Disease relevance of TSG101

• Retraction. The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer [1].
• Taken together, these experiments define new components of the human ESCRT-I complex and characterize several TSG101 protein/protein interactions required for HIV-1 budding and infectivity [2].
• Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas [3].
• Reduced TSG101 protein was observed in 36% (8/22) of ovarian and 17% (1/6) of endometrial adenocarcinoma [4].
• Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families [5].
• Silencing of TSG101 by short interfering RNA in ovarian cancer cells led to growth inhibition and cell death [6].
• Suppressing TSG101 by siRNA in ovarian cancer cells led to growth inhibition, cell cycle arrest, and apoptosis with concurrent increases in p21 mRNA and protein [7].

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

• Loss of the TSG101 leucine zipper domain in aggressive non-Hodgkin's lymphomas [12].
• Shen et al reported that transient transfection of TSG101 siRNA reduced the expression level of TSG101 protein as well as resistance to vincristine and adriamycin in gastric cancer cells [13].

Biological context of TSG101

• In yeast and mammalian cells, TSG101 represses whereas DRIP150 enhances GR AF-1-mediated transactivation [14].
• TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation [15].
• Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1) [16].
• Our observations show that Rabaptin-5, ubiquitin, and TSG101 bind to overlapping but distinct binding sites on the trihelical bundle [17].
• While human TSG101 is located in a region where frequent loss of heterozygosity can be detected in a variety of cancers, no genomic deletion in TSG101 gene has been reported, casting a doubt on the role of TSG101 as a classical tumor suppressor [3].

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

• HCRP1 cofractionates with Tsg101 and hVps28 by size exclusion chromatography and colocalizes with hVps28 on LAMP1-positive endosomes [26].

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

• Co-immunoprecipitation and cross-linking experiments demonstrated that hVPS28 and TSG101 interact directly and that binding requires structural information within the conserved C-terminal portion of TSG101 [23].
• In addition, semi-quantitative RT-PCR and subsequent Southern hybridization verify that the amounts of TSG101 transcripts are indeed lower in three normal thyroid tissues than in PTC specimens [3].
• Further sequence analysis reveals no mutation in cDNA region encoding steadiness box in these PTC specimens, indicating that the upregulation of TSG101 protein is not caused by the alteration of this region [3].
• In situ hybridization analysis confirms that overexpression of TSG101 also occurs at the transcriptional level [3].
• On the basis of this information, we have analysed TSG101 gene expression in 20 human papillary thyroid carcinomas (PTCs) by immunohistochemistry and demonstrated that the overexpression of TSG101 protein is closely associated with human PTCs [3].

References