Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cells

Liu, Jianghuai; Kumar, Krishna; Yu, Duonan; Molton, Sarah A; McMahon, Martin; Herlyn, Meenhard; Thomas-Tikhonenko, Andrei; Fuchs, Serge Y.

doi:10.1038/sj.onc.1209994

Cited by 99 publications

(91 citation statements)

References 17 publications

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“…In addition, the mutation of ubiquitin ligase FBXW7 resulted in hyper‐activation of Notch1 signalling and subsequent sustained proliferation of melanoma cells by up‐regulation of cell‐cycle mediators 28, 29, 30. What is more, the pro‐proliferative NF‐κB pathway was potentiated due to the facilitated degradation of IκB by E3 ubiquitin ligase β‐Trcp, which was up‐regulated by BRAF over‐activation in melanoma 12. Therefore, these results demonstrated the critical pathologic role of ubiquitination in melanoma development.…”

Section: Discussionmentioning

confidence: 99%

“…For melanoma, the mutations of ubiquitination‐related genes such as BRCA1‐associated protein‐1(BAP1), F‐boxand WD repeat domain‐containing 7 (FBXW7) and PARK2 are frequently identified and participated in melanoma tumourigenesis 11. What is more, the activation of some critical signalling pathways in melanoma development including NF‐κB and MITF are also subtly regulated by ubiquitination,12, 13 demonstrating its vital pathogenic role in melanoma. Notably, previous studies mainly focused on the regulatory role of ubiquitin‐conjugating enzymes, especially E3 ubiquitin ligases in melanoma.…”

Section: Introductionmentioning

confidence: 99%

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Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin‐specific peptidase (USP) families are greatly implicated in modulating cancer biology. Herein, we first found that the expression of the deubiquitinase USP4 was significantly up‐regulated in melanoma tissues and cell lines. Furthermore, although USP4 knockdown had little impact on melanoma cell proliferation, it could increase the sensitivity to DNA damage agent cisplatin. We subsequently showed that USP4 regulated cisplatin‐induced cell apoptosis via p53 signalling. More importantly, USP4 could accentuate the invasive and migratory capacity of melanoma cells by promoting epithelial‐mesenchymal transition. Altogether, our results demonstrate that the up‐regulated USP4 plays an oncogenic role in melanoma by simultaneously suppressing stress‐induced cell apoptosis and facilitating tumour metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

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“…47 Finally, kinases of the Raf family including B-Raf interact with Spry1, 1 and Raf activation has been mechanistically linked to activation of the NFkB pathway. 48 In conclusion, there are many potential mechanisms by which Spry1 can induce NFkB activity that deserve further investigation. In this regard, our preliminary data indicate that overexpression of Spry1 in 293 cells enhances NFkB activity in luciferase assays (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

et al. 2013

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Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFjB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated b-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation. The Sprouty family of genes is composed of four members in mammals (Spry1-4), orthologous to a single Drosophila melanogaster gene (dSpry). With some well-documented exceptions, Sprouty proteins function as feedback inhibitors of receptor tyrosine kinase (RTK) signaling. In Drosophila, dSpry inhibits signaling by FGF and EGF in the airways and the eye, respectively. Genetic experiments in mice establish that Spry1 and Spry2 are negative regulators of signaling by FGFR and Ret RTKs. Thus, the deletion of Spry2 and/or Spry4 causes different craniofacial abnormalities because of hypersensitivity to FGF. On the other hand, excessive Ret signaling underlies kidney and enteric nervous system defects found in Spry1 and Spry2 knockout mice, respectively (reviewed in Guy et al. 1 ). Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood. 1,2 Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies. Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.In this work, we show that Spry1 null mice exhibit overgrowth of the thyroid gland owing to increased proliferation of thyrocytes. Surprisingly, such increase in cell proliferation does not correlate with eith...

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“…Upregulation of mitogen-activated protein kinase pathway frequently occurs in melanomas as a result of oncogenic mutation of BRAF and NRAS genes (Smalley and Herlyn, 2004). Recent studies indicate that induction of the mutant BRAF v600E in melanocytes enhances bTrCP2 expression and stimulates IkB degradation (Liu et al, 2007). These observations suggest that multiple mechanisms are implicated in the upregulation of SCF bÀTrCP1 E3 ubiquitin ligase and activation of NF-kB in malignant melanomas.…”

mentioning

confidence: 91%

“…Accelerated degradation of IkB was shown to be responsible for activation of NF-kB in melanoma cells (Shattuck-Brandt and Richmond, 1997;Yang and Richmond, 2001). Most of the analysed melanoma cell lines express high levels of bTrCP, compared with normal human melanocytes (Liu et al, 2007). Inhibition of b-TrCP function sensitizes human melanoma cells for apoptosis (Soldatenkov et al, 1999).…”

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confidence: 99%

Overexpression of mRNA-binding protein CRD-BP in malignant melanomas

et al. 2008

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Wnt/b-catenin signaling pathway plays an important role in embryogenesis, stem cell maintenance, tumorigenesis and aging. Here, we show that RNA-binding protein, coding region determinant-binding protein (CRD-BP) (a transcriptional target of Wnt signaling pathway), is highly expressed in primary human malignant melanomas and melanoma cell lines with activated Wnt/b-catenin signaling pathway. Upregulation of CRD-BP is associated with an elevated level of b-TrCP1 ubiquitin ligase receptor and activation of nuclear transcriptional factors-kappa B (NF-jB) signaling. Knockdown of CRD-BP inhibits NF-jB activity, induces apoptosis, and suppresses proliferation and tumorigenic properties of melanoma cells. Keywords: CRD-BP; b-TrCP; mRNA stability; melanoma; Wnt/b-catenin signaling; NF-kB The increased incidence of cutaneous melanoma in the past three decades, its highly progressive nature and resistance to treatment, has prompted enhanced attention to this disease (reviewed in Chin et al., 2006;Herlyn, 2006). Despite numerous studies conducted on melanocytic lesions, the molecular mechanisms of melanoma development and progression are still poorly understood.Wnt/b-catenin signaling plays an important role in normal development and stem cells maintenance, whereas its aberrant upregulation is involved in tumorigenesis (Giles et al., 2003;Weeraratna, 2005). The defining events of an active canonical Wnt pathway include accumulation of cytoplasmic b-catenin, its subsequent nuclear translocation and initiation of bcatenin/Tcf-dependent transcription. In the absence of WNT, abundance and transcriptional activity of b-catenin is regulated by the large multicomponent machinery that includes adenomatous polyposis coli protein (APC), axin, CK1 and glycogen synthase kinase 3-b. This complex facilitates phosphorylation of bcatenin and determines its subsequent degradation. Binding of WNT ligand with its Frizzled and lowdensity lipoprotein receptor-related protein (5/6) receptors starts a cascade of events that results in disruption of b-catenin phosphorylation, subsequent accumulation of free b-catenin in the cytoplasm, its nuclear translocation and transcriptional activation of target genes. Overexpression of WNT proteins, mutations in APC and/or stabilizing b-catenin mutations are the most common alterations associated with constitutively upregulated Wnt signaling and tumor development. Nuclear localization of b-catenin, the hallmark of an active canonical Wnt pathway, was observed in approximately 30% of primary and metastatic human melanoma samples (Rimm et al., 1999).Activation of nuclear transcriptional factors-kappa B (NF-kB) is frequently observed in various types of human tumors, including melanoma (Basseres and Baldwin, 2006;Gilmore, 2006). In many cells, the major NF-kB heterodimer is composed of p50 and RelA/p65 subunits that are responsible for activation of canonical NF-kB signaling. The inhibitors of NF-kB (IkBs) tightly regulate activity of p50/RelA dimer. The IkBs bind to NF-kB dimers and block their nuclear locali...

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Oncogenic BRAF regulates β-Trcp expression and NF-κB activity in human melanoma cells

Cited by 99 publications

References 17 publications

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

Overexpression of mRNA-binding protein CRD-BP in malignant melanomas

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