Identification of Functionally Distinct TRAF Proinflammatory and Phosphatidylinositol 3-Kinase/Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (PI3K/MEK) Transforming Activities Emanating from RET/PTC Fusion Oncoprotein

Wixted, Josephine; Rothstein, Jay L.; Eisenlohr, Laurence C.

doi:10.1074/jbc.m111.322677

Cited by 15 publications

(13 citation statements)

References 74 publications

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“…Seven members of the TRAF family have been identified (TRAF1-7), and play an important role in a variety of signaling pathways. TRAF6, a unique TRAF family member, possesses a unique receptor-binding specificity, which is important for its crucial role as the signaling mediator for not only the TNF receptor superfamily but also the IL-1R/Toll-like receptor superfamily [ 43 , 44 ]. The downstream signals activated by TRAF6 mainly include NF-κB and AP-1, while NF-κB and AP-1 play an important role in the transcription and expression of numerous genes (including carcinogenesis, invasion and metastasis etc.)…”

Section: Discussionmentioning

confidence: 99%

miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25

et al. 2014

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BackgroundGrowing evidence indicates that miR-200c is involved in carcinogenesis and tumor progression in non-small-cell lung cancer (NSCLC). However, its precise biological role remains largely elusive.MethodsThe functions of miR-200c and USP25 in migration/invasion and lung metastasis formation were determined by transwell and tail vein injection assays, respectively. The potential regulatory targets of miR-200c were determined by prediction tools, correlation with target protein expression, and luciferase reporter assay. The mRNA expression levels of miR-200c and USP25 were examined in NSCLC cell lines and patient specimens using quantitative reverse transcription-PCR. The protein expression levels of USP25 were examined in NSCLC cell lines and patient specimens using western blot and immunohistochemical staining.ResultsWe demonstrated that over-expression of miR-200c inhibited NSCLC cells migration, invasion, epithelial-mesenchymal transition (EMT) in vitro and lung metastasis formation in vivo. Further studies revealed that USP25 was a downstream target of miR-200c in NSCLC cells as miR-200c bound directly to the 3’-untranslated region of USP25, thus reducing both the messenger RNA and protein levels of USP25. Silencing of the USP25 gene recapitulated the effects of miR-200c over-expression. Clinical analysis indicated that miR-200c was negatively correlated with clinical stage, lymph node metastasis in NSCLC patients. Moreover, USP25 protein and mRNA level expressions were higher in NSCLC patients, compared to healthy control, and correlated with clinical stage and lymphatic node metastasis.ConclusionsThese findings indicate that miR-200c exerts tumor-suppressive effects for NSCLC through the suppression of USP25 expression and suggests a new therapeutic application of miR-200c in the treatment of NSCLC.

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Section: Discussionmentioning

confidence: 99%

miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25

et al. 2014

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“…A wide range of signal pathways are mediated by TRAFs involving activation of nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK) or Toll-like receptors (TLRs) cascades 2, 3. In recent years, there has been great interest in the roles of TRAF3 and TRAF5 play in cells of the immune system 4.…”

Section: Introductionmentioning

confidence: 99%

Up-regulation and Pre-activation of TRAF3 and TRAF5 in Inflammatory Bowel Disease

Shen¹,

Qiao

Ran³

et al. 2013

Int. J. Med. Sci.

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Objective: TRAF3 and TRAF5 share a common ancestral gene, and interact as essential components of signaling pathways in immunity. TRAF3 and TRAF5 are overexpressed in the colon of rat/mouse models with colitis. However, the expressions of TRAF3 and TRAF5 in patients with inflammatory bowel disease have not been elucidated. The aim of the present study is to explore the potential roles of TRAF3 and TRAF5 in patients with inflammatory bowel disease.Methods: Plasma levels of TRAF3 and TRAF5 proteins were detected by Enzyme-linked Immunosorbent Assay (ELISA). Colonic expression of TRAF3 and TRAF5 proteins was detected by western blot analysis. Quantitative Real-time PCR (qRT-PCR) was applied for gene expression. Inflamed intestinal mucosa and non-inflamed intestinal mucosa in patients with inflammatory bowel disease and normal mucosa was analyzed from healthy controls.Results: The plasma levels of TRAF3 and TRAF5 were significantly higher both in patients with Crohn's disease and ulcerative colitis than in healthy controls. Only soluble TRAF5 showed a weak correlation with endoscopic disease activity index (Baron score) in patients with ulcerative colitis (spearman's r=0.358, P=0.022). Gene expressions of TRAF3 and TRAF5 in peripheral blood mononuclear cells were significantly higher both in patients with Crohn's disease and ulcerative colitis than in healthy controls (all P<0.0001). Gene and protein expressions of TRAF3 and TRAF5 were significantly higher in inflamed colonic mucosa of patients with Crohn's disease and ulcerative colitis than in non-inflamed colonic mucosa and normal mucosa of healthy controls (all P<0.0001). Furthermore, gene and protein expressions of TRAF3 and TRAF5 were also significantly higher in non-inflamed colonic mucosa of patients with Crohn's disease and ulcerative colitis than in normal mucosa of healthy controls.Conclusions: TRAF3 and TRAF5 are overexpressed in inflammatory bowel disease. Although the endoscopic appearance can be normal, TRAF3 and TRAF5 pre-activation can be detected in non-inflamed colonic segments.

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“…Interestingly, CD11b+ Gr1+ myelocyte-, but not CD8+ T lymphocyte-infiltration, was dependent on the integrity of RET/PTC3 Y588, that corresponds to the RET multidocking site Y1062. These data suggest that while CD11b+ Gr1+ recruitment might be due to RET Y1062-dependent proinflammatory signaling, the recruitment of CD8 T cells could be the result of the expression of tumor-specific antigens, possibly endowed in the RET/ PTC3 oncoprotein , Shinohara & Rothstein 2004, Pufnock & Rothstein 2009, Neely et al 2011, Wixted et al 2012.…”

Section: Immune-inflammatory Component In Tumor Microenvironmentmentioning

confidence: 91%

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

Castellone¹,

Melillo²

2018

Endocrine-Related Cancer

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Medullary thyroid carcinomas (MTC) arise from thyroid parafollicular, calcitoninproducing C-cells and can occur either as sporadic or as hereditary diseases in the context of familial syndromes, including multiple endocrine neoplasia 2A (MEN2A), multiple endocrine neoplasia 2B (MEN2B) and familial MTC (FMTC). In a large fraction of sporadic cases, and virtually in all inherited cases of MTC, activating point mutations of the RET proto-oncogene are found. RET encodes for a receptor tyrosine kinase protein endowed with transforming potential on thyroid parafollicular cells. As in other cancer types, microenvironmental factors play a critical role in MTC. Tumor-associated extracellular matrix, stromal cells and immune cells interact and influence the behavior of cancer cells both in a tumor-promoting and in a tumor-suppressing manner. Several studies have shown that, besides the neoplastic transformation of thyroid C-cells, a profound modification of tumor microenvironment has been associated to the RET FMTC/MEN2-associated oncoproteins. They influence the surrounding stroma, activating cancerassociated fibroblasts (CAFs), promoting cancer-associated inflammation and suppressing anti-cancer immune response. These mechanisms might be exploited to develop innovative anti-cancer therapies and novel prognostic tools in the context of familial, RET-associated MTC.

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Identification of Functionally Distinct TRAF Proinflammatory and Phosphatidylinositol 3-Kinase/Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (PI3K/MEK) Transforming Activities Emanating from RET/PTC Fusion Oncoprotein

Cited by 15 publications

References 74 publications

miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25

miRNA-200c inhibits invasion and metastasis of human non-small cell lung cancer by directly targeting ubiquitin specific peptidase 25

Up-regulation and Pre-activation of TRAF3 and TRAF5 in Inflammatory Bowel Disease

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

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