TSC1

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Tuberozna skleroza 1
Identifikatori
SimboliTSC1; LAM; TSC
Vanjski IDOMIM: 605284 MGI: 1929183 HomoloGene: 314 GeneCards: TSC1 Gene
Ontologija gena
Molekulska funkcija • proteinsko vezivanje
• Aktivnost GTPaznog regulatora
• GTPazno aktivirajuće proteinsko vezivanje
Ćelijska komponenta • citoplazma
• citozol
• aktinski filament
Biološki proces • razviće bubrega
• zatvaranje neuralnih tubula
• regulacija ćelijsko-matriksne adhezije
Pregled RNK izražavanja
podaci
Ortolozi
VrstaČovekMiš
Entrez724864930
EnsemblENSG00000165699ENSMUSG00000026812
UniProtQ92574Q9EP53
Ref. Sekv. (iRNK)NM_000368NM_001289575
Ref. Sekv. (protein)NP_000359NP_001276504
Lokacija (UCSC)Chr 9:
135.77 - 135.82 Mb		Chr 2:
28.64 - 28.69 Mb
PubMed pretraga[1][2]

Hamartin takođe poznat kao tuberozno sklerozni protein 1 je kod ljudi kodiran TSC1 genom.[1]

Funkcija

Ovaj periferno membranski protein učestvuje u supresiji tumora. On formira kompleks sa TSC2 koji reguliše mTORC1 signalizaciju. Smatra se isto tako učestvuje u vezikularnom trasportu i dokingu.

Klinički značaj

Defekti ovog gena mogu da uzrokuju tuberoznu sklerozu, usled neadequatnog delovanja hamartin-tuberinskog kompleksa. Defekti TSC1 proteina takođe mogu a uzrokuju fokalnu kortikalnu displaziju. Smatra se da TSC1 doprinosi zaštiti moždanih neurona u CA3 regionu hipokampusa od efekata moždanog udara.[2]

Interakcije

TSC1 formira interakcije sa:

  • AKT1,[3][4]
  • NEFL,[5]
  • PLK1,[6] and
  • TSC2.[4][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]

Povezano

  • Tuberozni sklerozni protein

Reference

  1. ↑ „Entrez Gene: TSC1 tuberous sclerosis 1”. 
  2. ↑ 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 (March 2013). „Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy”. Nat. Med. 19 (3): 351–7. DOI:10.1038/nm.3097. PMID 23435171. 
  3. ↑ Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (2004). „Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase”. Proc. Natl. Acad. Sci. U.S.A. 101 (37): 13489-94. DOI:10.1073/pnas.0405659101. PMC 518784. PMID 15342917. 
  4. ↑ 4,0 4,1 Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (2002). „Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin”. J. Biol. Chem. 277 (38): 35364-70. DOI:10.1074/jbc.M205838200. PMID 12167664. 
  5. ↑ Haddad LA, Smith N, Bowser M, Niida Y, Murthy V, Gonzalez-Agosti C, Ramesh V (2002). „The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton”. J. Biol. Chem. 277 (46): 44180-6. DOI:10.1074/jbc.M207211200. PMID 12226091. 
  6. ↑ 6,0 6,1 Astrinidis A, Senapedis W, Henske EP (2006). „Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner”. Hum. Mol. Genet. 15 (2): 287-97. DOI:10.1093/hmg/ddi444. PMID 16339216. 
  7. ↑ Hodges AK, Li S, Maynard J, Parry L, Braverman R, Cheadle JP, DeClue JE, Sampson JR (2001). „Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin”. Hum. Mol. Genet. 10 (25): 2899-905. DOI:10.1093/hmg/10.25.2899. PMID 11741833. 
  8. ↑ Aicher LD, Campbell JS, Yeung RS (2001). „Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis”. J. Biol. Chem. 276 (24): 21017-21. DOI:10.1074/jbc.C100136200. PMID 11290735. 
  9. ↑ 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 (1998). „Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products”. Hum. Mol. Genet. 7 (6): 1053-7. DOI:10.1093/hmg/7.6.1053. PMID 9580671. 
  10. ↑ Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ (2002). „Identification and characterization of the interaction between tuberin and 14-3-3zeta”. J. Biol. Chem. 277 (42): 39417-24. DOI:10.1074/jbc.M204802200. PMID 12176984. 
  11. ↑ Li Y, Inoki K, Guan KL (2004). „Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity”. Mol. Cell. Biol. 24 (18): 7965-75. DOI:10.1128/MCB.24.18.7965-7975.2004. PMC 515062. PMID 15340059. 
  12. ↑ Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (2003). „The tuberin-hamartin complex negatively regulates beta-catenin signaling activity”. J. Biol. Chem. 278 (8): 5947-51. DOI:10.1074/jbc.C200473200. PMID 12511557. 
  13. ↑ Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (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. 
  14. ↑ Cai SL, Tee AR, Short JD, Bergeron JM, Kim J, Shen J, Guo R, Johnson CL, Kiguchi K, Walker CL (2006). „Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning”. J. Cell Biol. 173 (2): 279-89. DOI:10.1083/jcb.200507119. PMC 2063818. PMID 16636147. 
  15. ↑ Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J (2006). „Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway”. J. Biol. Chem. 281 (52): 40242-51. DOI:10.1074/jbc.M608116200. PMID 17077083. 
  16. ↑ Inoki K, Zhu T, Guan KL (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. 
  17. ↑ Nellist M, Burgers PC, van den Ouweland AM, Halley DJ, Luider TM (2005). „Phosphorylation and binding partner analysis of the TSC1-TSC2 complex”. Biochem. Biophys. Res. Commun. 333 (3): 818-26. DOI:10.1016/j.bbrc.2005.05.175. PMID 15963462. 
  18. ↑ Goncharova EA, Goncharov DA, Spaits M, Noonan DJ, Talovskaya E, Eszterhas A, Krymskaya VP (2006). „Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: Role for tumor suppressor TSC2”. Am. J. Respir. Cell Mol. Biol. 34 (5): 561-72. DOI:10.1165/rcmb.2005-0300OC. PMC 2644221. PMID 16424383. 
  19. ↑ Astrinidis A, Senapedis W, Coleman TR, Henske EP (2003). „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. 278 (51): 51372-9. DOI:10.1074/jbc.M303956200. PMID 14551205. 
  20. ↑ Nellist M, Verhaaf B, Goedbloed MA, Reuser AJ, van den Ouweland AM, Halley DJ (2001). „TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex”. Hum. Mol. Genet. 10 (25): 2889-98. DOI:10.1093/hmg/10.25.2889. PMID 11741832. 
  21. ↑ Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, Halley DJ, Sampson JR, Wienecke R, DeClue JE (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. 
  22. ↑ Murthy V, Haddad LA, Smith N, Pinney D, Tyszkowski R, Brown D, Ramesh V (2000). „Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney”. Am. J. Physiol. Renal Physiol. 278 (5): F737-46. PMID 10807585. 
  23. ↑ Miloloza A, Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschläger M (2000). „The TSC1 gene product, hamartin, negatively regulates cell proliferation”. Hum. Mol. Genet. 9 (12): 1721-7. DOI:10.1093/hmg/9.12.1721. PMID 10915759. 

Literatura

  • Hengstschläger M (2002). „Tuberous sclerosis complex genes: from flies to human genetics.”. Arch. Dermatol. Res. 293 (8): 383–6. DOI:10.1007/s004030100250. PMID 11686512. 
  • Ramesh V (2004). „Aspects of tuberous sclerosis complex (TSC) protein function in the brain.”. Biochem. Soc. Trans. 31 (Pt 3): 579–83. DOI:10.1042/BST0310579. PMID 12773159. 
  • Knowles MA, Hornigold N, Pitt E (2004). „Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours.”. Biochem. Soc. Trans. 31 (Pt 3): 597–602. DOI:10.1042/BST0310597. PMID 12773163. 
  • Ellisen LW (2007). „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 (2007). „Giant cells: contradiction to two-hit model of tuber formation?”. Cell. Mol. Neurobiol. 27 (2): 251–61. DOI:10.1007/s10571-006-9106-0. PMID 16897363. 
  • Nagase T, Seki N, Ishikawa K, et al. (1997). „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 Res. 3 (5): 321–9, 341–54. DOI:10.1093/dnares/3.5.321. PMID 9039502. 
  • van Slegtenhorst M, de Hoogt R, Hermans C, et al. (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, et al. (1997). „Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.”. Hum. Mol. Genet. 6 (12): 2155–61. DOI:10.1093/hmg/6.12.2155. PMID 9328481. 
  • van Slegtenhorst M, Nellist M, Nagelkerken B, et al. (1998). „Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products.”. Hum. Mol. Genet. 7 (6): 1053–7. DOI:10.1093/hmg/7.6.1053. PMID 9580671. 
  • Plank TL, Yeung RS, Henske EP (1998). „Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles.”. Cancer Res. 58 (21): 4766–70. PMID 9809973. 
  • Kwiatkowska J, Jozwiak S, Hall F, et al. (1999). „Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance.”. Ann. Hum. Genet. 62 (Pt 4): 277–85. DOI:10.1046/j.1469-1809.1998.6240277.x. PMID 9924605. 
  • van Slegtenhorst M, Verhoef S, Tempelaars A, et al. (1999). „Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.”. J. Med. Genet. 36 (4): 285–9. DOI:10.1136/jmg.36.4.285. PMC 1734341. PMID 10227394. 
  • Niida Y, Lawrence-Smith N, Banwell A, et al. (2000). „Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.”. Hum. Mutat. 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, et al. (2000). „Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex.”. J. Hum. Genet. 44 (6): 391–6. DOI:10.1007/s100380050185. PMID 10570911. 
  • Nellist M, van Slegtenhorst MA, Goedbloed M, et al. (2000). „Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin.”. J. Biol. Chem. 274 (50): 35647–52. DOI:10.1074/jbc.274.50.35647. PMID 10585443. 
  • Yamashita Y, Ono J, Okada S, et al. (2000). „Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations.”. Am. J. Med. Genet. 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, et al. (2000). „The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho.”. Nat. Cell Biol. 2 (5): 281–7. DOI:10.1038/35010550. PMID 10806479. 
  • Miloloza A, Rosner M, Nellist M, et al. (2000). „The TSC1 gene product, hamartin, negatively regulates cell proliferation.”. Hum. Mol. Genet. 9 (12): 1721–7. DOI:10.1093/hmg/9.12.1721. PMID 10915759. 
  • Murthy V, Stemmer-Rachamimov AO, Haddad LA, et al. (2001). „Developmental expression of the tuberous sclerosis proteins tuberin and hamartin.”. Acta Neuropathol. 101 (3): 202–10. PMID 11307618. 
  • Catania MG, Mischel PS, Vinters HV (2001). „Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B.”. J. Neuropathol. Exp. Neurol. 60 (7): 711–23. PMID 11444800. 

Vanjske veze

  • GeneReviews/NIH/NCBI/UW entry on Tuberous Sclerosis Complex or Bourneville Disease
  • p
  • r
  • u
Aktivirajući protein GTPaze
Monomerni
Heterotrimeni
Faktor razmene guanin nukleotida
EIF2B • Son of Sevenless • Ras-GRF1

FGD: FGD1 • FGD2 • FGD3 • FGD4

ALS2 • SIL1 • IQSEC2
Drugi
B trdu: peptidi (nrpl/grfl/cytl/horl), receptori (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd, signalni putevi (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)