.; Proud, C.G. Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling. J. Biol. Chem., 2008, 283(45), 30482-30492.
[http://dx.doi.org/10.1074/jbc.M803348200] [PMID: 18676370]
[71]
Rehmann, H.; Brüning, M.; Berghaus, C.; Schwarten, M.; Köhler, K.; Stocker, H.; Stoll, R.; Zwartkruis, F.J.; Wittinghofer, A. Biochemical characterisation of TCTP questions its function as a guanine nucleotide exchange factor for Rheb. FEBS Lett., 2008, 582(20), 3005-3010.
[http://dx.doi.org/10.1016/j.febslet.2008.07.057] [PMID: 18692051]
[72]
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(1), 64-80.
[http://dx.doi.org/10.1086/316951] [PMID: 11112665]
[73]
Lewis, J.C.; Thomas, H.V.; Murphy, K.C.; Sampson, J.R. Genotype and psychological phenotype in tuberous sclerosis. J. Med. Genet., 2004, 41(3), 203-207.
[http://dx.doi.org/10.1136/jmg.2003.012757] [PMID: 14985384]
[74]
Ali, M.; Girimaji, S.C.; Markandaya, M.; Shukla, A.K.; Sacchidanand, S.; Kumar, A. Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex. Acta Neurol. Scand., 2005, 111(1), 54-63.
[http://dx.doi.org/10.1111/j.1600-0404.2004.00366.x] [PMID: 15595939]
[75]
Rakowski, S.K.; Winterkorn, E.B.; Paul, E.; Steele, D.J.R.; Halpern, E.F.; Thiele, E.A. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int., 2006, 70(10), 1777-1782.
[http://dx.doi.org/10.1038/sj.ki.5001853] [PMID: 17003820]
[76]
Jóźwiak, S.; Kotulska, K.; Kasprzyk-Obara, J.; Domańska-Pakieła, D.; Tomyn-Drabik, M.; Roberts, P.; Kwiatkowski, D. Clinical and genotype studies of cardiac tumors in 154 patients with tuberous sclerosis complex. Pediatrics, 2006, 118(4), e1146-e1151.
[http://dx.doi.org/10.1542/peds.2006-0504] [PMID: 16940165]
[77]
Au, K.; Williams, A.; Roach, E. et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet. Med., 2007, 9, 88-100.
[78]
Winterkorn, E.B.; Pulsifer, M.B.; Thiele, E.A. Cognitive prognosis of patients with tuberous sclerosis complex. Neurology, 2007, 68(1), 62-64.
[http://dx.doi.org/10.1212/01.wnl.0000250330.44291.54] [PMID: 17200495]
[79]
Langkau, N.; Martin, N.; Brandt, R.; Zügge, K.; Quast, S.; Wiegele, G.; Jauch, A.; Rehm, M.; Kuhl, A.; Mack-Vetter, M.; Zimmerhackl, L.B.; Janssen, B. TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/TSC2 frequency ratios. Eur. J. Pediatr., 2002, 161(7), 393-402.
[http://dx.doi.org/10.1007/s00431-001-0903-7] [PMID: 12111193]
[80]
Au, K.S.; Williams, A.T.; Roach, E.S.; Batchelor, L.; Sparagana, S.P.; Delgado, M.R.; Wheless, J.W.; Baumgartner, J.E.; Roa, B.B.; Wilson, C.M.; Smith-Knuppel, T.K.; Cheung, M.Y.; Whittemore, V.H.; King, T.M.; Northrup, H. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet. Med., 2007, 9(2), 88-100.
[http://dx.doi.org/10.1097/GIM.0b013e31803068c7] [PMID: 17304050]
[81]
Kozlowski, P.; Roberts, P.; Dabora, S.; Franz, D.; Bissler, J.; Northrup, H.; Au, K.S.; Lazarus, R.; Domanska-Pakiela, D.; Kotulska, K.; Jozwiak, S.; Kwiatkowski, D.J. Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum. Genet., 2007, 121(3-4), 389-400.
[http://dx.doi.org/10.1007/s00439-006-0308-9] [PMID: 17287951]
[82]
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(11), 1991-1996.
[http://dx.doi.org/10.1093/hmg/6.11.1991] [PMID: 9302281]
[83]
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(1), 59-68.
[http://dx.doi.org/10.1038/sj.ejhg.5201276] [PMID: 15483652]
[84]
Strizheva, G.D.; Carsillo, T.; Kruger, W.D.; Sullivan, E.J.; Ryu, J.H.; Henske, E.P. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am. J. Respir. Crit. Care Med., 2001, 163(1), 253-258.
[http://dx.doi.org/10.1164/ajrccm.163.1.2005004] [PMID: 11208653]
[85]
Carsillo, T.; Astrinidis, A.; Henske, E.P. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc. Natl. Acad. Sci. USA, 2000, 97(11), 6085-6090.
[http://dx.doi.org/10.1073/pnas.97.11.6085] [PMID: 10823953]
[86]
Vézina, C.; Kudelski, A.; Sehgal, S.N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo), 1975, 28(10), 721-726.
[http://dx.doi.org/10.7164/antibiotics.28.721] [PMID: 1102508]
[87]
Collier, S.J. Immunosuppressive drugs. Curr. Opin. Immunol., 1989-1990, 2(6), 854-858.
[http://dx.doi.org/10.1016/0952-7915(89)90169-6] [PMID: 2484794]
[88]
Kunz, J.; Henriquez, R.; Schneider, U.; Deuter-Reinhard, M.; Movva, N.R.; Hall, M.N. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell, 1993, 73(3), 585-596.
[http://dx.doi.org/10.1016/0092-8674(93)90144-F] [PMID: 8387896]
[89]
Helliwell, S.B.; Wagner, P.; Kunz, J.; Deuter-Reinhard, M.; Henriquez, R.; Hall, M.N. TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol. Biol. Cell, 1994, 5(1), 105-118.
[http://dx.doi.org/10.1091/mbc.5.1.105] [PMID: 8186460]
[90]
Yonezawa, K.; Tokunaga, C.; Oshiro, N.; Yoshino, K. Raptor, a binding partner of target of rapamycin. Biochem. Biophys. Res. Commun., 2004, 313(2), 437-441.
[http://dx.doi.org/10.1016/j.bbrc.2003.07.018] [PMID: 14684181]
[91]
Sarbassov, D.D.; Ali, S.M.; Sengupta, S.; Sheen, J-H.; Hsu, P.P.; Bagley, A.F.; Markhard, A.L.; Sabatini, D.M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell, 2006, 22(2), 159-168.
[http://dx.doi.org/10.1016/j.molcel.2006.03.029] [PMID: 16603397]
[92]
Loewith, R.; Jacinto, E.; Wullschleger, S.; Lorberg, A.; Crespo, J.L.; Bonenfant, D.; Oppliger, W.; Jenoe, P.; Hall, M.N. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell, 2002, 10(3), 457-468.
[http://dx.doi.org/10.1016/S1097-2765(02)00636-6] [PMID: 12408816]
[93]
Zhang, H.; Bajraszewski, N.; Wu, E.; Wang, H.; Moseman, A.P.; Dabora, S.L.; Griffin, J.D.; Kwiatkowski, D.J. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J. Clin. Invest., 2007, 117(3), 730-738.
[http://dx.doi.org/10.1172/JCI28984] [PMID: 17290308]
[94]
Harrington, L.S.; Findlay, G.M.; Gray, A.; Tolkacheva, T.; Wigfield, S.; Rebholz, H.; Barnett, J.; Leslie, N.R.; Cheng, S.; Shepherd, P.R.; Gout, I.; Downes, C.P.; Lamb, R.F. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol., 2004, 166(2), 213-223.
[http://dx.doi.org/10.1083/jcb.200403069] [PMID: 15249583]
[95]
Shah, O.J.; Wang, Z.; Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol., 2004, 14(18), 1650-1656.
[http://dx.doi.org/10.1016/j.cub.2004.08.026] [PMID: 15380067]
[96]
Krueger, D.A.; Care, M.M.; Agricola, K.; Tudor, C.; Mays, M.; Franz, D.N. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology, 2013, 80(6), 574-580.
[http://dx.doi.org/10.1212/WNL.0b013e3182815428] [PMID: 23325902]
[97]
Darling, T.N. Topical sirolimus to treat tuberous sclerosis complex (TSC). JAMA Dermatol., 2018, 154(7), 761-762.
[http://dx.doi.org/10.1001/jamadermatol.2018.0465] [PMID: 29800103]
[98]
Manning, B.D. The role of target of rapamycin signaling in tuberous sclerosis complex. In:Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics; Wiley and Sons: Hoboken, 2010.
[99]
Basso, A.D.; Mirza, A.; Liu, G.; Long, B.J.; Bishop, W.R.; Kirschmeier, P. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J. Biol. Chem., 2005, 280(35), 31101-31108.
[http://dx.doi.org/10.1074/jbc.M503763200] [PMID: 16006564]
[100]
Ding, H.; McDonald, J.S.; Yun, S.; Schneider, P.A.; Peterson, K.L.; Flatten, K.S.; Loegering, D.A.; Oberg, A.L.; Riska, S.M.; Huang, S.; Sinicrope, F.A.; Adjei, A.A.; Karp, J.E.; Meng, X.W.; Kaufmann, S.H. Farnesyltransferase inhibitor tipifarnib inhibits Rheb prenylation and stabilizes Bax in acute myelogenous leukemia cells. Haematologica, 2014, 99(1), 60-69.
[http://dx.doi.org/10.3324/haematol.2013.087734] [PMID: 23996484]
[101]
Wang, J.; Yao, X.; Huang, J. New tricks for human farnesyltransferase inhibitor: cancer and beyond. MedChemComm, 2017, 8(5), 841-854.
[http://dx.doi.org/10.1039/C7MD00030H] [PMID: 30108801]
[102]
Baines, A.T.; Xu, D.; Der, C.J. Inhibition of Ras for cancer treatment: the search continues. Future Med. Chem., 2011, 3(14), 1787-1808.
[http://dx.doi.org/10.4155/fmc.11.121] [PMID: 22004085]
[103]
Ellis, C.A.; Vos, M.D.; Howell, H.; Vallecorsa, T.; Fults, D.W.; Clark, G.J. Rig is a novel Ras-related protein and potential neural tumor suppressor. Proc. Natl. Acad. Sci. USA, 2002, 99(15), 9876-9881.
[http://dx.doi.org/10.1073/pnas.142193799] [PMID: 12107278]