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Dive into the research topics where Christiaan Karreman is active.

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Featured researches published by Christiaan Karreman.


The EMBO Journal | 2012

IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation

Tripat Kaur Oberoi; Taner Dogan; Jennifer C. Hocking; Rolf-Peter Scholz; Juliane Mooz; Carrie L Anderson; Christiaan Karreman; Dagmar Meyer zu Heringdorf; Gudula Schmidt; Mika Ruonala; Kazuhiko Namikawa; Gregory S. Harms; Alejandro Carpy; Boris Macek; Reinhard W. Köster; Krishnaraj Rajalingam

Inhibitors of apoptosis proteins (IAPs) are a highly conserved class of multifunctional proteins. Rac1 is a well‐studied Rho GTPase that controls numerous basic cellular processes. While the regulation of nucleotide binding to Rac1 is well understood, the molecular mechanisms controlling Rac1 degradation are not known. Here, we demonstrate X‐linked IAP (XIAP) and cellular IAP1 (c‐IAP1) directly bind to Rac1 in a nucleotide‐independent manner to promote its polyubiquitination at Lys147 and proteasomal degradation. These IAPs are also required for degradation of Rac1 upon CNF1 toxin treatment or RhoGDI depletion. Consistently, downregulation of XIAP or c‐IAP1 by various strategies led to an increase in Rac1 protein levels in primary and tumour cells, leading to an elongated morphology and enhanced cell migration. Further, XIAP counteracts Rac1‐dependent cellular polarization in the developing zebrafish hindbrain and promotes the delamination of neurons from the normal tissue architecture. These observations unveil an evolutionarily conserved role of IAPs in controlling Rac1 stability thereby regulating the plasticity of cell migration and morphogenesis.


Nature Cell Biology | 2008

X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility

Taner Dogan; Gregory S. Harms; Mirko Hekman; Christiaan Karreman; Tripat Kaur Oberoi; Emad S. Alnemri; Ulf R. Rapp; Krishnaraj Rajalingam

Inhibitor of apoptosis proteins (IAP) are evolutionarily conserved anti-apoptotic regulators. C-RAF protein kinase is a direct RAS effector protein, which initiates the classical mitogen-activated protein kinase (MAPK) cascade. This signalling cascade mediates diverse biological functions, such as cell growth, proliferation, migration, differentiation and survival. Here we demonstrate that XIAP and c-IAPs bind directly to C-RAF kinase and that siRNA-mediated silencing of XIAP and c-IAPs leads to stabilization of C-RAF in human cells. XIAP binds strongly to C-RAF and promotes the ubiquitylation of C-RAF in vivo through the Hsp90-mediated quality control system, independently of its E3 ligase activity. In addition, XIAP or c-IAP-1/2 knockdown cells showed enhanced cell migration in a C-RAF-dependent manner. XIAP promotes binding of CHIP (carboxy terminal Hsc70-interacting protein), a chaperone-associated ubiquitin ligase, to the C-RAF–Hsp90 complex in vivo. Interfering with CHIP expression resulted in stabilization of C-RAF and enhanced cell migration, as observed in XIAP knockdown cells. Our data show an unexpected role of XIAP and c-IAPs in the turnover of C-RAF protein, thereby modulating the MAPK signalling pathway and cell migration.


PLOS ONE | 2009

Myc Is a Metastasis Gene for Non-Small-Cell Lung Cancer

Ulf R. Rapp; Christian Korn; Fatih Ceteci; Christiaan Karreman; Katharina Luetkenhaus; Valentina Serafin; Emanuele Zanucco; Inês Castro; Tamara Potapenko

Background Metastasis is a process by which cancer cells learn to form satellite tumors in distant organs and represents the principle cause of death of patients with solid tumors. NSCLC is the most lethal human cancer due to its high rate of metastasis. Methodology/Principal Findings Lack of a suitable animal model has so far hampered analysis of metastatic progression. We have examined c-MYC for its ability to induce metastasis in a C-RAF-driven mouse model for non-small-cell lung cancer. c-MYC alone induced frank tumor growth only after long latency at which time secondary mutations in K-Ras or LKB1 were detected reminiscent of human NSCLC. Combination with C-RAF led to immediate acceleration of tumor growth, conversion to papillary epithelial cells and angiogenic switch induction. Moreover, addition of c-MYC was sufficient to induce macrometastasis in liver and lymph nodes with short latency associated with lineage switch events. Thus we have generated the first conditional model for metastasis of NSCLC and identified a gene, c-MYC that is able to orchestrate all steps of this process. Conclusions/Significance Potential markers for detection of metastasis were identified and validated for diagnosis of human biopsies. These markers may represent targets for future therapeutic intervention as they include genes such as Gata4 that are exclusively expressed during lung development.


Journal of Neurochemistry | 2013

Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies.

Stefan Schildknecht; Hanne R. Gerding; Christiaan Karreman; Malte Drescher; Hilal A. Lashuel; Tiago F. Outeiro; Donato A. Di Monte; Marcel Leist

Alpha‐synuclein (ASYN) is a major constituent of the typical protein aggregates observed in several neurodegenerative diseases that are collectively referred to as synucleinopathies. A causal involvement of ASYN in the initiation and progression of neurological diseases is suggested by observations indicating that single‐point (e.g., A30P, A53T) or multiplication mutations of the gene encoding for ASYN cause early onset forms of Parkinsons disease (PD). The relative regional specificity of ASYN pathology is still a riddle that cannot be simply explained by its expression pattern. Also, transgenic over‐expression of ASYN in mice does not recapitulate the typical dopaminergic neuronal death observed in PD. Thus, additional factors must contribute to ASYN‐related toxicity. For instance, synucleinopathies are usually associated with inflammation and elevated levels of oxidative stress in affected brain areas. In turn, these conditions favor oxidative modifications of ASYN. Among these modifications, nitration of tyrosine residues, formation of covalent ASYN dimers, as well as methionine sulfoxidations are prominent examples that are observed in post‐mortem PD brain sections. Oxidative modifications can affect ASYN aggregation, as well as its binding to biological membranes. This would affect neurotransmitter recycling, mitochondrial function and dynamics (fission/fusion), ASYNs degradation within a cell and, possibly, the transfer of modified ASYN to adjacent cells. Here, we propose a model on how covalent modifications of ASYN link energy stress, altered proteostasis, and oxidative stress, three major pathogenic processes involved in PD progression. Moreover, we hypothesize that ASYN may act physiologically as a catalytically regenerated scavenger of oxidants in healthy cells, thus performing an important protective role prior to the onset of disease or during aging.


ChemBioChem | 2014

Alpha-Synuclein Binds to the Inner Membrane of Mitochondria in an α-Helical Conformation

Marta Robotta; Hanne R. Gerding; Antonia Vogel; Karin Hauser; Stefan Schildknecht; Christiaan Karreman; Marcel Leist; Vinod Subramaniam; Malte Drescher

The human alpha‐Synuclein (αS) protein is of significant interest because of its association with Parkinsons disease and related neurodegenerative disorders. The intrinsically disordered protein (140 amino acids) is characterized by the absence of a well‐defined structure in solution. It displays remarkable conformational flexibility upon macromolecular interactions, and can associate with mitochondrial membranes. Site‐directed spin‐labeling in combination with electron paramagnetic resonance spectroscopy enabled us to study the local binding properties of αS on artificial membranes (mimicking the inner and outer mitochondrial membranes), and to evaluate the importance of cardiolipin in this interaction. With pulsed, twofrequency, double‐electron electron paramagnetic resonance (DEER) approaches, we examined, to the best of our knowledge for the first time, the conformation of αS bound to isolated mitochondria.


ALTEX-Alternatives to Animal Experimentation | 2013

Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases

Stefan Schildknecht; Christiaan Karreman; Dominik Pöltl; Liudmila Efremova; Cornelius Kullmann; Simon Gutbier; Anne-Kathrin Krug; Diana Scholz; Hanne R. Gerding; Marcel Leist

Human differentiated cell types, such as neurons or hepatocytes, are of limited availability, and their use for experiments requiring ectopic gene expression is challenging. Using the human conditionally-immortalized neuronal precursor line LUHMES, we explored whether genetic modification in the proliferating state could be used for experiments in the differentiated post-mitotic neurons. First, alpha-synuclein (ASYN), a gene associated with the pathology of Parkinsons disease, was overexpressed. Increased amounts of the protein were tolerated without change of phenotype, and this approach now allows further studies on protein variants. Knockdown of ASYN attenuated the toxicity of the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP+). Different lentiviral constructs then were tested: cells labeled ubiquitously with green (GFP) or red fluorescent protein (RFP) allowed the quantification of neurite growth and of its disturbance by toxicants; expression of proteins of interest could be targeted to different organelles; production of two different proteins from a single read-through construct was achieved successfully by an expression strategy using a linker peptide between the two proteins, which is cleaved by deubiquitinases; LUHMES, labeled with GFP in the cytosol and RFP in the mitochondria, were used to quantify mitochondrial mobility along the neurites. MPP+ reduced such organelle movement before any other detectable cellular change, and this toxicity was prevented by simultaneous treatment with the antioxidant ascorbic acid. Thus, a strategy has been outlined here to study new functional endpoints, and subtle changes of structure and proteostasis relevant in toxicology and biomedicine in post-mitotic human cells.


Neurotoxicology | 2012

Uncoupling of ATP-depletion and cell death in human dopaminergic neurons

Dominik Pöltl; Stefan Schildknecht; Christiaan Karreman; Marcel Leist

The mitochondrial inhibitor 1-methyl-4-phenylpyridinium (MPP(+)) is the toxicologically relevant metabolite of 1-methyl-4-phenyltetrahydropyridine (MPTP), which causes relatively selective degeneration of dopaminergic neurons in the substantia nigra. Dopaminergic LUHMES cells were used to investigate whether ATP-depletion can be uncoupled from cell death as a downstream event in these fully post-mitotic human neurons. Biochemical assays indicated that in the homogeneously differentiated cell cultures, MPP(+) was taken up by the dopamine transporter (DAT). MPP(+) then triggered oxidative stress and caspase activation, as well as ATP-depletion followed by cell death. Enhanced survival of the neurons in the presence of agents interfering with mitochondrial pathology, such as the fission inhibitor Mdivi-1 or a Bax channel blocker suggested a pivotal role of mitochondria in this model. However, these compounds did not prevent cellular ATP-depletion. To further investigate whether cells could be rescued despite respiratory chain inhibition by MPP(+), we have chosen a diverse set of pharmacological inhibitors well-known to interfere with MPP(+) toxicity. The antioxidant ascorbate, the iron chelator desferoxamine, the stress kinase inhibitor CEP1347, and different caspase inhibitors reduced cell death, but allowed ATP-depletion in protected cells. None of these compounds interfered with MPP(+) accumulation in the cells. These findings suggest that ATP-depletion, as the initial mitochondrial effect of MPP(+), requires further downstream processes to result in neuronal death. These processes may form self-enhancing signaling loops, that aggravate an initial energetic impairment and eventually determine cell fate.


ChemBioChem | 2011

Autoproteolytic Fragments Are Intermediates in the Oligomerization/Aggregation of the Parkinson's Disease Protein Alpha-Synuclein as Revealed by Ion Mobility Mass Spectrometry

Camelia Vlad; Kathrin Lindner; Christiaan Karreman; Stefan Schildknecht; Marcel Leist; Nick Tomczyk; John Rontree; James Langridge; Karin M. Danzer; Thomas Ciossek; Alina Petre; Michael L. Gross; Bastian Hengerer; Michael Przybylski

Gas-phase protein separation by ion mobility: With its ability to separate the Parkinsons disease protein α-synuclein and its autoproteolytic products-despite the small concentrations of the latter-ion-mobility MS has enabled the characterization of intermediate fragments in in vitro oligomerization-aggregation. In particular, a possible key fragment, the highly aggregating C-terminal fragment, αSyn(72-140), has been revealed.


Journal of Biological Chemistry | 2012

Role of Melanoma Inhibitor of Apoptosis (ML-IAP) Protein, a Member of the Baculoviral IAP Repeat (BIR) Domain Family, in the Regulation of C-RAF Kinase and Cell Migration

Tripat Kaur Oberoi-Khanuja; Christiaan Karreman; Sarit Larisch; Ulf R. Rapp; Krishnaraj Rajalingam

Background: The possible role of ML-IAP in regulating MAPK signaling and cell migration is examined. Results: ML-IAP directly binds to C-RAF and targets it for proteasomal degradation. Loss of ML-IAP leads to an increase in MAPK activity and cell migration. ML-IAP interacts directly with XIAP. Conclusion: ML-IAP regulates C-RAF stability and cell migration. Significance: There is a novel role of ML-IAP in regulating cell migration and MAPK signaling. IAPs exist in heteromeric complexes and regulate C-RAF stability. Inhibitor of apoptosis (IAPs) proteins are characterized by the presence of evolutionarily conserved baculoviral inhibitor of apoptosis repeat (BIR) domains, predominantly known for their role in inhibiting caspases and, thereby, apoptosis. We have shown previously that multi-BIR domain-containing IAPs, cellular IAPs, and X-linked IAP can control tumor cell migration by directly regulating the protein stability of C-RAF kinase. Here, we extend our observations to a single BIR domain containing IAP family member melanoma-IAP (ML-IAP). We show that ML-IAP can directly bind to C-RAF and that ML-IAP depletion leads to an increase in C-RAF protein levels, MAPK activation, and cell migration in melanoma cells. Thus, our results unveil a thus far unknown role for ML-IAP in controlling C-RAF stability and cell migration.


Biochemistry | 2012

Locally Resolved Membrane Binding Affinity of the N-Terminus of α-Synuclein

Marta Robotta; Christian Hintze; Stefan Schildknecht; Niels Zijlstra; Christian Jüngst; Christiaan Karreman; Martina Huber; Marcel Leist; Vinod Subramaniam; Malte Drescher

α-Synuclein is abundantly present in Lewy bodies, characteristic of Parkinsons disease. Its exact physiological role has yet to be determined, but mitochondrial membrane binding is suspected to be a key aspect of its function. Electron paramagnetic resonance spectroscopy in combination with site-directed spin labeling allowed for a locally resolved analysis of the protein-membrane binding affinity for artificial phospholipid membranes, supported by a study of binding to isolated mitochondria. The data reveal that the binding affinity of the N-terminus is nonuniform.

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Ulf R. Rapp

University of Würzburg

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