A5025138388- Cancer Mechanisms and Therapy
- Chronic Lymphocytic Leukemia Research
- interferon and immune responses
- Peptidase Inhibition and Analysis
- Acute Myeloid Leukemia Research
- Multiple Myeloma Research and Treatments
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Synthesis and biological activity
- Cancer, Hypoxia, and Metabolism
- Cytokine Signaling Pathways and Interactions
- Synthesis and Biological Evaluation
- Protein Degradation and Inhibitors
- Rabies epidemiology and control
- PI3K/AKT/mTOR signaling in cancer
- Chronic Myeloid Leukemia Treatments
- Adenosine and Purinergic Signaling
- Biochemical and Molecular Research
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- Melanoma and MAPK Pathways
- Viral Infections and Vectors
- RNA modifications and cancer
- FOXO transcription factor regulation
- Galectins and Cancer Biology
Collegium Civitas
2015-2019
State Agency for the Prevention of Alcohol Related Problems
2015-2017
Ludwig-Maximilians-Universität München
2004-2014
Friedrich-Loeffler-Institut
2012
University of Bonn
2006
Osaka University
2006
University Hospital Bonn
2006
The structural basis for the distinction of viral RNA from abundant self in cytoplasm virally infected cells is largely unknown. We demonstrated that 5'-triphosphate end generated by polymerases responsible retinoic acid-inducible protein I (RIG-I)-mediated detection molecules. Detection abrogated capping or nucleoside modification RNA, both occurring during posttranscriptional processing eukaryotes. Genomic prepared a negative-strand virus and virus-infected (but not noninfected cells)...
Rabies virus (RV) of the Rhabdoviridae family grows in alpha/beta interferon (IFN)-competent cells, suggesting existence viral mechanisms preventing IFN gene expression. We here identify phosphoprotein P as responsible antagonist. The critical involvement was first suggested by observation that an RV expressing enhanced green fluorescent protein (eGFP)-P fusion (SAD eGFP-P) (S. Finke, K. Brzozka, and Conzelmann, J. Virol. 78:12333-12343, 2004) eliminated IFN-competent HEp-2 cell cultures,...
ABSTRACT Human plasmacytoid dendritic cells (PDC) are key sentinels alerting both innate and adaptive immune responses through production of huge amounts alpha/beta interferon (IFN). IFN induction in PDC is triggered by outside-in signal transduction pathways Toll-like receptor 7 (TLR7) TLR9 as well recognition cytosolic virus-specific patterns. TLR7 ligands include single-stranded RNA CpG-rich DNA, respectively, synthetic derivatives thereof which being evaluated therapeutic modulators...
Rabies virus (RV) phosphoprotein P is an interferon (IFN) antagonist counteracting transcriptional activation of type I IFN (K. Brzózka, S. Finke, and K. Conzelmann, J. Virol 79:7673-7681, 2005). We here show that RV in addition responsible for preventing IFN-alpha/beta- IFN-gamma-stimulated JAK-STAT signaling RV-infected cells by the retention activated STATs cytoplasm. Expression IFN-stimulated response element- gamma-activated sequence-controlled genes was severely impaired infected with...
ABSTRACT The rabies virus (RV) phosphoprotein (P) is a type I interferon (IFN) antagonist preventing both transcriptional induction of IFN and IFN-mediated JAK/STAT signaling. In addition, P an essential cofactor the viral polymerase required for encapsidation RNA into nucleoprotein during replication. By site-directed mutagenesis, we have identified domain efficient inhibition induction. Phosphoproteins lacking amino acids (aa) 176 to 181, 182 186, or 186 were severely compromised in...
Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, novel inhibitor Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be type I forming halogen bonds protein's hinge region and hydrophobic complementarities within its front pocket. inhibits phosphorylation STAT1 S727 STAT5 S726 in cancer cells vitro....
Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment these patients with C-KIT inhibitors has proven challenging, prompting us to investigate downstream effectors receptor. We determined that stimulates MAP kinase-interacting serine/threonine kinases 1 2 (MNK1/2), phosphorylate...
Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays central role in the pathogenesis of this malignancy, controlling genes involved apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate methionine cycles, supporting certain amino acids, nucleotides, glutathione, methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes,...
Rhabdoviruses such as rabies virus (RV) encode only five multifunctional proteins accomplishing viral gene expression and formation. The phosphoprotein, P, is a structural component of the ribonucleoprotein (RNP) complex an essential cofactor for RNA-dependent RNA polymerase. We show here that RV P fused to enhanced green fluorescent protein (eGFP) can substitute throughout life cycle, allowing fluorescence labeling tracking RNPs under live cell conditions. To first assess functions fusion...
Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought be major drivers phenotype and their inhibition relapsed samples restores cell sensitivity inhibitors. Thus, simultaneous represents a promising strategy AML therapy. For such reasons, we have developed...
Abstract The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development small-molecule inhibitors therapeutic targeting lymphomas. However, detailed consequences inhibition DLBCL remain undefined. Using...
Prenatal Alcohol Exposure is a major cause of brain damage and developmental delay, known as Fetal Spectrum Disorders (FASD) but in Poland rarely diagnosed the scale problem not known.An active case ascertainment approach was applied to estimate prevalence FASD among 7-9 years olds. Pre-screening conducted 113 randomly selected regular special schools. In screening phase participated 280 children (54% from risk group, 60% boys). The entire number eligible students (N = 2500) taken...
Abstract Lymph node microenvironment provides chronic lymphocytic leukaemia ( CLL ) cells with signals promoting their survival and granting resistance to chemotherapeutics. overexpress PIM kinases, which regulate apoptosis, cell cycle migration. We demonstrate that BCR crosslinking, CD 40 stimulation, coculture stromal increases s expression in cells, indicating microenvironment‐dependent regulation. 1 2 at diagnosis was higher patients advanced disease (Binet C vs. Binet A/B) those, who...
Abstract Energy and biomass production in cancer cells are largely supported by aerobic glycolysis what is called the Warburg effect. The process regulated key enzymes, among which phosphofructokinase PFK‐2 plays a significant role producing fructose‐2,6‐biphosphate; most potent activator of rate‐limiting step performed PFK‐1. Herein, synthesis, biological evaluation structure–activity relationship novel inhibitors 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), ubiquitous...
Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types tumors. Hence, it suggested that HO-1 may serve as a potential target anticancer therapies. A novel approach to inhibit related the synthetic lethality this enzyme and fumarate hydratase (FH). In current study, we aimed validate effect genetic pharmacological inhibition cells isolated from patients suffering hereditary leiomyomatosis renal cell carcinoma (HLRCC)-an inherited cancer syndrome, caused...
// Ewa M. Kosciuczuk 1 , 2 3 * Aroop K. Kar 4 Gavin T. Blyth Mariafausta Fischietti Sameem Abedin 5 Alain A. Mina Rebekah Siliezar Tomasz Rzymski 6 Krzysztof Brzozka Elizabeth Eklund Elspeth Beauchamp Frank Eckerdt 7 Diana Saleiro and Leonidas C. Platanias Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA Division Hematology-Oncology, Department Medicine, Feinberg School Jesse Brown Veterans Affairs Medical Center, Hematology/Oncology/Stem Cell...