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Tsc2  -  tuberous sclerosis 2

Mus musculus

Synonyms: Nafld, Tcs2, Tuberin, Tuberous sclerosis 2 protein homolog, tuberin
 
 
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Disease relevance of Tsc2

 

Psychiatry related information on Tsc2

 

High impact information on Tsc2

 

Biological context of Tsc2

  • Whereas increased astrocyte numbers in vivo were suggestive of a proliferative advantage, Tsc2+/- primary astrocyte cultures did not show a cell-autonomous growth advantage, anchorage-independent growth, increased saturation density, or increased fluid-phase endocytosis compared to wild type astrocytes [9].
  • Like their human counterparts, the mouse Tsc2 and Pkd1 genes are arranged in a tail-to-tail orientation with a distance of only 63 bp between the polyadenylation signals of the two genes [10].
  • Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development [11].
  • Mouse Tctex3 gene was mapped adjacent to Tsc2 gene on mouse Chromosome (Chr) 17, and HUTEX3 was located closely to HSET gene in the HLA class II region of chromosome 6 [12].
  • Increased signal transducers and activators of transcription (STAT) 1 expression and phosphorylation at Ser 727 and increased pSTAT3 Tyr705 levels also are seen in Tsc1 null and Tsc2 null cells and in tumors [13].
 

Anatomical context of Tsc2

  • Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice [2].
  • Some Tsc2-/- embryos exhibited an unclosed neural tube and/or thickened myocardium [2].
  • Tsc2 null mouse embryonic fibroblasts (MEFs) however, did exhibit increased saturation density compared to Tsc2 wild type controls [9].
  • Tsc1- and Tsc2-null cells exhibit abnormal caveolin-1 localization that is accompanied by disorganized microtubules in the subcortical region [14].
  • We demonstrate a dramatic decrease of IFN-gamma expression in tumors and mouse embryo fibroblast cell lines that lack either Tsc1 or Tsc2, which is reversed by rapamycin (mammalian target of rapamycin inhibitor) therapy [13].
 

Associations of Tsc2 with chemical compounds

  • 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 [15].
  • In this study, we showed that tuberin is phosphorylated at serine and tyrosine residues in response to serum and other factors, and it undergoes serial phosphorylation that can be detected by differences in electrophoretic mobilities [16].
  • We have detected a novel variant of the TSC2 mRNA lacking 129 nucleotides, predicting an in-frame deletion of 43 amino acids spanning codons 946-988 of tuberin [17].
 

Regulatory relationships of Tsc2

  • Akt activation promotes degradation of tuberin and FOXO3a via the proteasome [18].
  • Recently, the small GTPase Rheb was identified as a target of the GTPase-activating domain of tuberin in mammalian cells and in Drosophila [15].
 

Other interactions of Tsc2

 

Analytical, diagnostic and therapeutic context of Tsc2

References

  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. Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Kobayashi, T., Minowa, O., Kuno, J., Mitani, H., Hino, O., Noda, T. Cancer Res. (1999) [Pubmed]
  3. 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]
  4. Transgenic expression of dominant negative tuberin through a strong constitutive promoter results in a tissue-specific tuberous sclerosis phenotype in the skin and brain. Govindarajan, B., Brat, D.J., Csete, M., Martin, W.D., Murad, E., Litani, K., Cohen, C., Cerimele, F., Nunnelley, M., Lefkove, B., Yamamoto, T., Lee, C., Arbiser, J.L. J. Biol. Chem. (2005) [Pubmed]
  5. Learning, memory, and transcription factors. Johnston, M.V., Alemi, L., Harum, K.H. Pediatr. Res. (2003) [Pubmed]
  6. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., Cantley, L.C. Mol. Cell (2002) [Pubmed]
  7. 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]
  8. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Johannessen, C.M., Reczek, E.E., James, M.F., Brems, H., Legius, E., Cichowski, K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. 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]
  10. The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy gene. Olsson, P.G., Löhning, C., Horsley, S., Kearney, L., Harris, P.C., Frischauf, A. Genomics (1996) [Pubmed]
  11. Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Rennebeck, G., Kleymenova, E.V., Anderson, R., Yeung, R.S., Artzt, K., Walker, C.L. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  12. Tctex3, related to Drosophila polycomblike, is expressed in male germ cells and mapped to the mouse t-complex. Kawakami, S., Mitsunaga, K., Kikuti, Y.Y., Ando, A., Inoko, H., Yamamura, K., Abe, K. Mamm. Genome (1998) [Pubmed]
  13. 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]
  14. Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Jiang, X., Yeung, R.S. Cancer Res. (2006) [Pubmed]
  15. 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]
  16. Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis. Aicher, L.D., Campbell, J.S., Yeung, R.S. J. Biol. Chem. (2001) [Pubmed]
  17. Alternative splicing of the tuberous sclerosis 2 (TSC2) gene in human and mouse tissues. Xu, L., Sterner, C., Maheshwar, M.M., Wilson, P.J., Nellist, M., Short, P.M., Haines, J.L., Sampson, J.R., Ramesh, V. Genomics (1995) [Pubmed]
  18. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. Plas, D.R., Thompson, C.B. J. Biol. Chem. (2003) [Pubmed]
  19. Chromosomal localization of three vacuolar-H+ -ATPase 16 kDa subunit (ATP6V0C) genes in the murine genome. Simckes, A.M., Swanson, S.K., White, R.A. Cytogenet. Genome Res. (2002) [Pubmed]
  20. 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]
  21. Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle. Williamson, D.L., Kubica, N., Kimball, S.R., Jefferson, L.S. J. Physiol. (Lond.) (2006) [Pubmed]
  22. Identification of functional elements in the bidirectional promoter of the mouse Nthl1 and Tsc2 genes. Ikeda, S., Mochizuki, A., Sarker, A.H., Seki, S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  23. A new strategy for studying protein kinase B and its three isoforms. Role of protein kinase B in phosphorylating glycogen synthase kinase-3, tuberin, WNK1, and ATP citrate lyase. Sale, E.M., Hodgkinson, C.P., Jones, N.P., Sale, G.J. Biochemistry (2006) [Pubmed]
  24. Cloning and characterization of a mouse homologue (mNthl1) of Escherichia coli endonuclease III. Sarker, A.H., Ikeda, S., Nakano, H., Terato, H., Ide, H., Imai, K., Akiyama, K., Tsutsui, K., Bo, Z., Kubo, K., Yamamoto, K., Yasui, A., Yoshida, M.C., Seki, S. J. Mol. Biol. (1998) [Pubmed]
 
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