Oh, K. B., Stanton, M. J., West, W. W., Todd, G. L. & Wagner, K. U. Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation. Oncogene 26, 5950-5959

Eppley Institute for Research in Cancer and Allied Diseases, 986805 University of Nebraska Medical Center, Omaha, NE 68198, USA.
Oncogene (Impact Factor: 8.46). 09/2007; 26(40):5950-9. DOI: 10.1038/sj.onc.1210401
Source: PubMed


Previous studies reported that the Tumor Susceptibility Gene 101 (TSG101) is upregulated in selected human malignancies, and the expression of exogenous Tsg101 was suggested to transform immortalized fibroblasts in culture. To date, the potential oncogenic properties of Tsg101 have not been examined in vivo owing to the lack of appropriate model systems. In this study, we show that Tsg101 is highly expressed in a subset of invasive human breast cancers. Based on this observation, we generated the first transgenic mouse model with a targeted overexpression of Tsg101 in the developing mammary gland to test whether exogenous Tsg101 is capable of initiating tumorigenesis. Normal functionality of exogenous Tsg101 was tested by rescuing the survival of Tsg101-deficient mammary epithelial cells in conditional knockout mice. The overexpression of Tsg101 resulted in increased phosphorylation of the epidermal growth factor receptor and downstream activation of MAP kinases. Despite an increase in the activation of these signal transducers, the mammary gland of females expressing exogenous Tsg101 developed normally throughout the reproductive cycle. In aging females, the overexpression of Tsg101 seemed to increase the susceptibility of mammary epithelia toward malignant transformation. However, owing to the long latency of tumor formation and the sporadic occurrence of bona fide mammary cancers, we conclude that the Tsg101 protein has only weak oncogenic properties. Instead of cancer initiation, it is therefore likely that Tsg101 plays a more predominant role in the progression of a subset of spontaneously arising breast cancers.

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    • "One study, using conditional Cre-mediated deletion of Tsg101 in mouse embryonic fibroblasts, reports the post-transcriptional down-regulation of the EGFR upon Tsg101 depletion and induction of autophagy prior to cell death (Morris et al., 2012). In an experimental set-up, where Tsg101 was overexpressed in the developing mammary gland, a weak oncogenic potential could be noted with Tsg101-overexpression resulting in increased signaling through ERK1/2 and Stat3/5 and development of mammary gland abnormalities and mammary cancer after a long latency (Oh et al., 2007). In support of these findings, human ovary SKOV-3 cells transfected with Tsg101 siRNA formed smaller tumors in athymic nude mice (Young et al., 2007b). "
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    ABSTRACT: Abstract The endosomal sorting complexes required for transport (ESCRT) are needed for three distinct cellular functions in higher eukaryotes: (i) Multivesicular body formation for the degradation of transmembrane proteins in lysosomes, (ii) midbody abscission during cytokinesis and (iii) retroviral budding. Not surprisingly, loss of ESCRT function has severe consequences, which include the failure to down-regulate growth factor receptors leading to deregulated mitogenic signaling. While it is clear that the function of the ESCRT machinery is important for embryonic development, its role in cancer is more controversial. Various experimental approaches in different model organisms arrive at partially divergent conclusions regarding the contribution of ESCRTs to tumorigenesis. Therefore the aim of this review is to provide an overview on different model systems used to study the role of the ESCRT machinery in cancer development, to highlight common grounds and present certain controversies in the field.
    Molecular Membrane Biology 03/2014; 31(4). DOI:10.3109/09687688.2014.894210 · 1.69 Impact Factor
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    • "Adventitious production of TSG101 triggers polyubiquitylation of the SB by TAL (TSG101-associated ligase), which promotes TSG101 degradation [20]. However, increased abundance of TSG101 protein has been observed in cancer cells [6], [21], and the additional ability of antisense RNA or siRNA directed against TSG101 to alter cellular functions [8] implies that autoregulation of TSG101 protein stability by the SB does not prevent the effects of perturbations that affect negatively TSG101 expression at the pre-translational level. "
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    ABSTRACT: 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 p21 (CIP1/WAF1) tumor 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.
    PLoS ONE 11/2013; 8(11):e79674. DOI:10.1371/journal.pone.0079674 · 3.23 Impact Factor
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    • "The ubiquitously expressed Tsg101 gene possesses all the hallmarks of a housekeeping gene [6], and the collective studies on Tsg101 knockout cells confirmed that the essential functions of this gene for cell proliferation and survival seem to apply to all cell types that have been examined thus far including those that have undergone neoplastic transformation [14]–[16]. In support of this notion, recent work from various research teams including our own shows that Tsg101 is overexpressed rather than lost in a subset of breast, lung, thyroid, ovarian, and colon cancers [17]–[21]. "
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    ABSTRACT: The Tumor Susceptibility Gene 101 (Tsg101) encodes a multi-domain protein that mediates a variety of molecular and biological processes including the trafficking and lysosomal degradation of cell surface receptors. Conventional and conditional knockout models have demonstrated an essential requirement of this gene for cell cycle progression and cell viability, but the consequences of a complete ablation of Tsg101 on intracellular processes have not been examined to date. In this study, we employed mouse embryonic fibroblasts that carry two Tsg101 conditional knockout alleles to investigate the expression of ErbB receptor tyrosine kinases as well as stress-induced intracellular processes that are known to be associated with a defect in growth and cell survival. The conditional deletion of the Tsg101 gene in this well-controlled experimental model resulted in a significant reduction in the steady-state levels of the EGFR and ErbB2 but a stress-induced elevation in the phosphorylation of mitogen activated protein (MAP) kinases independent of growth factor stimulation. As part of an integrated stress response, Tsg101-deficient cells exhibited extensive remodeling of actin filaments and greatly enlarged lysosomes that were enriched with the autophagy-related protein LC3. The increase in the transcriptional activation and expression of LC3 and its association with Lamp1-positive lysosomes in a PI3K-dependent manner suggest that Tsg101 knockout cells utilize autophagy as a survival mechanism prior to their ultimate death. Collectively, this study shows that a knockout of the Tsg101 gene causes complex intracellular changes associated with stress response and cell death. These multifaceted alterations need to be recognized as they have an impact on defining particular functions for Tsg101 in processes such as signal transduction and lysosomal/endosomal trafficking.
    PLoS ONE 03/2012; 7(3):e34308. DOI:10.1371/journal.pone.0034308 · 3.23 Impact Factor
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