TNFAIP1 interacts with KCTD10 to promote the degradation of KCTD10 proteins and inhibit the transcriptional activities of NF-κB and AP-1

Hu, Xiang; Yan, Feng; Wang, Fangmei; Yang, Zijian; Xiao, Ling; Li, Li; Xiang, Sheng; Zhou, Jianlin; Ding, Xiaofeng; Zhang, Jian

doi:10.1007/s11033-012-1858-7

Cited by 19 publications

(20 citation statements)

References 30 publications

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“…The cDNA fragments encoding full-length GSK-3β and β-TrCP were cloned into pCMV-Myc vector, and the truncated APC (1-453 a.a.) and (454-1020 a.a.) fragments were ligated into pCMV-Myc vector. The pCMV-Myc-Ubiquitin plasmid was described previously [40]. The pCMV-HA-p53 plasmid was constructed as described [41].…”

Section: Methodsmentioning

confidence: 99%

KCTD1 Suppresses Canonical Wnt Signaling Pathway by Enhancing β-catenin Degradation

Chen

Wang

et al. 2014

PLoS ONE

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The canonical Wnt signaling pathway controls normal embryonic development, cellular proliferation and growth, and its aberrant activity results in human carcinogenesis. The core component in regulation of this pathway is β-catenin, but molecular regulation mechanisms of β-catenin stability are not completely known. Here, our recent studies have shown that KCTD1 strongly inhibits TCF/LEF reporter activity. Moreover, KCTD1 interacted with β-catenin both in vivo by co-immunoprecipitation as well as in vitro through GST pull-down assays. We further mapped the interaction regions to the 1-9 armadillo repeats of β-catenin and the BTB domain of KCTD1, especially Position Ala-30 and His-33. Immunofluorescence analysis indicated that KCTD1 promotes the cytoplasmic accumulation of β-catenin. Furthermore, protein stability assays revealed that KCTD1 enhances the ubiquitination/degradation of β-catenin in a concentration-dependent manner in HeLa cells. And the degradation of β-catenin mediated by KCTD1 was alleviated by the proteasome inhibitor, MG132. In addition, KCTD1-mediated β-catenin degradation was dependent on casein kinase 1 (CK1)- and glycogen synthase kinase-3β (GSK-3β)-mediated phosphorylation and enhanced by the E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP). Moreover, KCTD1 suppressed the expression of endogenous Wnt downstream genes and transcription factor AP-2α. Finally, we found that Wnt pathway member APC and tumor suppressor p53 influence KCTD1-mediated downregulation of β-catenin. These results suggest that KCTD1 functions as a novel inhibitor of Wnt signaling pathway.

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Section: Methodsmentioning

confidence: 99%

KCTD1 Suppresses Canonical Wnt Signaling Pathway by Enhancing β-catenin Degradation

Chen

Wang

et al. 2014

PLoS ONE

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“…It has been reported that NF-κB-mediated transcriptional upregulation of TNFAIP2 by the Epstein-Barr virus oncoprotein, LMP1, promotes cell motility in NPC (20). However, few studies have shown that TNFAIP1 inhibits the transcriptional activities of NF-κB (25). In the present study, we found that knockdown of TNFAIP1 downregulated the expression of NF-κB at the translational level in OS cells, suggesting that TNFAIP1 may promote the progression of OS through activation of the NF-κB pathway.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of TNFAIP1 inhibits growth and induces apoptosis in osteosarcoma cells through inhibition of the nuclear factor-κB pathway

et al. 2014

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Abstract. Tumor necrosis factor-α-inducible protein-1 (TNFAIP1) plays a role in DNA synthesis, DNA repair, cell apoptosis and human diseases including cancer, and may be involved in tumor progression and metastases. However, little is known concerning the function of TNFAIP1 in human osteosarcoma (OS). The aim of the present study was to investigate the function and underlying mechanisms of TNFAIP1 in human OS. The expression of TNFAIP1 was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was performed to explore the effects of lentiviral-mediated TNFAIP1 siRNA (siTNFAIP1) on cell proliferation, invasive potential and apoptosis by MTT and Transwell assays and flow cytometric analysis in OS (MG-63 and U-2 OS) cells. The results showed that the expression of TNFAIP1 protein was significantly increased in OS tissues compared with that in adjacent noncancerous tissues (ANCTs) (73.3 vs. 48.9%, P=0.018), and was correlated with the distant metastasis of the patients with OS (P=0.029). Knockdown of TNFAIP1 suppressed cell proliferation and invasion, and induced cell apoptosis in the OS cells together with the downregulation of p65 nuclear factor-κB (NF-κB), proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2) and upregulation of caspase-3. Collectively, our findings indicate that high expression of TNFAIP1 is associated with distant metastasis of OS, and knockdown of TNFAIP1 inhibits the growth and invasion, and induces apoptosis in OS cells through inhibition of the NF-κB pathway, suggesting that TNFAIP1 may act as a potential therapeutic target for the treatment of cancer.

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“…In contrast, the results of our immunohistochemical study were contrary to expectation: the expression level of KCTD10 was higher in patients with a favorable outcome (Figure 4, Table 2). Recently, Hu et al reported that KCTD10 inhibited the transcriptional activities of NF-κB and AP-1 [26]. These inhibitory effects were strongly promoted by treatment with a proteasome inhibitor, as KCTD10 expression is regulated through ubiquitination and degradation [26].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Hu et al reported that KCTD10 inhibited the transcriptional activities of NF-κB and AP-1 [26]. These inhibitory effects were strongly promoted by treatment with a proteasome inhibitor, as KCTD10 expression is regulated through ubiquitination and degradation [26]. Therefore, further investigation of KCTD10, especially in vivo experiments, would be of interest from the view point of biomarker research and novel therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Network Analysis of ETV1 Reveals KCTD10 as a Novel Prognostic Biomarker in Gastrointestinal Stromal Tumor

et al. 2013

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BackgroundPrognostic biomarkers are required for risk stratification therapy in the patients with gastrointestinal stromal tumor (GIST). In this study, we aimed to identify prognostic biomarkers in GIST. We assessed the prognostic value of E twenty-six variant 1 (ETV1), a recently identified transcription factor unique to GIST. We also examined the clinical utility and functions of its downstream gene, potassium channel tetramerization domain containing protein 10 (KCTD10).MethodsThe levels of ETV1 and KCTD10 were evaluated immunohistochemically in 112 patients with GIST treated at two hospitals. The functional properties of KCTD10 were examined by gene silencing assay in cultured GIST cells.ResultsImmunohistochemistry revealed that ETV1 expression in GIST had no prognostic significance. In contrast, the disease-free survival rate was 88.5% in patients with KCTD10-positive tumors and 55.8% in those with KCTD10-negative tumors (p <0.0001). KCTD10 was an independent prognostic factor (p <0.05). In the low-risk classification group, KCTD10 was significantly associated with favorable prognosis (p = 0.0008). Gene silencing of KCTD10 increased cell proliferation and invasion, suggesting that KCTD10 has a tumor-suppressive function.ConclusionsThe GIST-specific transcription factor ETV1 may have no prognostic potential, whereas its downstream gene KCTD10 is associated with a favorable prognosis. Our study indicated the novel prognostic utility of KCTD10 in GIST, and suggested its tumor-suppressive effects on GIST cells. Further validation studies of KCTD10 for clinical applications, and functional verification of KCTD10 for better understanding of molecular basis of malignant phenotypes are worth challenging in GIST.

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TNFAIP1 interacts with KCTD10 to promote the degradation of KCTD10 proteins and inhibit the transcriptional activities of NF-κB and AP-1

Cited by 19 publications

References 30 publications

KCTD1 Suppresses Canonical Wnt Signaling Pathway by Enhancing β-catenin Degradation

KCTD1 Suppresses Canonical Wnt Signaling Pathway by Enhancing β-catenin Degradation

Knockdown of TNFAIP1 inhibits growth and induces apoptosis in osteosarcoma cells through inhibition of the nuclear factor-κB pathway

Gene Expression Network Analysis of ETV1 Reveals KCTD10 as a Novel Prognostic Biomarker in Gastrointestinal Stromal Tumor

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