A5103195984- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- BRCA gene mutations in cancer
- Microtubule and mitosis dynamics
- Pancreatic and Hepatic Oncology Research
- Genetic Neurodegenerative Diseases
- Cancer-related Molecular Pathways
- Carcinogens and Genotoxicity Assessment
- PARP inhibition in cancer therapy
- Cancer Genomics and Diagnostics
- Ubiquitin and proteasome pathways
- Phagocytosis and Immune Regulation
- Calcium signaling and nucleotide metabolism
- Cancer Cells and Metastasis
- Mitochondrial Function and Pathology
- Erythrocyte Function and Pathophysiology
- Immune cells in cancer
- Cancer, Hypoxia, and Metabolism
- Cellular transport and secretion
- Cancer Research and Treatments
- Peptidase Inhibition and Analysis
- Sperm and Testicular Function
- Reproductive Biology and Fertility
- Technology, Environment, Urban Planning
- Lysosomal Storage Disorders Research
University of Siegen
2018-2023
Folkwang University of the Arts
2018-2022
Springer Nature (Germany)
2022
Carl von Ossietzky Universität Oldenburg
2022
Goethe University Frankfurt
2022
Martin Luther University Halle-Wittenberg
2022
E Ink (South Korea)
2022
Saarland University
2022
University of Münster
2022
The Ohio State University
2013-2020
Objective Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features PDAC and enhance the anti-programmed death-1-ligand 1 (PD-L1) inhibitor Design Transcription profiles IL-6 secretion from primary patient-derived stellate cells (PSCs) were analyzed via Nanostring immunohistochemistry, respectively. In vivo mechanistic...
The properties of breast cancer susceptibility protein required for tumor suppression have been explored.
We have determined that hMOF, the human ortholog of Drosophila MOF gene (males absent on first), encoding a protein with histone acetyltransferase activity, interacts ATM (ataxia-telangiectasia-mutated) protein. Cellular exposure to ionizing radiation (IR) enhances hMOF-dependent acetylation its target substrate, lysine 16 (K16) H4 independently function. Blocking IR-induced increase in at K16, either by expression dominant negative mutant ΔhMOF or RNA interference-mediated hMOF knockdown,...
Recombinant MG53 translocates to sites of injury in the proximal tubule kidney and protects mice from acute induced by ischemia or drugs.
Homologous recombination (HR) is initiated by DNA end resection, a process in which stretches of single-strand (ssDNA) are generated and used for homology search. Factors implicated resection include nucleases MRE11, EXO1, DNA2, ends into 3′ ssDNA overhangs; helicases such as BLM, unwind DNA; other proteins BRCA1 CtIP whose functions remain unclear. CDK-mediated phosphorylation on T847 required to promote whereas CDK-dependent CtIP-S327 interaction with BRCA1. Here, we provide evidence that...
Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic defects. In this paper, we report mice carrying homozygous kinase-dead mutations Atm (AtmKD/KD) died during early development. AtmKD/− cells exhibited proliferation defects...
Abstract Caveolin-1 (Cav-1) is a 21 kDa protein enriched in caveolae and has been implicated oncogenic cell transformation, tumorigenesis metastasis. We explored roles for Cav-1 pancreatic cancer (PC) prognostication, tumor progression, resistance to therapy whether targeted downregulation could lead therapeutic sensitization. expression was assessed lines, mouse models patient samples knocked down order compare changes proliferation, invasion, migration, response chemotherapy radiation...
We isolated the mas proto‐oncogene from a mouse genomic library. Sequence analysis showed that it contains an open reading frame without intervening sequences. The amino acid sequence deduced confirms seven‐transmembrane‐domain structure and exhibits 97% 91% homology with rat human Mas, respectively. In mice rats, mRNA was detected in testis, kidney, heart, brain regions: hippocampus, forebrain, piriform cortex, olfactory bulb. Testicular rats increases markedly during development, while...
Hereditary cases of breast and ovarian cancer are often attributed to germ-line mutations the BRCA1 tumor suppressor gene. Although is involved in diverse cellular processes, its role maintenance genomic integrity may be a key component suppression activity. The protein encoded by interacts vivo with related BARD1 form heterodimeric complex that acts as ubiquitin E3 ligase. Because enzymatic activity BRCA1/BARD1 heterodimer conserved over broad phylogenetic range, it thought critical for...
Abstract The breast cancer susceptibility gene 1 (BRCA1) plays a key role in mammary tumorigenesis. However, the reasons why silencing Brca1 leads to tumorigenesis are not clearly understood. We report here that BRCA1 deficiency activates AKT oncogenic pathway, one of most common alterations associated with human malignancy. Mutation increases phosphorylation and kinase activity AKT. BRCA1-BRCT domains bind phosphorylated (pAKT) lead its ubiquitination toward protein degradation. mutant...
Homology-directed repair (HDR) is a critical pathway for the of DNA double-strand breaks (DSBs) in mammalian cells. Efficient HDR thought to be crucial maintenance genomic integrity during organismal development and tumor suppression. However, most studies have focused on transformed immortalized cell lines. We report here generation Direct Repeat (DR)-GFP reporter-based mouse model study primary types derived from diverse lineages. Embryonic adult fibroblasts these mice as well cells...
Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and phosphorylated colocalizes with γ-H2AX, ATM, 53BP1 foci. Mutation site (MOF-T392A) impedes in S G2 but not G1 cells. Expression MOF-T392A also blocks reduction DSB-associated seen wild-type S/G2 cells,...
The CtIP protein facilitates homology-directed repair (HDR) of double-strand DNA breaks (DSBs) by initiating resection, a process in which DSB ends are converted into 3′-ssDNA overhangs. BRCA1 tumor suppressor, interacts with phospho-dependent manner, has also been implicated through the HDR pathway. It was recently reported that BRCA1–CtIP interaction is essential for chicken DT40 cells. To examine role this mammalian cells, we generated cells and mice express Ctip polypeptides (Ctip-S326A)...
Induced pluripotent stem cells (iPSCs) hold great promise for personalized regenerative medicine. However, recent studies show that iPSC lines carry genetic abnormalities, suggesting reprogramming may be mutagenic. Here, we the ectopic expression of factors increases level phosphorylated histone H2AX, one earliest cellular responses to DNA double-strand breaks (DSBs). Additional mechanistic uncover a direct role homologous recombination (HR) pathway, pathway essential error-free repair DSBs,...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2'-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, found globally decreased 5-methyl-cytosine (5-mC) malignant epithelial cells and cancer-associated myofibroblasts (CAF), along with increased amounts 5-hydroxymethyl-cytosine (5-HmC) CAFs,...
PALB2 links BRCA1 and BRCA2 in homologous recombinational repair of DNA double strand breaks (DSBs). Mono-allelic mutations increase the risk breast, pancreatic, other cancers, biallelic cause Fanconi anemia (FA). Like Brca1 Brca2, systemic knock-out Palb2 mice results embryonic lethality. In this study, we generated a hypomorphic allele expressing mutant protein unable to bind BRCA1. Consistent with an FA-like phenotype, cells from showed hypersensitivity chromosomal breakage when treated...
Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It unknown if this association causal.
Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms, such pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy more than 25 years. Using a novel combination of shIDO-ST, Salmonella-based targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, depletes extracellular matrix hyaluronan, we observed extended survival frequent total regression...
Abstract Proneural glioblastoma is defined by an expression pattern resembling that of oligodendrocyte progenitor cells and carries a distinctive set genetic alterations. Whether there functional relationship between the proneural phenotype associated alterations unknown. To evaluate this possible relationship, we performed longitudinal molecular characterization tumor progression in mouse model glioma. In setting, tumors acquired remarkably consistent deletions at late stages progression,...
Significance The tumor suppressors BRCA1 and ATM have both been implicated in the early steps of homologous recombination, also termed homology-directed repair (HDR). However, how genetically interacts with this process is unclear. In mice carrying a breast cancer-derived mutation C-terminal (BRCT) domain, we find that becomes essential for supporting residual levels HDR necessary to DNA break. ATM-mediated not affected by status 53BP1, an antagonizing factor BRCA1. loss associated synthetic...
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven cancer progression, is currently unclear. Here we show that disruption paracrine Hedgehog signaling via genetic ablation Smoothened (Smo) stromal fibroblasts Kras(G12D) mouse model increased ADM. Smo-deleted had higher expression transforming growth factor-α (Tgfa) mRNA and secreted levels TGFα, leading activation EGFR acinar cells mechanism involved...
Although the BRCA1 tumor suppressor has been implicated in many cellular processes, biochemical mechanisms by which it influences these diverse pathways are poorly understood. The only known enzymatic function of is E3 ubiquitin ligase activity mediated its highly conserved RING domain. In vivo, associates with BARD1 polypeptide to form a heterodimeric BRCA1/BARD1 complex that catalyzes autoubiquitination and trans ubiquitination other protein substrates. most cases, BRCA1-dependent...