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TSG101  -  tumor susceptibility gene 101

Homo sapiens

 
 
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Disease relevance of TSG101

 

High impact information on TSG101

  • The primary late assembly (L) domain in the p6 region of HIV-1 Gag mediates the detachment of the virion by recruiting host Tsg101, a component of the class E vacuolar protein sorting (Vps) machinery [8].
  • DMAP1 has intrinsic transcription repressive activity, and binds to the transcriptional co-repressor TSG101 [9].
  • Absence of rearrangements in the tumour susceptibility gene TSG101 in human breast cancer [10].
  • In 7 of 15 uncultured primary human breast carcinomas, intragenic deletions were shown in TSG101 genomic DNA and transcripts by gel and sequence analysis, and mutations affecting two TSG101 alleles were identified in four of these cancers [11].
  • Recent work has identified a mouse gene (tsg101) whose inactivation in fibroblasts results in cellular transformation and the ability to produce metastatic tumors in nude mice [11].
 

Chemical compound and disease context of TSG101

 

Biological context of TSG101

 

Anatomical context of TSG101

  • Our results reveal the TSG101 interaction with HRS as a crucial step in endocytic down-regulation of mitogenic signaling and suggest a role for this interaction in linking the functions of early and late endosomes [15].
  • In addition, transcripts from TSG101, FHIT and seven other genes were analysed in RNA isolated from normal peripheral blood lymphocytes [18].
  • We screened TSG101 for somatic mutations in DNA and RNA samples isolated from a variety of common human malignancies, EBV-immortalised B-cells, and normal lung parenchyma [18].
  • Full-length TSG101 protein was detected in these tumors and cell lines indicating that intragenic deletions were not characteristic of TSG101 [4].
  • Expression of TSG101 was also examined in various tumor cell lines (PA-1, AN3CA, HeLa, HS578T, HCT116) [4].
 

Associations of TSG101 with chemical compounds

  • Direct binding of ALG-2 to the TSG101 PRR was demonstrated by an overlay assay using biotin-labelled ALG-2 as a probe [19].
  • A conserved P(S/T)AP tetrapeptide motif within Gag (the "late domain") binds directly to the NH2-terminal ubiquitin E2 variant (UEV) domain of Tsg101 [20].
  • The capacity of cells to efflux adriamycin markedly decreased in TSG101 siRNA transfectants [21].
  • Moreover, the cyclophilin binding site in the CA domain downstream of MA was more accessible in the unmyristylated Gag protein, while the Tsg101 binding site in the C-terminal region was equally available in the unmyristylated and myristylated Gag proteins [22].
 

Physical interactions of TSG101

  • We have identified the mammalian orthologue of Vps28p as a 221- amino acid cytosolic protein that interacts with TSG101/mammalian VPS23 to form part of a multiprotein complex [23].
  • 1) TSG101 bound to several different sites on VPS37B, including a putative coiled-coil region and a PTAP motif [2].
  • TSG101 formed a complex with Daxx through its coiled-coil domain and co-localized in the nucleus [24].
  • Thus, in absence of a ligand, TSG101 binds GR and protects the non-phosphorylated receptor from degradation [25].
  • In this study, we define the Rabaptin-5 binding site on the GGA1-GAT domain and its relationship to the binding sites for ubiquitin and TSG101 [17].
 

Co-localisations of TSG101

 

Regulatory relationships of TSG101

  • Further studies of ESCRT-I revealed that TSG101 mutations that inhibited PTAP or VPS28 binding blocked HIV-1 budding [2].
  • Furthermore, TSG101 enhanced Daxx-mediated repression of glucocorticoid receptor transcriptional activity [24].
  • We propose that TSG101 activates androgen receptor-induced transcription by transient stabilization of the monoubiquitinated state, thus revealing a novel regulatory mechanism for nuclear receptors [27].
  • Further, a PSAP motif-mutated ORF3 protein was unable to associate with TSG101 and also lost its ability to enhance the secretion of alpha1 microglobulin [28].
  • Depletion of Tsg101 potently inhibits EGF degradation and MVB formation and causes the vacuolar domains of the early endosome to tubulate [29].
 

Other interactions of TSG101

  • Our results identify TSG101 as both a regulator of, and target of, MDM2/p53 circuitry [30].
  • 2) TSG101 and VPS28 co-immunoprecipitated with VPS37B-FLAG, and the three proteins comigrated together in soluble complexes of the correct size for human ESCRT-I ( approximately 350 kDa) [2].
  • 4) Finally, VPS37B could recruit TSG101/ESCRT-I activity and thereby rescue the budding of both mutant Gag particles and HIV-1 viruses lacking native late domains [2].
  • In search of novel interaction partners of AATF, we identified the tumor susceptibility gene product TSG101, which had also been recognized as a co-regulator of nuclear hormone receptors [27].
  • This led to the proposition of three alleles of PML, TSG101, and PPIA as potentially associated with differences in progression of HIV-1 disease [31].
 

Analytical, diagnostic and therapeutic context of TSG101

References

  1. Retraction. The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer. Li, L., Francke, U., Cohen, S.N. Cell (1998) [Pubmed]
  2. The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding. Stuchell, M.D., Garrus, J.E., Müller, B., Stray, K.M., Ghaffarian, S., McKinnon, R., Kräusslich, H.G., Morham, S.G., Sundquist, W.I. J. Biol. Chem. (2004) [Pubmed]
  3. Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas. Liu, R.T., Huang, C.C., You, H.L., Chou, F.F., Hu, C.C., Chao, F.P., Chen, C.M., Cheng, J.T. Oncogene (2002) [Pubmed]
  4. TSG101 expression in gynecological tumors: relationship to cyclin D1, cyclin E, p53 and p16 proteins. Bennett, N.A., Pattillo, R.A., Lin, R.S., Hsieh, C.Y., Murphy, T., Lyn, D. Cell. Mol. Biol. (Noisy-le-grand) (2001) [Pubmed]
  5. Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families. Balz, V., Prisack, H.B., Bier, H., Bojar, H. Cancer Genet. Cytogenet. (2002) [Pubmed]
  6. Up-regulation of tumor susceptibility gene 101 protein in ovarian carcinomas revealed by proteomics analyses. Young, T.W., Mei, F.C., Rosen, D.G., Yang, G., Li, N., Liu, J., Cheng, X. Mol. Cell Proteomics (2007) [Pubmed]
  7. Up-regulation of tumor susceptibility gene 101 conveys poor prognosis through suppression of p21 expression in ovarian cancer. Young, T.W., Rosen, D.G., Mei, F.C., Li, N., Liu, J., Wang, X.F., Cheng, X. Clin. Cancer Res. (2007) [Pubmed]
  8. AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Strack, B., Calistri, A., Craig, S., Popova, E., Göttlinger, H.G. Cell (2003) [Pubmed]
  9. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Rountree, M.R., Bachman, K.E., Baylin, S.B. Nat. Genet. (2000) [Pubmed]
  10. Absence of rearrangements in the tumour susceptibility gene TSG101 in human breast cancer. Steiner, P., Barnes, D.M., Harris, W.H., Weinberg, R.A. Nat. Genet. (1997) [Pubmed]
  11. The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer. Li, L., Li, X., Francke, U., Cohen, S.N. Cell (1997) [Pubmed]
  12. Loss of the TSG101 leucine zipper domain in aggressive non-Hodgkin's lymphomas. Ferrer, M., Hernández, S., Campo, E., Lazo, P.A. Leukemia (2000) [Pubmed]
  13. Pharmacogenomics on gastric cancer. Katoh, M., Katoh, M. Cancer Biol. Ther. (2004) [Pubmed]
  14. Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. Hittelman, A.B., Burakov, D., Iñiguez-Lluhí, J.A., Freedman, L.P., Garabedian, M.J. EMBO J. (1999) [Pubmed]
  15. TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation. Lu, Q., Hope, L.W., Brasch, M., Reinhard, C., Cohen, S.N. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  16. Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). Oh, H., Mammucari, C., Nenci, A., Cabodi, S., Cohen, S.N., Dotto, G.P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  17. The trihelical bundle subdomain of the GGA proteins interacts with multiple partners through overlapping but distinct sites. Mattera, R., Puertollano, R., Smith, W.J., Bonifacino, J.S. J. Biol. Chem. (2004) [Pubmed]
  18. Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours. Gayther, S.A., Barski, P., Batley, S.J., Li, L., de Foy, K.A., Cohen, S.N., Ponder, B.A., Caldas, C. Oncogene (1997) [Pubmed]
  19. The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B. Katoh, K., Suzuki, H., Terasawa, Y., Mizuno, T., Yasuda, J., Shibata, H., Maki, M. Biochem. J. (2005) [Pubmed]
  20. HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein. Pornillos, O., Higginson, D.S., Stray, K.M., Fisher, R.D., Garrus, J.E., Payne, M., He, G.P., Wang, H.E., Morham, S.G., Sundquist, W.I. J. Cell Biol. (2003) [Pubmed]
  21. Reversal of multidrug resistance of gastric cancer cells by downregulation of TSG101 with TSG101siRNA. Shen, H., Pan, Y., Han, Z., Hong, L., Liu, N., Han, S., Yao, L., Xie, H., Zhaxi, C., Shi, Y., Fan, D. Cancer Biol. Ther. (2004) [Pubmed]
  22. Role of myristylation in HIV-1 Gag assembly. Bouamr, F., Scarlata, S., Carter, C. Biochemistry (2003) [Pubmed]
  23. TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes. Bishop, N., Woodman, P. J. Biol. Chem. (2001) [Pubmed]
  24. Physical and functional interactions between Daxx and TSG101. Muromoto, R., Sugiyama, K., Yamamoto, T., Oritani, K., Shimoda, K., Matsuda, T. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  25. Stabilization of the unliganded glucocorticoid receptor by TSG101. Ismaili, N., Blind, R., Garabedian, M.J. J. Biol. Chem. (2005) [Pubmed]
  26. The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation. Bache, K.G., Slagsvold, T., Cabezas, A., Rosendal, K.R., Raiborg, C., Stenmark, H. Mol. Biol. Cell (2004) [Pubmed]
  27. TSG101 interacts with apoptosis-antagonizing transcription factor and enhances androgen receptor-mediated transcription by promoting its monoubiquitination. Burgdorf, S., Leister, P., Scheidtmann, K.H. J. Biol. Chem. (2004) [Pubmed]
  28. Enhanced alpha1 microglobulin secretion from Hepatitis E virus ORF3-expressing human hepatoma cells is mediated by the tumor susceptibility gene 101. Surjit, M., Oberoi, R., Kumar, R., Lal, S.K. J. Biol. Chem. (2006) [Pubmed]
  29. Distinct roles for Tsg101 and Hrs in multivesicular body formation and inward vesiculation. Razi, M., Futter, C.E. Mol. Biol. Cell (2006) [Pubmed]
  30. A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control. Li, L., Liao, J., Ruland, J., Mak, T.W., Cohen, S.N. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  31. Use of a combined ex vivo/in vivo population approach for screening of human genes involved in the human immunodeficiency virus type 1 life cycle for variants influencing disease progression. Bleiber, G., May, M., Martinez, R., Meylan, P., Ott, J., Beckmann, J.S., Telenti, A. J. Virol. (2005) [Pubmed]
 
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