14 results match your criteria: "Cancer Genomics Centre Netherlands and Centre for BioMedical Genetics[Affiliation]"

High expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity of FER is essential for its oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MB-231 cells reduces migration and invasion, as well as metastasis when xenografted into a mouse model of breast cancer.

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Determining TGF-β Receptor Levels in the Cell Membrane.

Methods Mol Biol

May 2016

Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600 2300 RC, Leiden, The Netherlands.

Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that signals via transmembrane TGF-β type I and type II serine/threonine kinases receptors, i.e., TβRI and TβRII.

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Unlabelled: To identify host factors relevant for severe acute respiratory syndrome-coronavirus (SARS-CoV) replication, we performed a small interfering RNA (siRNA) library screen targeting the human kinome. Protein kinases are key regulators of many cellular functions, and the systematic knockdown of their expression should provide a broad perspective on factors and pathways promoting or antagonizing coronavirus replication. In addition to 40 proteins that promote SARS-CoV replication, our study identified 90 factors exhibiting an antiviral effect.

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Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation.

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Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia.

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Regulation of TGF-β Superfamily Signaling by SMAD Mono-Ubiquitination.

Cells

October 2014

Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600 2300 RC Leiden, The Netherlands.

TGF-β(transforming growth factor-β) superfamily signaling mediators are important regulators of diverse physiological and pathological events. TGF-β signals are transduced by transmembrane type I and type II serine/threonine kinase receptors and their downstream effectors, the SMAD(drosophila mothers against decapentaplegic protein) proteins. Numerous studies have already demonstrated crucial regulatory roles for modification of TGF-β pathway components by poly-ubiquitination.

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Loss of SMAD4 alters BMP signaling to promote colorectal cancer cell metastasis via activation of Rho and ROCK.

Gastroenterology

July 2014

Department of Gastroenterology and Hepatology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background & Aims: SMAD4 frequently is lost from colorectal cancers (CRCs), which is associated with the development of metastases and a poor prognosis. SMAD4 loss is believed to alter transforming growth factor β signaling to promote tumor progression. However, SMAD4 is also a central component of the bone morphogenetic protein (BMP) signaling pathway, implicated in CRC pathogenesis by human genetic studies.

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Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling.

Nat Commun

March 2014

1] Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China [2] Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.

In advanced cancers, the TGF-β pathway acts as an oncogenic factor and is considered to be a therapeutic target. Here using a genome-wide cDNA screen, we identify nuclear receptor NR4A1 as a strong activator of TGF-β signalling. NR4A1 promotes TGF-β/SMAD signalling by facilitating AXIN2-RNF12/ARKADIA-induced SMAD7 degradation.

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Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy.

Expert Opin Investig Drugs

November 2013

Leiden University Medical Centre, Cancer Genomics Centre Netherlands and Centre for BioMedical Genetics, Department of Molecular Cell Biology , Building-2, S1-P, PO box 9600, 2300 RC Leiden , The Netherlands +31 71 526 9272 ; +31 71 526 8270 ;

Introduction: Formation of blood vessels from pre-existing ones, also termed angiogenesis, is of crucial importance for the outgrowth of tumours beyond 1 - 2 mm³. Therefore, anti-angiogenic therapies, mainly focussing on inhibition of vascular endothelial growth factor (VEGF) are used in clinical therapy. However, although initially reducing tumour size, therapy resistance occurs frequently and new targets are needed.

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Transforming growth factor-β (TGF-β)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation.

J Biol Chem

October 2013

the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands,. Electronic address:

In fibrotic liver, connective tissue growth factor (CTGF) is constantly expressed in activated hepatic stellate cells (HSCs) and acts downstream of TGF-β to modulate extracellular matrix production. Distinct from other cell types in which Smad signaling plays major role in regulating CTGF production, TGF-β stimulated CTGF expression in activated HSCs is only in part dependent on Smad3. Other signaling molecules like MAPKs and PI3Ks may also participate in this process, and the underlying mechanisms have yet to be clarified.

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TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis.

Mol Cell

September 2013

Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands; Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.

TGF-β signaling is a therapeutic target in advanced cancers. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a key component mediating pro-oncogenic TGF-β-induced SMAD and non-SMAD signaling. Upon TGF-β stimulation, TRAF4 is recruited to the active TGF-β receptor complex, where it antagonizes E3 ligase SMURF2 and facilitates the recruitment of deubiquitinase USP15 to the TGF-β type I receptor (TβRI).

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UBE2O negatively regulates TRAF6-mediated NF-κB activation by inhibiting TRAF6 polyubiquitination.

Cell Res

March 2013

Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.

Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key regulator of the activation of transcription factor NF-κB by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily. Recruitment of TRAF6 to the receptor-associated IRAK1-IRAK4-MyD88 adaptor protein complex induces lysine 63 (K63) autopolyubiquitination of TRAF6, which leads to further recruitment of downstream regulators, such as TAB2/3 and TAK1, and subsequently triggers NF-κB activation. Here, we identified the putative E2 ubiquitin-conjugating (UBC) enzyme UBE2O as a novel negative regulator of TRAF6-dependent NF-κB signaling.

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Endoglin for tumor imaging and targeted cancer therapy.

Expert Opin Ther Targets

April 2013

Cancer Genomics Centre Netherlands and Centre for BioMedical Genetics, Department of Molecular Cell Biology, Leiden University Medical Center, Building-2, S1-P, PO-box 9600, 2300 RC Leiden, The Netherlands.

Introduction: Although cancer treatment has evolved substantially in the past decades, cancer-related mortality rates are still increasing. Therapies targeting tumor angiogenesis, crucial for the growth of solid tumors, mainly target vascular endothelial growth factor (VEGF) and have been clinically applied during the last decade. However, these therapies have not met high expectations, which were based on therapeutic efficacy in animal models.

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