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Gene Review

TSC1  -  tuberous sclerosis 1

Homo sapiens

Synonyms: Hamartin, KIAA0243, LAM, TSC, Tuberous sclerosis 1 protein, ...
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Disease relevance of TSC1


Psychiatry related information on TSC1


High impact information on TSC1


Chemical compound and disease context of TSC1


Biological context of TSC1


Anatomical context of TSC1

  • IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb [22].
  • The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton [23].
  • CONCLUSION: TSC1 genes are aberrantly expressed in human breast cancer cell lines and breast tumour tissues and their promoters are seen to be methylated in breast tumour tissues [24].
  • Here, we performed microarray analyses of the gene expression response to overexpressed TSC1 or TSC2 in HeLa cells [25].
  • We used a recently described DHPLC assay allowing the efficient detection of mutations in TSC1 to analyze the DNA extracted from a chorion villus sample in order to perform a prenatal diagnosis for TSC [26].

Associations of TSC1 with chemical compounds

  • Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation [27].
  • Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G2/M arrest and during the G2/M phase of a normal cell cycle [28].
  • Here we show that tuberin-hamartin heterodimers block protein kinase C (PKC)/MAPK- and phosphatidic acid-mediated signaling toward mammalian target of rapamycin-dependent targets [29].
  • Additionally, either Tsc1/2 or Tor1 are required for growth on a poor nitrogen source such as proline [30].
  • Mutants lacking Tsc1 or Tsc2 are highly sensitive to rapamycin under poor nitrogen conditions, suggesting that the function of Tor1 under such conditions is sensitive to rapamycin [30].

Physical interactions of TSC1


Regulatory relationships of TSC1


Other interactions of TSC1

  • This study provides new insights into the cellular roles of TSC proteins and initiates a discussion of whether separable functions of these proteins might be associated with the clinical differences of TSC1- and TSC2-associated disease [39].
  • Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 [40].
  • Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target [41].
  • Rheb fills a GAP between TSC and TOR [42].
  • We also demonstrate that hamartin interacts with CDK1 and cyclin B1 [43].

Analytical, diagnostic and therapeutic context of TSC1

  • Here, to analyze the function of the Tsc1 product, we established a line of Tsc1 (TSC1 homologue) knockout mouse by gene targeting [44].
  • Using methylation specific PCR, the TSC1 promoter was found to be heavily methylated in ZR751, MDA MB 435, and BT549, but not in MCF-7 which expressed highly level of hamartin [24].
  • In this study, we performed two-dimensional gel electrophoresis with subsequent mass spectrometrical identification of protein spots after overexpression of TSC1 or TSC2 [45].
  • Western blot analyses confirmed the deregulation of 14-3-3 proteins upon ectopic overexpression of TSC1 and TSC2 [46].
  • Investigations of TSC1 and TSC2 in a number of model organisms and cell-culture systems have provided new insights into the mechanisms through which these roles are effected [47].


  1. Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Astrinidis, A., Senapedis, W., Henske, E.P. Hum. Mol. Genet. (2006) [Pubmed]
  2. The TSC1 gene product, hamartin, negatively regulates cell proliferation. Miloloza, A., Rosner, M., Nellist, M., Halley, D., Bernaschek, G., Hengstschläger, M. Hum. Mol. Genet. (2000) [Pubmed]
  3. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. Chan, J.A., Zhang, H., Roberts, P.S., Jozwiak, S., Wieslawa, G., Lewin-Kowalik, J., Kotulska, K., Kwiatkowski, D.J. J. Neuropathol. Exp. Neurol. (2004) [Pubmed]
  4. Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. Carbonara, C., Longa, L., Grosso, E., Mazzucco, G., Borrone, C., Garrè, M.L., Brisigotti, M., Filippi, G., Scabar, A., Giannotti, A., Falzoni, P., Monga, G., Garini, G., Gabrielli, M., Riegler, P., Danesino, C., Ruggieri, M., Magro, G., Migone, N. Genes Chromosomes Cancer (1996) [Pubmed]
  5. Frequent [corrected] hyperphosphorylation of ribosomal protein S6 [corrected] in lymphangioleiomyomatosis-associated angiomyolipomas. Robb, V.A., Astrinidis, A., Henske, E.P. Mod. Pathol. (2006) [Pubmed]
  6. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Jones, A.C., Daniells, C.E., Snell, R.G., Tachataki, M., Idziaszczyk, S.A., Krawczak, M., Sampson, J.R., Cheadle, J.P. Hum. Mol. Genet. (1997) [Pubmed]
  7. The tuberous sclerosis genes and regulation of the cyclin-dependent kinase inhibitor p27. Rosner, M., Freilinger, A., Hengstschläger, M. Mutat. Res. (2006) [Pubmed]
  8. Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis. Ali, J.B., Sepp, T., Ward, S., Green, A.J., Yates, J.R. J. Med. Genet. (1998) [Pubmed]
  9. Study of the relationship between tuberous sclerosis complex and autistic disorder. Wong, V. J. Child Neurol. (2006) [Pubmed]
  10. Molecular genetics, recombinant DNA techniques, and genetic neurological disease. Rosenberg, R.N. Ann. Neurol. (1984) [Pubmed]
  11. TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth. 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. Cell (2006) [Pubmed]
  12. Dysregulation of the TSC-mTOR pathway in human disease. Inoki, K., Corradetti, M.N., Guan, K.L. Nat. Genet. (2005) [Pubmed]
  13. Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. Kwiatkowska, J., Wigowska-Sowinska, J., Napierala, D., Slomski, R., Kwiatkowski, D.J. N. Engl. J. Med. (1999) [Pubmed]
  14. Images in clinical medicine. Ash-leaf spots in tuberous sclerosis. Kurlemann, G., Schuierer, G. N. Engl. J. Med. (1998) [Pubmed]
  15. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome. 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. Nat. Genet. (1994) [Pubmed]
  16. New developments in the neurobiology of the tuberous sclerosis complex. Crino, P.B., Henske, E.P. Neurology (1999) [Pubmed]
  17. Multifocal micronodular pneumocyte hyperplasia in a man with tuberous sclerosis. Kobashi, Y., Yoshida, K., Miyashita, N., Niki, Y., Matsushima, T., Irei, T. Intern. Med. (2005) [Pubmed]
  18. Cross-talk between tuberin, calmodulin, and estrogen signaling pathways. York, B., Lou, D., Panettieri, R.A., Krymskaya, V.P., Vanaman, T.C., Noonan, D.J. FASEB J. (2005) [Pubmed]
  19. The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. Maeda, N., Nigou, J., Herrmann, J.L., Jackson, M., Amara, A., Lagrange, P.H., Puzo, G., Gicquel, B., Neyrolles, O. J. Biol. Chem. (2003) [Pubmed]
  20. Randomized trial of vigabatrin in patients with infantile spasms. Elterman, R.D., Shields, W.D., Mansfield, K.A., Nakagawa, J. Neurology (2001) [Pubmed]
  21. TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. Nellist, M., Verhaaf, B., Goedbloed, M.A., Reuser, A.J., van den Ouweland, A.M., Halley, D.J. Hum. Mol. Genet. (2001) [Pubmed]
  22. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Shah, O.J., Hunter, T. Mol. Cell. Biol. (2006) [Pubmed]
  23. The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton. Haddad, L.A., Smith, N., Bowser, M., Niida, Y., Murthy, V., Gonzalez-Agosti, C., Ramesh, V. J. Biol. Chem. (2002) [Pubmed]
  24. Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: the role of promoter methylation of TSC genes. Jiang, W.G., Sampson, J., Martin, T.A., Lee-Jones, L., Watkins, G., Douglas-Jones, A., Mokbel, K., Mansel, R.E. Eur. J. Cancer (2005) [Pubmed]
  25. The tuberous sclerosis genes, TSC1 and TSC2, trigger different gene expression responses. Rosner, M., Freilinger, A., Lubec, G., Hengstschläger, M. Int. J. Oncol. (2005) [Pubmed]
  26. Denaturing high-performance liquid chromatography (DHPLC)-based prenatal diagnosis for tuberous sclerosis. Bénit, P., Bonnefont, J.P., Kara Mostefa, A., Francannet, C., Munnich, A., Ray, P.F. Prenat. Diagn. (2001) [Pubmed]
  27. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Roux, P.P., Ballif, B.A., Anjum, R., Gygi, S.P., Blenis, J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  28. Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. Astrinidis, A., Senapedis, W., Coleman, T.R., Henske, E.P. J. Biol. Chem. (2003) [Pubmed]
  29. Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin. Tee, A.R., Anjum, R., Blenis, J. J. Biol. Chem. (2003) [Pubmed]
  30. Opposite effects of tor1 and tor2 on nitrogen starvation responses in fission yeast. Weisman, R., Roitburg, I., Schonbrun, M., Harari, R., Kupiec, M. Genetics (2007) [Pubmed]
  31. The tuberous sclerosis complex genes in tumor development. Mak, B.C., Yeung, R.S. Cancer Invest. (2004) [Pubmed]
  32. Tuberous sclerosis complex: genetics to pathogenesis. Narayanan, V. Pediatric neurology. (2003) [Pubmed]
  33. Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins. A molecular link of two tumor suppressor pathways. Birchenall-Roberts, M.C., Fu, T., Bang, O.S., Dambach, M., Resau, J.H., Sadowski, C.L., Bertolette, D.C., Lee, H.J., Kim, S.J., Ruscetti, F.W. J. Biol. Chem. (2004) [Pubmed]
  34. Hamartin and tuberin: working together for tumour suppression. Jozwiak, J. Int. J. Cancer (2006) [Pubmed]
  35. Akt regulates nuclear/cytoplasmic localization of tuberin. Rosner, M., Freilinger, A., Hengstschläger, M. Oncogene (2007) [Pubmed]
  36. Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma. Gemmill, R.M., Zhou, M., Costa, L., Korch, C., Bukowski, R.M., Drabkin, H.A. Br. J. Cancer (2005) [Pubmed]
  37. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Brugarolas, J., Kaelin, W.G. Cancer Cell (2004) [Pubmed]
  38. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). Kagawa, K., Chugani, D.C., Asano, E., Juhász, C., Muzik, O., Shah, A., Shah, J., Sood, S., Kupsky, W.J., Mangner, T.J., Chakraborty, P.K., Chugani, H.T. J. Child Neurol. (2005) [Pubmed]
  39. Evidence for separable functions of tuberous sclerosis gene products in mammalian cell cycle regulation. Miloloza, A., Kubista, M., Rosner, M., Hengstschläger, M. J. Neuropathol. Exp. Neurol. (2002) [Pubmed]
  40. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Garami, A., Zwartkruis, F.J., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S.C., Hafen, E., Bos, J.L., Thomas, G. Mol. Cell (2003) [Pubmed]
  41. MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development. Li, S., Takeuchi, F., Wang, J.A., Fuller, C., Pacheco-Rodriguez, G., Moss, J., Darling, T.N. J. Exp. Med. (2005) [Pubmed]
  42. Rheb fills a GAP between TSC and TOR. Manning, B.D., Cantley, L.C. Trends Biochem. Sci. (2003) [Pubmed]
  43. Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. Catania, M.G., Mischel, P.S., Vinters, H.V. J. Neuropathol. Exp. Neurol. (2001) [Pubmed]
  44. 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. Kobayashi, T., Minowa, O., Sugitani, Y., Takai, S., Mitani, H., Kobayashi, E., Noda, T., Hino, O. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  45. Regulation of PCNA and CAF-1 expression by the two tuberous sclerosis gene products. Hengstschläger, M., Rosner, M., Fountoulakis, M., Lubec, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  46. Tuberous sclerosis genes regulate cellular 14-3-3 protein levels. Hengstschläger, M., Rosner, M., Fountoulakis, M., Lubec, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  47. TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis. Sampson, J.R. Biochem. Soc. Trans. (2003) [Pubmed]
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