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

Turpin, Elisabeth; Dalle, B; Plassa, Louis-François; Marty, Michel; Janin, Anne; Beuzard, Yves

doi:10.1038/sj.onc.1203196

Cited by 23 publications

(17 citation statements)

References 28 publications

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“…The mucosal hypoxia characteristic of UC is interesting in light of research showing hypoxia can activate NF-κB (42,43), which is capable of specifically increasing expression of tr-NK-1R (24). In addition, hypoxia has been shown to induce alternative splicing events in other genes in vitro, and these splice variants are also associated with mutations to the tumor suppressor p53, a common finding in CAC (44). Evidence therefore suggests that both proinflammatory and hypoxic signaling may work together to increase the expression of tr-NK-1R in UC and CAC.…”

Section: Discussionmentioning

confidence: 99%

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Patients with chronic ulcerative colitis (UC) are at high risk for developing colorectal cancer. In this study, archival formalin-fixed paraffin-embedded colonic tissue from patients with UC who developed carcinoma (CA) or high-grade dysplasia (HGD) was examined for changes in expression of the proinflammatory and mitogenic neurokinin-1 receptor (NK-1R). Laser capture microscopy was used to microdissect epithelia from areas of colons that showed histologic evidence of CA, HGD, and epithelia that were not dysplastic or cancerous but did contain evidence of prior inflammation (quiescent colitis). mRNA was extracted from the dissected tissue, and PCR array analysis was performed on extracted mRNA. Two antibodies were necessary to separately estimate the protein levels of the truncated (tr-NK-1R) and full-length (fl-NK-1R) receptors by immunohistochemistry. mRNA expression of tr-NK-1R increased 14-fold (P = 0.02) when comparing the HGD and CA groups. In contrast, the fl-NK-1R transcript showed no significant differences among groups. The protein levels of the total NK-1R increased by 40% (P = 0.02) in HGD and 80% (P = 0.0007) in CA compared with quiescent colitis. There were no significant changes in protein levels of the fl-NK-1R. We conclude that the increase in total NK-1R protein in HGD and CA is attributable to an increase in tr-NK-1R, suggesting there may be a functional role for tr-NK-1R in malignant transformation in colitis-associated cancer. The tr-NK-1R could prove useful as a diagnostic marker to identify patients at risk for neoplasia and may serve as a useful therapeutic target in the treatment of colitisassociated cancer.colon cancer | receptor splice variants | substance P | IBD C hronic inflammation is associated with a higher rate of cancer development in various organs (1). More specifically, patients with ulcerative colitis (UC) are at high risk for developing colorectal cancer (2); both extent and duration of intestinal inflammation further increase risk (3, 4). These associations suggest that chronic intestinal inflammation is a causative factor in carcinogenesis in patients with UC, and that there is a causal link between chronic inflammation and increased risk of cancer. These observations raise the question of the signaling pathways by which long-standing inflammation might underlie the development of cancer.Substance P (SP) is a proinflammatory neuropeptide described by von Euler and Gaddum (5) and later isolated and characterized by Chang and Leeman (6). SP is synthesized by a variety of cells, most notably neurons and inflammatory cells such as macrophages (7). SP's primary receptor, the neurokinin-1 receptor (NK-1R), can mediate a variety of physiologic and pathophysiologic responses, including cell proliferation, migration, and inflammation (8). The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation (9, 10) and in patients with UC as well as Crohn disease (11)(12)(13)(14). However, not all of these studies are in agreement regarding epithelial NK-1R e...

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Section: Discussionmentioning

confidence: 99%

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Gillespie¹,

Leeman²,

Watts³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The steady-state level of TSG101 protein normally is regulated posttranslationally in cells within a narrow range (3), and overexpression of TSG101 from an adventitious promoter can also lead to neoplastic transformation (1). Truncated TSG101 transcripts, which are observed in a variety of human tumors as well as in normal cells (4 -7), have been attributed to aberrant or alternative RNA splicing (8) and have been correlated with both cellular stress (4,5) and mutation of p53 (5). The TSG101 protein contains motifs common to transcription regulators (1) and can modulate transcriptional activation by steroid hormone receptors (9 -11).…”

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confidence: 99%

A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control

Liu

Liao

Ruland

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

149

138

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The p53 tumor suppressor protein and the MDM2 oncoprotein form a feedback-control loop that up-regulates cellular MDM2 production, blocks p53 activity, and promotes p53 decay. tsg101 was discovered as a gene whose deficiency results in neoplastic transformation of NIH 3T3 cells and the ability to generate metastatic tumors in nude mice. Its protein product contains a domain, Ubc, characteristic of the catalytic domain of ubiquitin conjugase (E2) enzymes but lacking an active-site cysteine crucial for ubiquitin conjugase activity. Here we report that TSG101 participates with MDM2 in an autoregulatory loop that modulates the cellular levels of both proteins, and also of p53, by affecting protein decay. We show that the Ubc domain of TSG101 interferes with ubiquitination of MDM2, that TSG101 inhibits MDM2 decay and elevates its steady-state level, and that these events are associated with down-regulation of p53 protein. Conversely, pulse-chase and Western blot experiments in wild-type and mutant fibroblasts indicate that elevation of MDM2 by overexpression of wild-type p53, by amplification of the endogenous MDM2 gene, or by transfection of MDM2-expressing constructs promotes TSG101 loss, which we show occurs by 26S proteasome-dependent decay. Our results identify TSG101 as both a regulator of, and target of, MDM2͞p53 circuitry.tumorigenesis ͉ ubiquitination ͉ proteolysis

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“…One purpose of our study was to determine whether postchemotherapy genetic abnormalities could occur at different rates in TP53-mutated versus TP53-nonmutated breast tumours. TP53 mutations are observed in 20 to 30% of breast carcinomas and are linked to poor prognosis (Turpin et al, 1999;Olivier et al, 2006). Loss of TP53 function may result in increased genetic instability with higher frequency of mutations, chromosomal abnormalities, gene amplifications, LOH and abnormal chromosome segregation (Fukasawa et al, 1996;Morris, 2002).…”

Section: Discussionmentioning

confidence: 99%

Changes in allelic imbalances in locally advanced breast cancers after chemotherapy

et al. 2007

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In advanced breast cancers, TP53 mutation is highly predictive of complete response to high-dose epirubicin/cyclophosphamide chemotherapy. In these tumours with an altered control of genomic stability, accumulation of chemotherapy-induced genetic alterations may contribute to cell death and account for complete response. To explore the effects of chemotherapy on stability of the tumour genome, allelic profiles were obtained from microdissected tumour samples before and after chemotherapy in 29 unresponsive breast cancers (9 with TP53 mutation). Ninety-four per cent allelic profiles remained unchanged after treatment. Interestingly, 11 profiles (6%) showed important changes after treatment; allelic imbalances significantly increased (four cases) or decreased (seven cases) after chemotherapy in three distinct experiments, two of which using laser microdissected tumour cells. These genetic changes were not linked to the TP53 status, but one tumour showed complete disappearance of TP53-mutated cells in the residual tumour after treatment. Altogether, these observations carry important implications for the clonal evolution of breast cancers treated with DNA-damaging agents, as they point both to the importance of tumour heterogeneity and chemotherapydriven selection of subclones.

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

Cited by 23 publications

References 28 publications

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer

A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control

Changes in allelic imbalances in locally advanced breast cancers after chemotherapy

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