TSC1
(Preusmjereno sa Hamartin)
Protein 1 gomoljaste skleroze (TSC1), poznat i kao hamartin, je protein koji je kod ljudi kodiran genom TSC1.[5]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 1.164 aminokiseline, а molekulska težina 129.767 Da.[6]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MAQQANVGEL | LAMLDSPMLG | VRDDVTAVFK | ENLNSDRGPM | LVNTLVDYYL | ||||
| ETSSQPALHI | LTTLQEPHDK | HLLDRINEYV | GKAATRLSIL | SLLGHVIRLQ | ||||
| PSWKHKLSQA | PLLPSLLKCL | KMDTDVVVLT | TGVLVLITML | PMIPQSGKQH | ||||
| LLDFFDIFGR | LSSWCLKKPG | HVAEVYLVHL | HASVYALFHR | LYGMYPCNFV | ||||
| SFLRSHYSMK | ENLETFEEVV | KPMMEHVRIH | PELVTGSKDH | ELDPRRWKRL | ||||
| ETHDVVIECA | KISLDPTEAS | YEDGYSVSHQ | ISARFPHRSA | DVTTSPYADT | ||||
| QNSYGCATST | PYSTSRLMLL | NMPGQLPQTL | SSPSTRLITE | PPQATLWSPS | ||||
| MVCGMTTPPT | SPGNVPPDLS | HPYSKVFGTT | AGGKGTPLGT | PATSPPPAPL | ||||
| CHSDDYVHIS | LPQATVTPPR | KEERMDSARP | CLHRQHHLLN | DRGSEEPPGS | ||||
| KGSVTLSDLP | GFLGDLASEE | DSIEKDKEEA | AISRELSEIT | TAEAEPVVPR | ||||
| GGFDSPFYRD | SLPGSQRKTH | SAASSSQGAS | VNPEPLHSSL | DKLGPDTPKQ | ||||
| AFTPIDLPCG | SADESPAGDR | ECQTSLETSI | FTPSPCKIPP | PTRVGFGSGQ | ||||
| PPPYDHLFEV | ALPKTAHHFV | IRKTEELLKK | AKGNTEEDGV | PSTSPMEVLD | ||||
| RLIQQGADAH | SKELNKLPLP | SKSVDWTHFG | GSPPSDEIRT | LRDQLLLLHN | ||||
| QLLYERFKRQ | QHALRNRRLL | RKVIKAAALE | EHNAAMKDQL | KLQEKDIQMW | ||||
| KVSLQKEQAR | YNQLQEQRDT | MVTKLHSQIR | QLQHDREEFY | NQSQELQTKL | ||||
| EDCRNMIAEL | RIELKKANNK | VCHTELLLSQ | VSQKLSNSES | VQQQMEFLNR | ||||
| QLLVLGEVNE | LYLEQLQNKH | SDTTKEVEMM | KAAYRKELEK | NRSHVLQQTQ | ||||
| RLDTSQKRIL | ELESHLAKKD | HLLLEQKKYL | EDVKLQARGQ | LQAAESRYEA | ||||
| QKRITQVFEL | EILDLYGRLE | KDGLLKKLEE | EKAEAAEAAE | ERLDCCNDGC | ||||
| SDSMVGHNEE | ASGHNGETKT | PRPSSARGSS | GSRGGGGSSS | SSSELSTPEK | ||||
| PPHQRAGPFS | SRWETTMGEA | SASIPTTVGS | LPSSKSFLGM | KARELFRNKS | ||||
| ESQCDEDGMT | SSLSESLKTE | LGKDLGVEAK | IPLNLDGPHP | SPPTPDSVGQ | ||||
| LHIMDYNETH | HEHS |
Funkcija
urediTSC1 funkcionira kao košaperon koji inhibira aktivnost šaperonskih ATPaza šaperona Hsp90 (protein toplotnog šoka-90) i usporava njegov ciklus praćenja. Tsc1 funkcionira kao posrednik Hsp90 u praćenju klijenata kinaze i nekinaze, uključujući Tsc2, čime se sprječava njihova sveprisutna i degradacija u proteasomu.[7] TSC1, TSC2 i TBC1D7 je kompleks više proteina poznat i kao kompleks TSC. Ovaj kompleks negativno regulira signalizaciju mTORC1, funkcionirajući kao protein koji aktivira GTPazu (GAP) za malu GTPazu Rheb, bitan aktivator mTORC1. TSC kompleks je uključen u supresiju tumora.
Klinički značaj
urediDefekti ovog gena mogu uzrokovati tuberoznu sklerozu, zbog funkcionalnog oštećenja kompleksa TSC. Oni u TSC1 mogu biti i uzrok fokusne korteksne displazije . TSC1 može biti uključen u zaštitu moždanih neurona u CA3 regiji hipokampusa od posljedica moždanog udara.[8]
Interakcije
urediPokazano je da TSC1 stupa u interakciju sa:
Također pogledajte
urediReference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000165699 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026812 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: TSC1 tuberous sclerosis 1".
- ^ "UniProt, Q92574". Pristupljeno 12. 9. 2021.
- ^ a b c Woodford MR, Sager RA, Marris E, Dunn DM, Blanden AR, Murphy RL, Rensing N, Shapiro O, Panaretou B, Prodromou C, Loh SN, Gutmann DH, Bourboulia D, Bratslavsky G, Wong M, Mollapour M (decembar 2017). "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients". The EMBO Journal. 36 (24): 3650–3665. doi:10.15252/embj.201796700. PMC 5730846. PMID 29127155.
- ^ Papadakis M, Hadley G, Xilouri M, Hoyte LC, Nagel S, McMenamin MM, Tsaknakis G, Watt SM, Drakesmith CW, Chen R, Wood MJ, Zhao Z, Kessler B, Vekrellis K, Buchan AM (mart 2013). "Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy". Nature Medicine. 19 (3): 351–7. doi:10.1038/nm.3097. PMC 3744134. PMID 23435171.
- ^ Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (septembar 2004). "Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase". Proceedings of the National Academy of Sciences of the United States of America. 101 (37): 13489–94. Bibcode:2004PNAS..10113489R. doi:10.1073/pnas.0405659101. PMC 518784. PMID 15342917.
- ^ a b Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (septembar 2002). "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". The Journal of Biological Chemistry. 277 (38): 35364–70. doi:10.1074/jbc.M205838200. PMID 12167664.
- ^ Haddad LA, Smith N, Bowser M, Niida Y, Murthy V, Gonzalez-Agosti C, Ramesh V (novembar 2002). "The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton". The Journal of Biological Chemistry. 277 (46): 44180–6. doi:10.1074/jbc.M207211200. PMID 12226091.
- ^ a b Astrinidis A, Senapedis W, Henske EP (januar 2006). "Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner". Human Molecular Genetics. 15 (2): 287–97. doi:10.1093/hmg/ddi444. PMID 16339216.
- ^ Hodges AK, Li S, Maynard J, Parry L, Braverman R, Cheadle JP, DeClue JE, Sampson JR (decembar 2001). "Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin". Human Molecular Genetics. 10 (25): 2899–905. doi:10.1093/hmg/10.25.2899. PMID 11741833.
- ^ Aicher LD, Campbell JS, Yeung RS (juni 2001). "Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis". The Journal of Biological Chemistry. 276 (24): 21017–21. doi:10.1074/jbc.C100136200. PMID 11290735.
- ^ 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 (juni 1998). "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products". Human Molecular Genetics. 7 (6): 1053–7. doi:10.1093/hmg/7.6.1053. PMID 9580671.
- ^ Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ (oktobar 2002). "Identification and characterization of the interaction between tuberin and 14-3-3zeta". The Journal of Biological Chemistry. 277 (42): 39417–24. doi:10.1074/jbc.M204802200. PMID 12176984.
- ^ Li Y, Inoki K, Guan KL (septembar 2004). "Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity". Molecular and Cellular Biology. 24 (18): 7965–75. doi:10.1128/MCB.24.18.7965-7975.2004. PMC 515062. PMID 15340059.
- ^ Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (februar 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". The Journal of Biological Chemistry. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557.
- ^ Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (april 2005). "Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis". Cell. 121 (2): 179–93. doi:10.1016/j.cell.2005.02.031. PMID 15851026. S2CID 18663447.
- ^ Cai SL, Tee AR, Short JD, Bergeron JM, Kim J, Shen J, Guo R, Johnson CL, Kiguchi K, Walker CL (april 2006). "Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning". The Journal of Cell Biology. 173 (2): 279–89. doi:10.1083/jcb.200507119. PMC 2063818. PMID 16636147.
- ^ Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J (decembar 2006). "Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway". The Journal of Biological Chemistry. 281 (52): 40242–51. doi:10.1074/jbc.M608116200. PMID 17077083.
- ^ Inoki K, Zhu T, Guan KL (novembar 2003). "TSC2 mediates cellular energy response to control cell growth and survival". Cell. 115 (5): 577–90. doi:10.1016/S0092-8674(03)00929-2. PMID 14651849. S2CID 18173817.
- ^ Nellist M, Burgers PC, van den Ouweland AM, Halley DJ, Luider TM (august 2005). "Phosphorylation and binding partner analysis of the TSC1-TSC2 complex". Biochemical and Biophysical Research Communications. 333 (3): 818–26. doi:10.1016/j.bbrc.2005.05.175. PMID 15963462.
- ^ Goncharova EA, Goncharov DA, Spaits M, Noonan DJ, Talovskaya E, Eszterhas A, Krymskaya VP (maj 2006). "Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: Role for tumor suppressor TSC2". American Journal of Respiratory Cell and Molecular Biology. 34 (5): 561–72. doi:10.1165/rcmb.2005-0300OC. PMC 2644221. PMID 16424383.
- ^ Astrinidis A, Senapedis W, Coleman TR, Henske EP (decembar 2003). "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B". The Journal of Biological Chemistry. 278 (51): 51372–9. doi:10.1074/jbc.M303956200. PMID 14551205.
- ^ Nellist M, Verhaaf B, Goedbloed MA, Reuser AJ, van den Ouweland AM, Halley DJ (decembar 2001). "TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex". Human Molecular Genetics. 10 (25): 2889–98. doi:10.1093/hmg/10.25.2889. PMID 11741832.
- ^ Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, Halley DJ, Sampson JR, Wienecke R, DeClue JE (decembar 2000). "The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination". Oncogene. 19 (54): 6306–16. doi:10.1038/sj.onc.1204009. PMID 11175345.
- ^ Murthy V, Haddad LA, Smith N, Pinney D, Tyszkowski R, Brown D, Ramesh V (maj 2000). "Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney". American Journal of Physiology. Renal Physiology. 278 (5): F737–46. doi:10.1152/ajprenal.2000.278.5.F737. PMID 10807585.
- ^ Miloloza A, Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschläger M (juli 2000). "The TSC1 gene product, hamartin, negatively regulates cell proliferation". Human Molecular Genetics. 9 (12): 1721–7. doi:10.1093/hmg/9.12.1721. PMID 10915759.
Dopunska literatura
uredi- Hengstschläger M (august 2001). "Tuberous sclerosis complex genes: from flies to human genetics". Archives of Dermatological Research. 293 (8): 383–6. doi:10.1007/s004030100250. PMID 11686512. S2CID 35702323.
- Ramesh V (juni 2003). "Aspects of tuberous sclerosis complex (TSC) protein function in the brain". Biochemical Society Transactions. 31 (Pt 3): 579–83. doi:10.1042/BST0310579. PMID 12773159.
- Knowles MA, Hornigold N, Pitt E (juni 2003). "Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours". Biochemical Society Transactions. 31 (Pt 3): 597–602. doi:10.1042/BST0310597. PMID 12773163.
- Ellisen LW (novembar 2005). "Growth control under stress: mTOR regulation through the REDD1-TSC pathway". Cell Cycle. 4 (11): 1500–02. doi:10.4161/cc.4.11.2139. PMID 16258273.
- Jozwiak J, Jozwiak S (mart 2007). "Giant cells: contradiction to two-hit model of tuber formation?". Cellular and Molecular Neurobiology. 27 (2): 251–61. doi:10.1007/s10571-006-9106-0. PMID 16897363. S2CID 31624726.
- Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N (oktobar 1996). "Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain". DNA Research. 3 (5): 321–9, 341–54. doi:10.1093/dnares/3.5.321. PMID 9039502.
- 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 RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ (august 1997). "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34". Science. 277 (5327): 805–8. doi:10.1126/science.277.5327.805. PMID 9242607.
- Jones AC, Daniells CE, Snell RG, Tachataki M, Idziaszczyk SA, Krawczak M, Sampson JR, Cheadle JP (novembar 1997). "Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis". Human Molecular Genetics. 6 (12): 2155–61. doi:10.1093/hmg/6.12.2155. PMID 9328481.
- 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 (juni 1998). "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products". Human Molecular Genetics. 7 (6): 1053–7. doi:10.1093/hmg/7.6.1053. PMID 9580671.
- Plank TL, Yeung RS, Henske EP (novembar 1998). "Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles". Cancer Research. 58 (21): 4766–70. PMID 9809973.
- Kwiatkowska J, Jozwiak S, Hall F, Henske EP, Haines JL, McNamara P, Braiser J, Wigowska-Sowinska J, Kasprzyk-Obara J, Short MP, Kwiatkowski DJ (juli 1998). "Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance". Annals of Human Genetics. 62 (Pt 4): 277–85. doi:10.1046/j.1469-1809.1998.6240277.x. PMID 9924605. S2CID 12987381.
- 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 (april 1999). "Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation". Journal of Medical Genetics. 36 (4): 285–9. doi:10.1136/jmg.36.4.285 (neaktivno 31. 5. 2021). PMC 1734341. PMID 10227394.CS1 održavanje: DOI nije aktivan od 2021 (link)
- Niida Y, Lawrence-Smith N, Banwell A, Hammer E, Lewis J, Beauchamp RL, Sims K, Ramesh V, Ozelius L (2000). "Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis". Human Mutation. 14 (5): 412–22. doi:10.1002/(SICI)1098-1004(199911)14:5<412::AID-HUMU7>3.0.CO;2-K. PMID 10533067.
- Zhang H, Nanba E, Yamamoto T, Ninomiya H, Ohno K, Mizuguchi M, Takeshita K (2000). "Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex". Journal of Human Genetics. 44 (6): 391–6. doi:10.1007/s100380050185. PMID 10570911.
- Nellist M, van Slegtenhorst MA, Goedbloed M, van den Ouweland AM, Halley DJ, van der Sluijs P (decembar 1999). "Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin". The Journal of Biological Chemistry. 274 (50): 35647–52. doi:10.1074/jbc.274.50.35647. PMID 10585443.
- Yamashita Y, Ono J, Okada S, Wataya-Kaneda M, Yoshikawa K, Nishizawa M, Hirayama Y, Kobayashi E, Seyama K, Hino O (januar 2000). "Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations". American Journal of Medical Genetics. 90 (2): 123–6. doi:10.1002/(SICI)1096-8628(20000117)90:2<123::AID-AJMG7>3.0.CO;2-L. PMID 10607950.
- Lamb RF, Roy C, Diefenbach TJ, Vinters HV, Johnson MW, Jay DG, Hall A (maj 2000). "The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho". Nature Cell Biology. 2 (5): 281–7. doi:10.1038/35010550. PMID 10806479. S2CID 25353057.
- Miloloza A, Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschläger M (juli 2000). "The TSC1 gene product, hamartin, negatively regulates cell proliferation". Human Molecular Genetics. 9 (12): 1721–7. doi:10.1093/hmg/9.12.1721. PMID 10915759.
- Murthy V, Stemmer-Rachamimov AO, Haddad LA, Roy JE, Cutone AN, Beauchamp RL, Smith N, Louis DN, Ramesh V (mart 2001). "Developmental expression of the tuberous sclerosis proteins tuberin and hamartin". Acta Neuropathologica. 101 (3): 202–10. doi:10.1007/s004010000269. PMID 11307618. S2CID 8067136.
- Catania MG, Mischel PS, Vinters HV (juli 2001). "Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B". Journal of Neuropathology and Experimental Neurology. 60 (7): 711–23. doi:10.1093/jnen/60.7.711. PMID 11444800.