Identical variantTSG101 transcripts in soft tissue sarcomas and various non-neoplastic tissues

Willeke, Frank; Ridder, Ruediger; Bork, Peer; Klaes, Ruediger; Mechtersheimer, Gunhild; Schwarzbach, Matthias; Zimmer, Dagmar; Kloor, Matthias; Lehnert, Thomas; Herfarth, Christian; Doeberitz, Magnus von Knebel

doi:10.1002/(sici)1098-2744(199812)23:4<195::aid-mc1>3.0.co;2-g

Cited by 9 publications

(5 citation statements)

References 13 publications

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“…These shorter RT ± PCR fragments varied in size and abundance compared to the full-length product. Note, however, that the abnormal fragment was in much lower abundance than the full-length one, as previously shown (Chang et al, 1999;Gayther et al, 1997;Lee and Feinberg, 1997;Li et al, 1997;Sun et al, 1997;Willeke et al, 1998). The speci®city of the shorter PCR fragments was veri®ed by Southern blot hybridization using a cDNA fragment internal to the primers as a probe (Figure 1b).…”

Section: Resultssupporting

confidence: 57%

“…The speci®city of the shorter PCR fragments was veri®ed by Southern blot hybridization using a cDNA fragment internal to the primers as a probe (Figure 1b). Sequence analysis showed that the abnormal fragment in Figure 1a, lane 3 (550 bp, deletion nt 133 ± 730) was previously described in other cancer samples (Chang et al, 1999;Gayther et al, 1997;Lee and Feinberg, 1997;Sun et al, 1997;Willeke et al, 1998). Southern blot analysis of the ®rst round PCR products allowed the detection of few truncated forms, demonstrating that truncation is not an artifact of the nested PCR procedure (not shown).…”

Section: Resultsmentioning

confidence: 55%

“…Detailed analysis of these truncated transcripts demonstrates that they result from aberrant splicing on a limited number of cryptic splice acceptor/donor sites (Gayther et al, 1997;Lee and Feinberg, 1997;Wagner et al, 1998). Finally, aberrantly spliced TSG101 transcripts were also found in normal tissues (Carney et al, 1998;Chang et al, 1999;Lee and Feinberg, 1997;Lin et al, 1998a;Willeke et al, 1998).…”

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confidence: 98%

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Stress-induced aberrant splicing of TSG101: association to high tumor grade and p53 status in breast cancers

et al. 1999

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The TSG101 gene, identi®ed through insertional mutagenesis, is localized in a region that exhibits LOH in human cancers, suggesting that TSG101 might be a tumor suppressor gene. Numerous studies have then shown the presence of abnormal transcripts in various tumors which appear to result from aberrant splicing of the gene, rather than from intragenic deletions. Moreover, many studies demonstrated that these aberrantly spliced transcripts were not found in matched normal tissues. We have analysed TSG101 transcripts in 85 breast cancer samples and found that abnormal splicing of the gene is tightly correlated with tumor grade and p53 mutation. In addition, stress induced the appearance of these abnormal transcripts in primary lymphocytes. Hence, TSG101 splicing defects, while unrelated to the oncogenic process per se, could re¯ect the cellular environment of the tumor cells. The proposed role of stress and hypoxia to select p53 mutant cells could account for the tight association with p53 status.

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 55%

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confidence: 98%

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Stress-induced aberrant splicing of TSG101: association to high tumor grade and p53 status in breast cancers

et al. 1999

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“…Aberrant splicing and production of TSG101 transcript variations have been detected in multiple types of human cancer, including carcinomas of the liver, lung, breast, cervix, and ovary [46] - [50] as well as in soft tissue sarcomas [51] , and leukemias [52] . It has been suggested that such aberrant transcripts are experimental artifacts of PCR analysis [53] ; however, it also has been reported that induction of the tumor suppressor gene p53 prevents the accumulation of variant transcripts [54] .…”

Section: Discussionmentioning

confidence: 99%

Identification of TSG101 Functional Domains and p21 Loci Required for TSG101-Mediated p21 Gene Regulation

et al. 2013

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TSG101 (tumor susceptibility gene 101) is a multi-domain protein known to act in the cell nucleus, cytoplasm, and periplasmic membrane. Remarkably, TSG101, whose location within cells varies with the stage of the cell cycle, affects biological events as diverse as cell growth and proliferation, gene expression, cytokinesis, and endosomal trafficking. The functions of TSG101 additionally are recruited for viral and microvesicle budding and for intracellular survival of invading bacteria. Here we report that the TSG101 protein also interacts with and down-regulates the promoter of the p21CIP1/WAF1tumor suppressor gene, and identify a p21 locus and TSG101 domains that mediate this interaction. TSG101 deficiency in Saos-2 human osteosarcoma cells was accompanied by an increased abundance of p21 mRNA and protein and the retardation of cell proliferation. A cis-acting element in the p21 promoter that interacts with TSG101 and is required for promoter repression was located using chromatin immunoprecipitation (ChIP) analysis and p21-driven luciferase reporter gene expression, respectively. Additional analysis of TSG101 deletion mutants lacking specific domains established the role of the central TSG101 domains in binding to the p21 promoter and demonstrated the additional essentiality of the TSG101 C-terminal steadiness box (SB) in the repression of p21 promoter activity. Neither binding of TSG101 to the p21 promoter nor repression of this promoter required the TSG101 N-terminal UEV domain, which mediates the ubiquitin-recognition functions of TSG101 and its actions as a member of ESCRT endocytic trafficking complexes, indicating that regulation of the p21 promoter by TSG101 is independent of its role in such trafficking.

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“…The human homologue TSG101 has been isolated and mapped to chromosome 11p, bands 15.1-15.2 (Li et al, 1997), a region known to exhibit a high incidence of loss of heterozygosity in a variety of human malignancies (Ali et al, 1987;Baffa et al, 1996;Byrne et al, 1993;Lothe et al, 1993;Ludwig et al, 1991;Reeve et al, 1989;Shaw and Knowles, 1995;Weitzel et al, 1994), suggesting that TSG101 might be a tumor suppressor. Although no genomic deletion has been identified, aberrant transcripts can be found in various tumors and their matched normal tissues (Carney et al, 1998;Chang et al, 1999;Lee and Feinberg, 1997;Lin et al, 1998a,b;Wang et al, 2000;Willeke et al, 1998), including thyroid tumors (McIver et al, 2000). Abnormally spliced transcripts of TSG101 have been found to very closely correlate with tumor grade and p53 mutation in breast cancer samples.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas

et al. 2002

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Functional inactivation of tumor susceptibility gene tsg101 leads to cellular transformation and tumorigenesis in mice. 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. Some studies have revealed that TSG101 is a frequent target of splicing defects, which correlate with cellular stress and p53 status. Furthermore, recent reports have identified TSG101 as a part of the MDM2/p53 regulatory circuitry, a well-recognized circuitry that upon deregulation results in tumorigenesis. Interestingly, overexpression of tsg101 from an adventitious promoter also leads to neoplastic transformation. 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. 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. In situ hybridization analysis confirms that overexpression of TSG101 also occurs at the transcriptional level. 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. Here we report the upregulation of TSG101 expression in PTC cells, providing the first evidence of the association of TSG101 overexpression with human tumors and suggesting that upregulation of TSG101 steady-state level might play a role in mediating tumorigenesis of human PTC.

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Identical variantTSG101 transcripts in soft tissue sarcomas and various non-neoplastic tissues

Cited by 9 publications

References 13 publications

Stress-induced aberrant splicing of TSG101: association to high tumor grade and p53 status in breast cancers

Stress-induced aberrant splicing of TSG101: association to high tumor grade and p53 status in breast cancers

Identification of TSG101 Functional Domains and p21 Loci Required for TSG101-Mediated p21 Gene Regulation

Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas

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