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Gene Review

Tsc1  -  tuberous sclerosis 1

Mus musculus

Synonyms: Hamartin, Kiaa0243, Tuberous sclerosis 1 protein homolog, hamartin
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Disease relevance of Tsc1


Psychiatry related information on Tsc1

  • Mutations in either TSC1 or TSC2 cause tuberous sclerosis complex, an autosomal dominant disorder characterized by seizures, mental retardation, and benign tumors of the skin, brain, heart, and kidneys [4].

High impact information on Tsc1

  • TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH) [5].
  • Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder in which benign hamartomas develop in multiple organs, caused by mutations in either TSC1 or TSC2 [6].
  • We found that FIP200 knockout (KO) embryos show reduced S6 kinase activation and cell size as a result of increased tuberous sclerosis complex function [7].
  • Finally, Tsc1(-/-) mouse embryonic fibroblasts (MEFs) have increased number of centrosomes and increased DNA content, compared to Tsc1(+/+) cells [8].
  • RNAi inhibition of Plk1 in Tsc1(-/-) MEFs failed to rescue the increased centrosome number phenotype [8].

Chemical compound and disease context of Tsc1


Biological context of Tsc1


Anatomical context of Tsc1

  • Tsc1- and Tsc2-null cells exhibit abnormal caveolin-1 localization that is accompanied by disorganized microtubules in the subcortical region [15].
  • In this report, we demonstrate that mice heterozygous for a targeted defect in either the Tsc1 or Tsc2 genes(Tsc1+/- and Tsc2+/- mice) exhibit a 1.5-fold increase in the number of astrocytes in vivo [16].
  • We found that vascular endothelial growth factor (VEGF) is secreted by Tsc1- or Tsc2-null fibroblasts at high levels compared with wild-type cells [17].
  • In an effort to model TSC-associated central nervous system abnormalities in mice, we generated two independent lines of astrocyte-specific Tsc1 conditional knockout mice by using the Cre-LoxP system [18].
  • Tsc1-null mice show significant increases in astrocyte numbers throughout the brain by 3 weeks of age and abnormal neuronal organization in the hippocampus between 3 and 5 weeks [18].

Associations of Tsc1 with chemical compounds

  • In addition, estrogen treatment significantly increased serum vascular endothelial growth factor levels in Tsc1+/- mice, whereas tamoxifen reduced vascular endothelial growth factor levels [9].
  • Tsc1 Haploinsufficiency without Mammalian Target of Rapamycin Activation Is Sufficient for Renal Cyst Formation in Tsc1+/- Mice [19].
  • Taken together, these findings support a model in which arginine uptake is regulated through tsc1+, tsc2+, and rhb1+ in S. pombe and also suggest a role for the Tsc1 and Tsc2 proteins in amino acid biosynthesis and sensing [4].
  • Here, we report that glutamate transporter expression and function is impaired in Tsc1 cKO astrocytes [10].
  • RESULTS: Human TS-related neoplasms demonstrate high-level expression of activated MAP kinase, as does a tumor arising in a mouse heterozygous for tuberin [20].

Other interactions of Tsc1


Analytical, diagnostic and therapeutic context of Tsc1

  • We developed a murine model of Tsc1 disease by gene targeting [1].
  • Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and how disruption of their expression gives rise to the variety of clinical features that characterize tuberous sclerosis complex [22].
  • Northern blot surveys demonstrated widespread TSC2 expression which was subject to developmental regulation in a tissue-specific manner [23].


  1. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Kwiatkowski, D.J., Zhang, H., Bandura, J.L., Heiberger, K.M., Glogauer, M., el-Hashemite, N., Onda, H. Hum. Mol. Genet. (2002) [Pubmed]
  2. Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation. Uhlmann, E.J., Li, W., Scheidenhelm, D.K., Gau, C.L., Tamanoi, F., Gutmann, D.H. Glia (2004) [Pubmed]
  3. A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes. Meikle, L., McMullen, J.R., Sherwood, M.C., Lader, A.S., Walker, V., Chan, J.A., Kwiatkowski, D.J. Hum. Mol. Genet. (2005) [Pubmed]
  4. Tsc1+ and tsc2+ regulate arginine uptake and metabolism in Schizosaccharomyces pombe. van Slegtenhorst, M., Carr, E., Stoyanova, R., Kruger, W.D., Henske, E.P. J. Biol. Chem. (2004) [Pubmed]
  5. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., Pandolfi, P.P. Cell (2005) [Pubmed]
  6. Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. Onda, H., Lueck, A., Marks, P.W., Warren, H.B., Kwiatkowski, D.J. J. Clin. Invest. (1999) [Pubmed]
  7. Role of FIP200 in cardiac and liver development and its regulation of TNF{alpha} and TSC-mTOR signaling pathways. Gan, B., Peng, X., Nagy, T., Alcaraz, A., Gu, H., Guan, J.L. J. Cell Biol. (2006) [Pubmed]
  8. 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]
  9. Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. El-Hashemite, N., Walker, V., Kwiatkowski, D.J. Cancer Res. (2005) [Pubmed]
  10. Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Wong, M., Ess, K.C., Uhlmann, E.J., Jansen, L.A., Li, W., Crino, P.B., Mennerick, S., Yamada, K.A., Gutmann, D.H. Ann. Neurol. (2003) [Pubmed]
  11. Magnetic resonance imaging and characterization of spontaneous lesions in a transgenic mouse model of tuberous sclerosis as a model for endothelial cell-based transgene delivery. Brown, A.B., Mahmood, U., Cortes, M.L., Tang, Y., Dai, G., Stemmer-Rachamimov, A., Prabhakar, S., Leishear, K., Onda, H., Kwiatkowski, D., Weissleder, R., Breakefield, X. Hum. Gene Ther. (2005) [Pubmed]
  12. The NTN2L gene encoding a novel human netrin maps to the autosomal dominant polycystic kidney disease region on chromosome 16p13.3. Van Raay, T.J., Foskett, S.M., Connors, T.D., Klinger, K.W., Landes, G.M., Burn, T.C. Genomics (1997) [Pubmed]
  13. Induction of renal tumorigenesis with elevated levels of somatic loss of heterozygosity in Tsc1+/- mice on a Blm-deficient background. Wilson, C., Idziaszczyk, S., Colley, J., Humphreys, V., Guy, C., Maynard, J., Sampson, J.R., Cheadle, J.P. Cancer Res. (2005) [Pubmed]
  14. Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment. El-Hashemite, N., Zhang, H., Walker, V., Hoffmeister, K.M., Kwiatkowski, D.J. Cancer Res. (2004) [Pubmed]
  15. Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Jiang, X., Yeung, R.S. Cancer Res. (2006) [Pubmed]
  16. Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/- cells. Uhlmann, E.J., Apicelli, A.J., Baldwin, R.L., Burke, S.P., Bajenaru, M.L., Onda, H., Kwiatkowski, D., Gutmann, D.H. Oncogene (2002) [Pubmed]
  17. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. El-Hashemite, N., Walker, V., Zhang, H., Kwiatkowski, D.J. Cancer Res. (2003) [Pubmed]
  18. Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Uhlmann, E.J., Wong, M., Baldwin, R.L., Bajenaru, M.L., Onda, H., Kwiatkowski, D.J., Yamada, K., Gutmann, D.H. Ann. Neurol. (2002) [Pubmed]
  19. Tsc1 Haploinsufficiency without Mammalian Target of Rapamycin Activation Is Sufficient for Renal Cyst Formation in Tsc1+/- Mice. Wilson, C., Bonnet, C., Guy, C., Idziaszczyk, S., Colley, J., Humphreys, V., Maynard, J., Sampson, J.R., Cheadle, J.P. Cancer Res. (2006) [Pubmed]
  20. Tuberous sclerosis-associated neoplasms express activated p42/44 mitogen-activated protein (MAP) kinase, and inhibition of MAP kinase signaling results in decreased in vivo tumor growth. Govindarajan, B., Mizesko, M.C., Miller, M.S., Onda, H., Nunnelley, M., Casper, K., Brat, D., Cohen, C., Arbiser, J.L., Nunnelly, M. Clin. Cancer Res. (2003) [Pubmed]
  21. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Lee, L., Sudentas, P., Donohue, B., Asrican, K., Worku, A., Walker, V., Sun, Y., Schmidt, K., Albert, M.S., El-Hashemite, N., Lader, A.S., Onda, H., Zhang, H., Kwiatkowski, D.J., Dabora, S.L. Genes Chromosomes Cancer (2005) [Pubmed]
  22. Mouse models of tuberous sclerosis complex. Scheidenhelm, D.K., Gutmann, D.H. J. Child Neurol. (2004) [Pubmed]
  23. Cloning, developmental expression, and evidence for alternative splicing of the murine tuberous sclerosis (TSC2) gene product. Kim, K.K., Pajak, L., Wang, H., Field, L.J. Cell. Mol. Biol. Res. (1995) [Pubmed]
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