Bernd Baumann - Academia.edu (original) (raw)

Papers by Bernd Baumann

Research paper thumbnail of Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Journal of Clinical Investigation, Jun 1, 2007

Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflamm... more Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-κB target genes, including mediators of the inflammatory response such as TNF-α and ICAM-1. Indeed, inhibition of TNF-α activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-κB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease.

Research paper thumbnail of Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone

Oncogene, Jan 21, 1999

PTH is a major regulator of calcium homeostasis by mobilizing calcium through bone resorption. We... more PTH is a major regulator of calcium homeostasis by mobilizing calcium through bone resorption. We show that the expression of collagenase-3 (MMP-13), a member of the family of matrix metalloproteinases, required for the cleavage of collagens in the bone, is increased upon PTH injection in mice. A cis-acting element in the collagenase-3 promoter was identi®ed which, together with AP-1, is required for induction by PTH. This element contains CCACA motifs which are required for binding of the 65 kDa osteoblast-speci®c splice variant of Cbfa1. Introduction of mutations in this binding site that interfere with protein interaction also eliminates PTH inducibilty and transactivation by Cbfa/ Runt proteins. While DNA binding activity of AP-1 is increased upon PTH treatment, high basal level of Cbfa/ Runt binding activity is detectable in untreated cells which is not further increased by PTH, suggesting that AP-1 and Cbfa1 contribute to transcriptional activation through dierent mechanisms. In agreement with the critical role of both proteins de®ned in tissue culture cells, expression of collagenase-3 is reduced in mice lacking c-fos and is completely absent in cbfa1 7/7 embryos. These data provide the ®rst evidence for a critical role of Cbfa1, a major regulator of bone development, in PTH-dependent processes such as bone resorption.

Research paper thumbnail of NF-κB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss

Molecular Neurodegeneration

Background Inflammaging represents an accepted concept where the immune system shifts to a low-gr... more Background Inflammaging represents an accepted concept where the immune system shifts to a low-grade chronic pro-inflammatory state without overt infection upon aging. In the CNS, inflammaging is mainly driven by glia cells and associated with neurodegenerative processes. White matter degeneration (WMD), a well-known process in the aging brain, manifests in myelin loss finally resulting in motor, sensory and cognitive impairments. Oligodendrocytes (OL) are responsible for homeostasis and maintenance of the myelin sheaths, which is a complex and highly energy demanding process sensitizing these cells to metabolic, oxidative and other forms of stress. Yet, the immediate impact of chronic inflammatory stress like inflammaging on OL homeostasis, myelin maintenance and WMD remains open. Methods To functionally analyze the role of IKK/NF-κB signaling in the regulation of myelin homeostasis and maintenance in the adult CNS, we established a conditional mouse model allowing NF-κB activation...

Research paper thumbnail of RESEARCH ARTICLE Open Access Sustained, neuron-specific IKK/NF-κB activation

generates a selective neuroinflammatory response of neuronal IKK2/NF-κB signalling, possibly as a... more generates a selective neuroinflammatory response of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis.

Research paper thumbnail of IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization

Cells, 2021

Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced ... more Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number ...

Research paper thumbnail of Fos is an essential component of the mammalian UV response

The EMBO Journal, 1995

2Corresponding author Mouse 3T3 fibroblasts lacking c-fos were employed to demonstrate an essenti... more 2Corresponding author Mouse 3T3 fibroblasts lacking c-fos were employed to demonstrate an essential function of the UV-inducible transcription factor AP-1 (Fos/Jun) in the response to the cytotoxic effects of short-wavelength ultraviolet (UVC) radiation. Clonogenic survival and proliferation of cells lacking c-fos were drastically reduced following UV irradiation. This UV hypersensitivity manifests itself primarily in increased cell death, partly by apoptosis, and prolonged recovery time from UVinduced cell cycle arrest. Co-culture with wild-type cells did not ameliorate the hypersensitivity of mutant cells. Transcriptional induction of the c-Fos target genes collagenase I, stromelysin-1 and stromelysin-2 by UV is almost absent in cells lacking c-fos which correlates with a reduced UV induction of AP-1 DNAbinding and transactivation activity. The repair of UVinduced DNA lesions was not affected, as shown by unscheduled DNA synthesis and host cell reactivation assays. These data demonstrate that c-Fos is involved in a novel protective function other than DNA repair against the harmful consequences of UVC.

Research paper thumbnail of IKK2/NF-κB signaling protects neurons after traumatic brain injury

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 29, 2017

Traumatic brain injury (TBI) is the leading cause of death in young adults. After the initial inj... more Traumatic brain injury (TBI) is the leading cause of death in young adults. After the initial injury, a poorly understood secondary phase, including a strong inflammatory response determines the final outcome of TBI. The inhibitor of NF-κB kinase (IKK)/NF-κB signaling system is the key regulator of inflammation and also critically involved in regulation of neuronal survival and synaptic plasticity. We addressed the neuron-specific function of IKK2/NF-κB signaling pathway in TBI using an experimental model of closed-head injury (CHI) in combination with mouse models allowing conditional regulation of IKK/NF-κB signaling in excitatory forebrain neurons. We found that repression of IKK2/NF-κB signaling in neurons increases the acute posttraumatic mortality rate, worsens the neurological outcome, and promotes neuronal cell death by apoptosis, thus resulting in enhanced proinflammatory gene expression. As a potential mechanism, we identified elevated levels of the proapoptotic mediators ...

Research paper thumbnail of Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration

Molecular Neurodegeneration, 2017

Background: Neuroinflammation is associated with a wide range of neurodegenerative disorders, how... more Background: Neuroinflammation is associated with a wide range of neurodegenerative disorders, however the specific contribution to individual disease pathogenesis and selective neuronal cell death is not well understood. Inflammatory cerebellar ataxias are neurodegenerative diseases occurring in various autoimmune/inflammatory conditions, e.g. paraneoplastic syndromes. However, how inflammatory insults can cause selective cerebellar neurodegeneration in the context of these diseases remains open, and appropriate animal models are lacking. A key regulator of neuroinflammatory processes is the NF-κB signalling pathway, which is activated by the IκB kinase 2 (IKK2) in response to various pathological conditions. Importantly, its activation is sufficient to initiate neuroinflammation on its own. Methods: To investigate the contribution of IKK/NF-κB-mediated neuroinflammation to neurodegeneration, we established conditional mouse models of cerebellar neuroinflammation, which depend either on the tetracyclineregulated expression of IKK2 in astrocytes or Cre-recombination based IKK2 activation in Bergmann glia. Results: We demonstrate that IKK2 activation for a limited time interval in astrocytes is sufficient to induce neuroinflammation, astrogliosis and loss of Purkinje neurons, resembling the pathogenesis of inflammatory cerebellar ataxias. We identified IKK2-driven irreversible dysfunction of Bergmann glia as critical pathogenic event resulting in Purkinje cell loss. This was independent of Lipocalin 2, an acute phase protein secreted by reactive astrocytes and well known to mediate neurotoxicity. Instead, downregulation of the glutamate transporters EAAT1 and EAAT2 and ultrastructural alterations suggest an excitotoxic mechanism of Purkinje cell degeneration. Conclusions: Our results suggest a novel pathogenic mechanism how diverse inflammatory insults can cause inflammation/autoimmune-associated cerebellar ataxias. Disease-mediated elevation of danger signals like TLR ligands and inflammatory cytokines in the cerebellum activates IKK2/NF-κB signalling in astrocytes, which as a consequence triggers astrogliosis-like activation of Bergmann glia and subsequent non-cell-autonomous Purkinje cell degeneration. Notably, the identified hit and run mechanism indicates only an early window for therapeutic interventions.

Research paper thumbnail of Differential Regulation of NF-κB-Mediated Proviral and Antiviral Host Gene Expression by Primate Lentiviral Nef and Vpu Proteins

Cell Reports, 2015

NF-κB is essential for effective transcription of primate lentiviral genomes and also activates a... more NF-κB is essential for effective transcription of primate lentiviral genomes and also activates antiviral host genes. Here, we show that the early protein Nef of most primate lentiviruses enhances NF-κB activation. In contrast, the late protein Vpu of HIV-1 and its simian precursors inhibits activation of NF-κB, even in the presence of Nef. Although this effect of Vpu did not correlate with its ability to interact with β-TrCP, it involved the stabilization of IκB and reduced nuclear translocation of p65. Interestingly, however, Vpu did not affect casein kinase II-mediated phosphorylation of p65. Lack of Vpu was associated with increased NF-κB activation and induction of interferon and interferon-stimulated genes (ISGs) in HIV-1-infected T cells. Thus, HIV-1 and its simian precursors employ Nef to boost NF-κB activation early during the viral life cycle to initiate proviral transcription, while Vpu is used to downmodulate NF-κB-dependent expression of ISGs at later stages.

Research paper thumbnail of Nuclear Factor κB Activation Impairs Ependymal Ciliogenesis and Links Neuroinflammation to Hydrocephalus Formation

The Journal of Neuroscience, 2012

Hydrocephalus formation is a frequent complication of neuropathological insults associated with n... more Hydrocephalus formation is a frequent complication of neuropathological insults associated with neuroinflammation. However, the mechanistic role of neuroinflammation in hydrocephalus development is unclear. We have investigated the function of the proinflammatory acting inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling system in neuroinflammatory processes and generated a novel mouse model that allows conditional activation of the IKK/NF-κB system in astrocytes. Remarkably, NF-κB activation in astrocytes during early postnatal life results in hydrocephalus formation and additional defects in brain development. NF-κB activation causes global neuroinflammation characterized by a strong, astrocyte-specific expression of proinflammatory NF-κB target genes as well as a massive infiltration and activation of macrophages. In this animal model, hydrocephalus formation is specifically induced during a critical time period of early postnatal development, in which IKK/NF-κB-indu...

Research paper thumbnail of IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

The Journal of Neuroscience, 2012

Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF... more Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF-κB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase (IKK)/NF-κB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF-κB-dependent synapse development and remodeling. Here, we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmi...

Research paper thumbnail of Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

The Journal of Neuroscience, 2006

The transcription factor nuclear factor κB (NF-κB) is well known for its antiapoptotic action. Ho... more The transcription factor nuclear factor κB (NF-κB) is well known for its antiapoptotic action. However, in some disorders, such as cerebral ischemia, a proapoptotic function of NF-κB has been demonstrated. To analyze which subunit of NF-κB is functional in cerebral ischemia, we induced focal cerebral ischemia in mice with a germline deletion of thep52orc-Relgene or with a conditional deletion of RelA in the brain. Only RelA deficiency reduced infarct size. Interestingly, expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genesBimandNoxain cerebral ischemia depended on RelA and the upstream kinase IKK (IκB kinase). RelA stimulated Bim and Noxa gene transcription in primary cortical neurons and bound to the promoter of both genes. Thus, the deleterious function in cerebral ischemia is specific for the NF-κB subunit RelA and may be mediated through Bim and Noxa.

Research paper thumbnail of Characterization of sonic hedgehog as a novel NF‐κB target gene that promotes NF‐κB‐mediated apoptosis resistance and tumor growth in vivo

The FASEB Journal, 2008

To explore mechanisms controlling sonic hedgehog (Shh) expression in human cancers, we investigat... more To explore mechanisms controlling sonic hedgehog (Shh) expression in human cancers, we investigated regulation of Shh by the transcription factor NF-B. We identify putative NF-B binding sites in the human Shh promoter region that specifically bind NF-B complexes. Further, NF-B activation by tumor necrosis factor ␣ (TNF-␣) or p65 overexpression stimulates Shh promoter activity and p65 binds to Shh promoter in vivo. NF-B-mediated transcriptional activation of Shh is mapped to a minimal NF-B consensus site at position ؉139 of Shh promoter. NF-B activation results in increased Shh mRNA and protein expression in vitro and, notably, also in vivo in a genetic mouse model of inducible NF-B activity. Specific NF-B inhibition by inhibitory NF-B␣ (I-B␣) superrepressor or p65 knockdown inhibits NF-B-induced Shh promoter activation and Shh expression. NF-B-mediated Shh expression promotes proliferation and confers resistance to TRAIL-induced apoptosis. Silencing of Shh prevents NF-B-stimulated proliferation, while the addition of Shh rescues the proliferation defect imposed by NF-B inhibition. Notably, NF-B-stimulated tumor growth is significantly impaired by Shh knockdown in an in vivo model of pancreatic cancer. By demonstrating that NF-B regulates Shh expression, which contributes to NF-B-mediated proliferation and apoptosis resistance in vitro and in vivo, our findings have important implications to target aberrant Shh expression in human cancers.-Kasperczyk, H., Baumann, B., Debatin, K.-M., Fulda, S. Characterization of sonic hedgehog as a novel NF-B target gene that promotes NF-B-mediated apoptosis resistance and tumor growth in vivo.

Research paper thumbnail of Raf induces NF-κB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation

Proceedings of the National Academy of Sciences, 2000

NF-κB is regulated by inhibitor proteins (IκBs), which retain NF-κB in the cytoplasm. Signal-indu... more NF-κB is regulated by inhibitor proteins (IκBs), which retain NF-κB in the cytoplasm. Signal-induced phosphorylation by the IκB-kinase complex containing the IκB-kinases 1 and 2 (IKK-1/2 or IKK-α/β) and subsequent degradation of the IκB proteins are prerequisites for NF-κB activation. Many signals induce NF-κB, one of them being oncogenic Raf kinase. We investigated whether NF-κB induction is critical for Raf-mediated transformation. Here, we demonstrate that inhibition of NF-κB interferes with transformation by the Raf-oncogene, and we characterized the mechanism of NF-κB induction by activated Raf kinase and the tumor promoter phorbol 12-myristate 13-acetate (PMA). NF-κB activation by PMA and Raf critically depends on the IκB-kinase complex, most notably on IKK-2. A major signaling pathway induced by Raf is the mitogenic cytoplasmic kinase cascade. However, different inhibitors of this cascade do not affect PMA- and Raf-mediated NF-κB activation. Raf does not phosphorylate the IκB...

Research paper thumbnail of Identification of a novel pro-apoptotic role of NF-κB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells

Oncogene, 2011

We recently reported that nuclear factor-kappa B (NF-jB) promotes DNA damage-triggered apoptosis ... more We recently reported that nuclear factor-kappa B (NF-jB) promotes DNA damage-triggered apoptosis in glioblastoma, the most common brain tumor. In the present study, we investigated the role of NF-jB in death receptor-mediated apoptosis. Here, we identify a novel pro-apopotic function of NF-jB in TRAIL-and CD95induced apoptosis. Inhibition of NF-jB by overexpression of the dominant-negative IjBa-superrepressor (IjBa-SR) significantly decreases tumor necrosis factor (TNF)related apoptosis-inducing ligand (TRAIL)-or CD95induced apoptosis. Vice versa, activation of NF-jB via overexpression of constitutively active IjB kinase complex (IKK)b (IKK-EE) significantly increases TRAIL-mediated apoptosis. Intriguingly, NF-jB inhibition reduces the recruitment of Fas-associated death domain and caspase-8 and formation of the deathinducing signaling complex (DISC) upon stimulation of TRAIL receptors or CD95. This results in reduced TRAIL-mediated activation of caspases, loss of mitochondrial potential and cytochrome c release in IjBa-SRexpressing cells. In comparison, NF-jB inhibition strongly enhances TNF-a-mediated apoptosis. Comparative studies revealed that TNF-a rapidly stimulates transcriptional activation and upregulation of anti-apoptotic proteins, whereas TRAIL causes apoptosis before transcriptional activation. Thus, this study demonstrates for the first time that NF-jB exerts a pro-apoptotic role in TRAIL-and CD95-induced apoptosis in glioblastoma cells by facilitating DISC formation.

Research paper thumbnail of NF-κB regulates DNA double-strand break repair in conjunction with BRCA1–CtIP complexes

Nucleic Acids Research, 2011

NF-iB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosi... more NF-iB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-iB can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-iB in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or crosstalk with p53. It was not mediated by the transcriptional NF-iB targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-iB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-iB interacts with CtIP-BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-iB activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-iBdependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-kB-mediated resistance to chemo-and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-kB activation.

Research paper thumbnail of Deficiency of Innate and Acquired Immunity Caused by an IKBKB Mutation

New England Journal of Medicine, 2013

Background Severe combined immunodeficiency (SCID) comprises a heterogeneous group of heritable d... more Background Severe combined immunodeficiency (SCID) comprises a heterogeneous group of heritable deficiencies of humoral and cell-mediated immunity. Many patients with SCID have lymphocyte-activation defects that remain uncharacterized. Methods We performed genetic studies in four patients, from four families of Northern Cree ancestry, who had clinical characteristics of SCID, including early onset of severe viral, bacterial, and fungal infections despite normal B-cell and T-cell counts. Genomewide homozygosity mapping was used to identify a candidate region, which was found on chromosome 8; all genes within this interval were sequenced. Immune-cell populations, signal transduction on activation, and effector functions were studied. Results The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and γδ T cells were absent. All patients carried a homozygous duplication-c.1292dupG in exon 13 of IKBKB, which encodes IκB kinase 2 (IKK2, also known as IKKβ)-leading to loss of expression of IKK2, a component of the IKK-nuclear factor κB (NF-κB) pathway. Immune cells from the patients had impaired responses to stimulation through T-cell receptors, B-cell receptors, toll-like receptors, inflammatory cytokine receptors, and mitogens. Conclusions A form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-κB signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.

Research paper thumbnail of Sustained, neuron-specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging

Molecular Neurodegeneration, 2013

Background Increasing evidence indicates that neuroinflammation is a critical factor contributing... more Background Increasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively ac...

Research paper thumbnail of Inhibition of NF-κB Signaling Ablates the Invasive Phenotype of Glioblastoma

Molecular Cancer Research, 2013

Glioblastoma multiforme, the most common primary brain tumor, is highly refractory to therapy, ma... more Glioblastoma multiforme, the most common primary brain tumor, is highly refractory to therapy, mainly due to its ability to form micrometastases, which are small clusters or individual cells that rapidly transverse the brain and make full surgical resection impossible. Here, it is demonstrated that the invasive phenotype of glioblastoma multiforme is orchestrated by the transcription factor NF-κB which, via metalloproteinases (MMP), regulates fibronectin processing. Both, cell lines and tumor stem cells from primary glioblastoma multiforme, secrete high levels of fibronectin which when cleaved by MMPs forms an extracellular substrate. Subsequently, forming and interacting with their own microenvironment, glioblastoma multiforme cells are licensed to invade their surroundings. Mechanistic study revealed that NF-κB inhibition, either genetically or pharmacologically, by treatment with Disulfiram, significantly abolished the invasive phenotype in the chick chorioallantoic membrane assa...

Research paper thumbnail of Proteasome Inhibition Results in TRAIL Sensitization of Primary Keratinocytes by Removing the Resistance-Mediating Block of Effector Caspase Maturation

Molecular and Cellular Biology, 2003

Research paper thumbnail of Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Journal of Clinical Investigation, Jun 1, 2007

Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflamm... more Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-κB target genes, including mediators of the inflammatory response such as TNF-α and ICAM-1. Indeed, inhibition of TNF-α activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-κB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease.

Research paper thumbnail of Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone

Oncogene, Jan 21, 1999

PTH is a major regulator of calcium homeostasis by mobilizing calcium through bone resorption. We... more PTH is a major regulator of calcium homeostasis by mobilizing calcium through bone resorption. We show that the expression of collagenase-3 (MMP-13), a member of the family of matrix metalloproteinases, required for the cleavage of collagens in the bone, is increased upon PTH injection in mice. A cis-acting element in the collagenase-3 promoter was identi®ed which, together with AP-1, is required for induction by PTH. This element contains CCACA motifs which are required for binding of the 65 kDa osteoblast-speci®c splice variant of Cbfa1. Introduction of mutations in this binding site that interfere with protein interaction also eliminates PTH inducibilty and transactivation by Cbfa/ Runt proteins. While DNA binding activity of AP-1 is increased upon PTH treatment, high basal level of Cbfa/ Runt binding activity is detectable in untreated cells which is not further increased by PTH, suggesting that AP-1 and Cbfa1 contribute to transcriptional activation through dierent mechanisms. In agreement with the critical role of both proteins de®ned in tissue culture cells, expression of collagenase-3 is reduced in mice lacking c-fos and is completely absent in cbfa1 7/7 embryos. These data provide the ®rst evidence for a critical role of Cbfa1, a major regulator of bone development, in PTH-dependent processes such as bone resorption.

Research paper thumbnail of NF-κB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss

Molecular Neurodegeneration

Background Inflammaging represents an accepted concept where the immune system shifts to a low-gr... more Background Inflammaging represents an accepted concept where the immune system shifts to a low-grade chronic pro-inflammatory state without overt infection upon aging. In the CNS, inflammaging is mainly driven by glia cells and associated with neurodegenerative processes. White matter degeneration (WMD), a well-known process in the aging brain, manifests in myelin loss finally resulting in motor, sensory and cognitive impairments. Oligodendrocytes (OL) are responsible for homeostasis and maintenance of the myelin sheaths, which is a complex and highly energy demanding process sensitizing these cells to metabolic, oxidative and other forms of stress. Yet, the immediate impact of chronic inflammatory stress like inflammaging on OL homeostasis, myelin maintenance and WMD remains open. Methods To functionally analyze the role of IKK/NF-κB signaling in the regulation of myelin homeostasis and maintenance in the adult CNS, we established a conditional mouse model allowing NF-κB activation...

Research paper thumbnail of RESEARCH ARTICLE Open Access Sustained, neuron-specific IKK/NF-κB activation

generates a selective neuroinflammatory response of neuronal IKK2/NF-κB signalling, possibly as a... more generates a selective neuroinflammatory response of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis.

Research paper thumbnail of IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization

Cells, 2021

Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced ... more Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number ...

Research paper thumbnail of Fos is an essential component of the mammalian UV response

The EMBO Journal, 1995

2Corresponding author Mouse 3T3 fibroblasts lacking c-fos were employed to demonstrate an essenti... more 2Corresponding author Mouse 3T3 fibroblasts lacking c-fos were employed to demonstrate an essential function of the UV-inducible transcription factor AP-1 (Fos/Jun) in the response to the cytotoxic effects of short-wavelength ultraviolet (UVC) radiation. Clonogenic survival and proliferation of cells lacking c-fos were drastically reduced following UV irradiation. This UV hypersensitivity manifests itself primarily in increased cell death, partly by apoptosis, and prolonged recovery time from UVinduced cell cycle arrest. Co-culture with wild-type cells did not ameliorate the hypersensitivity of mutant cells. Transcriptional induction of the c-Fos target genes collagenase I, stromelysin-1 and stromelysin-2 by UV is almost absent in cells lacking c-fos which correlates with a reduced UV induction of AP-1 DNAbinding and transactivation activity. The repair of UVinduced DNA lesions was not affected, as shown by unscheduled DNA synthesis and host cell reactivation assays. These data demonstrate that c-Fos is involved in a novel protective function other than DNA repair against the harmful consequences of UVC.

Research paper thumbnail of IKK2/NF-κB signaling protects neurons after traumatic brain injury

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 29, 2017

Traumatic brain injury (TBI) is the leading cause of death in young adults. After the initial inj... more Traumatic brain injury (TBI) is the leading cause of death in young adults. After the initial injury, a poorly understood secondary phase, including a strong inflammatory response determines the final outcome of TBI. The inhibitor of NF-κB kinase (IKK)/NF-κB signaling system is the key regulator of inflammation and also critically involved in regulation of neuronal survival and synaptic plasticity. We addressed the neuron-specific function of IKK2/NF-κB signaling pathway in TBI using an experimental model of closed-head injury (CHI) in combination with mouse models allowing conditional regulation of IKK/NF-κB signaling in excitatory forebrain neurons. We found that repression of IKK2/NF-κB signaling in neurons increases the acute posttraumatic mortality rate, worsens the neurological outcome, and promotes neuronal cell death by apoptosis, thus resulting in enhanced proinflammatory gene expression. As a potential mechanism, we identified elevated levels of the proapoptotic mediators ...

Research paper thumbnail of Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration

Molecular Neurodegeneration, 2017

Background: Neuroinflammation is associated with a wide range of neurodegenerative disorders, how... more Background: Neuroinflammation is associated with a wide range of neurodegenerative disorders, however the specific contribution to individual disease pathogenesis and selective neuronal cell death is not well understood. Inflammatory cerebellar ataxias are neurodegenerative diseases occurring in various autoimmune/inflammatory conditions, e.g. paraneoplastic syndromes. However, how inflammatory insults can cause selective cerebellar neurodegeneration in the context of these diseases remains open, and appropriate animal models are lacking. A key regulator of neuroinflammatory processes is the NF-κB signalling pathway, which is activated by the IκB kinase 2 (IKK2) in response to various pathological conditions. Importantly, its activation is sufficient to initiate neuroinflammation on its own. Methods: To investigate the contribution of IKK/NF-κB-mediated neuroinflammation to neurodegeneration, we established conditional mouse models of cerebellar neuroinflammation, which depend either on the tetracyclineregulated expression of IKK2 in astrocytes or Cre-recombination based IKK2 activation in Bergmann glia. Results: We demonstrate that IKK2 activation for a limited time interval in astrocytes is sufficient to induce neuroinflammation, astrogliosis and loss of Purkinje neurons, resembling the pathogenesis of inflammatory cerebellar ataxias. We identified IKK2-driven irreversible dysfunction of Bergmann glia as critical pathogenic event resulting in Purkinje cell loss. This was independent of Lipocalin 2, an acute phase protein secreted by reactive astrocytes and well known to mediate neurotoxicity. Instead, downregulation of the glutamate transporters EAAT1 and EAAT2 and ultrastructural alterations suggest an excitotoxic mechanism of Purkinje cell degeneration. Conclusions: Our results suggest a novel pathogenic mechanism how diverse inflammatory insults can cause inflammation/autoimmune-associated cerebellar ataxias. Disease-mediated elevation of danger signals like TLR ligands and inflammatory cytokines in the cerebellum activates IKK2/NF-κB signalling in astrocytes, which as a consequence triggers astrogliosis-like activation of Bergmann glia and subsequent non-cell-autonomous Purkinje cell degeneration. Notably, the identified hit and run mechanism indicates only an early window for therapeutic interventions.

Research paper thumbnail of Differential Regulation of NF-κB-Mediated Proviral and Antiviral Host Gene Expression by Primate Lentiviral Nef and Vpu Proteins

Cell Reports, 2015

NF-κB is essential for effective transcription of primate lentiviral genomes and also activates a... more NF-κB is essential for effective transcription of primate lentiviral genomes and also activates antiviral host genes. Here, we show that the early protein Nef of most primate lentiviruses enhances NF-κB activation. In contrast, the late protein Vpu of HIV-1 and its simian precursors inhibits activation of NF-κB, even in the presence of Nef. Although this effect of Vpu did not correlate with its ability to interact with β-TrCP, it involved the stabilization of IκB and reduced nuclear translocation of p65. Interestingly, however, Vpu did not affect casein kinase II-mediated phosphorylation of p65. Lack of Vpu was associated with increased NF-κB activation and induction of interferon and interferon-stimulated genes (ISGs) in HIV-1-infected T cells. Thus, HIV-1 and its simian precursors employ Nef to boost NF-κB activation early during the viral life cycle to initiate proviral transcription, while Vpu is used to downmodulate NF-κB-dependent expression of ISGs at later stages.

Research paper thumbnail of Nuclear Factor κB Activation Impairs Ependymal Ciliogenesis and Links Neuroinflammation to Hydrocephalus Formation

The Journal of Neuroscience, 2012

Hydrocephalus formation is a frequent complication of neuropathological insults associated with n... more Hydrocephalus formation is a frequent complication of neuropathological insults associated with neuroinflammation. However, the mechanistic role of neuroinflammation in hydrocephalus development is unclear. We have investigated the function of the proinflammatory acting inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling system in neuroinflammatory processes and generated a novel mouse model that allows conditional activation of the IKK/NF-κB system in astrocytes. Remarkably, NF-κB activation in astrocytes during early postnatal life results in hydrocephalus formation and additional defects in brain development. NF-κB activation causes global neuroinflammation characterized by a strong, astrocyte-specific expression of proinflammatory NF-κB target genes as well as a massive infiltration and activation of macrophages. In this animal model, hydrocephalus formation is specifically induced during a critical time period of early postnatal development, in which IKK/NF-κB-indu...

Research paper thumbnail of IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

The Journal of Neuroscience, 2012

Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF... more Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF-κB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase (IKK)/NF-κB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF-κB-dependent synapse development and remodeling. Here, we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmi...

Research paper thumbnail of Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

The Journal of Neuroscience, 2006

The transcription factor nuclear factor κB (NF-κB) is well known for its antiapoptotic action. Ho... more The transcription factor nuclear factor κB (NF-κB) is well known for its antiapoptotic action. However, in some disorders, such as cerebral ischemia, a proapoptotic function of NF-κB has been demonstrated. To analyze which subunit of NF-κB is functional in cerebral ischemia, we induced focal cerebral ischemia in mice with a germline deletion of thep52orc-Relgene or with a conditional deletion of RelA in the brain. Only RelA deficiency reduced infarct size. Interestingly, expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genesBimandNoxain cerebral ischemia depended on RelA and the upstream kinase IKK (IκB kinase). RelA stimulated Bim and Noxa gene transcription in primary cortical neurons and bound to the promoter of both genes. Thus, the deleterious function in cerebral ischemia is specific for the NF-κB subunit RelA and may be mediated through Bim and Noxa.

Research paper thumbnail of Characterization of sonic hedgehog as a novel NF‐κB target gene that promotes NF‐κB‐mediated apoptosis resistance and tumor growth in vivo

The FASEB Journal, 2008

To explore mechanisms controlling sonic hedgehog (Shh) expression in human cancers, we investigat... more To explore mechanisms controlling sonic hedgehog (Shh) expression in human cancers, we investigated regulation of Shh by the transcription factor NF-B. We identify putative NF-B binding sites in the human Shh promoter region that specifically bind NF-B complexes. Further, NF-B activation by tumor necrosis factor ␣ (TNF-␣) or p65 overexpression stimulates Shh promoter activity and p65 binds to Shh promoter in vivo. NF-B-mediated transcriptional activation of Shh is mapped to a minimal NF-B consensus site at position ؉139 of Shh promoter. NF-B activation results in increased Shh mRNA and protein expression in vitro and, notably, also in vivo in a genetic mouse model of inducible NF-B activity. Specific NF-B inhibition by inhibitory NF-B␣ (I-B␣) superrepressor or p65 knockdown inhibits NF-B-induced Shh promoter activation and Shh expression. NF-B-mediated Shh expression promotes proliferation and confers resistance to TRAIL-induced apoptosis. Silencing of Shh prevents NF-B-stimulated proliferation, while the addition of Shh rescues the proliferation defect imposed by NF-B inhibition. Notably, NF-B-stimulated tumor growth is significantly impaired by Shh knockdown in an in vivo model of pancreatic cancer. By demonstrating that NF-B regulates Shh expression, which contributes to NF-B-mediated proliferation and apoptosis resistance in vitro and in vivo, our findings have important implications to target aberrant Shh expression in human cancers.-Kasperczyk, H., Baumann, B., Debatin, K.-M., Fulda, S. Characterization of sonic hedgehog as a novel NF-B target gene that promotes NF-B-mediated apoptosis resistance and tumor growth in vivo.

Research paper thumbnail of Raf induces NF-κB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation

Proceedings of the National Academy of Sciences, 2000

NF-κB is regulated by inhibitor proteins (IκBs), which retain NF-κB in the cytoplasm. Signal-indu... more NF-κB is regulated by inhibitor proteins (IκBs), which retain NF-κB in the cytoplasm. Signal-induced phosphorylation by the IκB-kinase complex containing the IκB-kinases 1 and 2 (IKK-1/2 or IKK-α/β) and subsequent degradation of the IκB proteins are prerequisites for NF-κB activation. Many signals induce NF-κB, one of them being oncogenic Raf kinase. We investigated whether NF-κB induction is critical for Raf-mediated transformation. Here, we demonstrate that inhibition of NF-κB interferes with transformation by the Raf-oncogene, and we characterized the mechanism of NF-κB induction by activated Raf kinase and the tumor promoter phorbol 12-myristate 13-acetate (PMA). NF-κB activation by PMA and Raf critically depends on the IκB-kinase complex, most notably on IKK-2. A major signaling pathway induced by Raf is the mitogenic cytoplasmic kinase cascade. However, different inhibitors of this cascade do not affect PMA- and Raf-mediated NF-κB activation. Raf does not phosphorylate the IκB...

Research paper thumbnail of Identification of a novel pro-apoptotic role of NF-κB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells

Oncogene, 2011

We recently reported that nuclear factor-kappa B (NF-jB) promotes DNA damage-triggered apoptosis ... more We recently reported that nuclear factor-kappa B (NF-jB) promotes DNA damage-triggered apoptosis in glioblastoma, the most common brain tumor. In the present study, we investigated the role of NF-jB in death receptor-mediated apoptosis. Here, we identify a novel pro-apopotic function of NF-jB in TRAIL-and CD95induced apoptosis. Inhibition of NF-jB by overexpression of the dominant-negative IjBa-superrepressor (IjBa-SR) significantly decreases tumor necrosis factor (TNF)related apoptosis-inducing ligand (TRAIL)-or CD95induced apoptosis. Vice versa, activation of NF-jB via overexpression of constitutively active IjB kinase complex (IKK)b (IKK-EE) significantly increases TRAIL-mediated apoptosis. Intriguingly, NF-jB inhibition reduces the recruitment of Fas-associated death domain and caspase-8 and formation of the deathinducing signaling complex (DISC) upon stimulation of TRAIL receptors or CD95. This results in reduced TRAIL-mediated activation of caspases, loss of mitochondrial potential and cytochrome c release in IjBa-SRexpressing cells. In comparison, NF-jB inhibition strongly enhances TNF-a-mediated apoptosis. Comparative studies revealed that TNF-a rapidly stimulates transcriptional activation and upregulation of anti-apoptotic proteins, whereas TRAIL causes apoptosis before transcriptional activation. Thus, this study demonstrates for the first time that NF-jB exerts a pro-apoptotic role in TRAIL-and CD95-induced apoptosis in glioblastoma cells by facilitating DISC formation.

Research paper thumbnail of NF-κB regulates DNA double-strand break repair in conjunction with BRCA1–CtIP complexes

Nucleic Acids Research, 2011

NF-iB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosi... more NF-iB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-iB can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-iB in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or crosstalk with p53. It was not mediated by the transcriptional NF-iB targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-iB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-iB interacts with CtIP-BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-iB activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-iBdependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-kB-mediated resistance to chemo-and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-kB activation.

Research paper thumbnail of Deficiency of Innate and Acquired Immunity Caused by an IKBKB Mutation

New England Journal of Medicine, 2013

Background Severe combined immunodeficiency (SCID) comprises a heterogeneous group of heritable d... more Background Severe combined immunodeficiency (SCID) comprises a heterogeneous group of heritable deficiencies of humoral and cell-mediated immunity. Many patients with SCID have lymphocyte-activation defects that remain uncharacterized. Methods We performed genetic studies in four patients, from four families of Northern Cree ancestry, who had clinical characteristics of SCID, including early onset of severe viral, bacterial, and fungal infections despite normal B-cell and T-cell counts. Genomewide homozygosity mapping was used to identify a candidate region, which was found on chromosome 8; all genes within this interval were sequenced. Immune-cell populations, signal transduction on activation, and effector functions were studied. Results The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and γδ T cells were absent. All patients carried a homozygous duplication-c.1292dupG in exon 13 of IKBKB, which encodes IκB kinase 2 (IKK2, also known as IKKβ)-leading to loss of expression of IKK2, a component of the IKK-nuclear factor κB (NF-κB) pathway. Immune cells from the patients had impaired responses to stimulation through T-cell receptors, B-cell receptors, toll-like receptors, inflammatory cytokine receptors, and mitogens. Conclusions A form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-κB signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.

Research paper thumbnail of Sustained, neuron-specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging

Molecular Neurodegeneration, 2013

Background Increasing evidence indicates that neuroinflammation is a critical factor contributing... more Background Increasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively ac...

Research paper thumbnail of Inhibition of NF-κB Signaling Ablates the Invasive Phenotype of Glioblastoma

Molecular Cancer Research, 2013

Glioblastoma multiforme, the most common primary brain tumor, is highly refractory to therapy, ma... more Glioblastoma multiforme, the most common primary brain tumor, is highly refractory to therapy, mainly due to its ability to form micrometastases, which are small clusters or individual cells that rapidly transverse the brain and make full surgical resection impossible. Here, it is demonstrated that the invasive phenotype of glioblastoma multiforme is orchestrated by the transcription factor NF-κB which, via metalloproteinases (MMP), regulates fibronectin processing. Both, cell lines and tumor stem cells from primary glioblastoma multiforme, secrete high levels of fibronectin which when cleaved by MMPs forms an extracellular substrate. Subsequently, forming and interacting with their own microenvironment, glioblastoma multiforme cells are licensed to invade their surroundings. Mechanistic study revealed that NF-κB inhibition, either genetically or pharmacologically, by treatment with Disulfiram, significantly abolished the invasive phenotype in the chick chorioallantoic membrane assa...

Research paper thumbnail of Proteasome Inhibition Results in TRAIL Sensitization of Primary Keratinocytes by Removing the Resistance-Mediating Block of Effector Caspase Maturation

Molecular and Cellular Biology, 2003