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P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim

′-GATGAGAACACTCCAATTA-3′), and CDK1 (5′-GGGGATTCAGAAATTGATC-3′) were cloned into pCL2 GFP lentiviral vectors provided by Dr. Helmut Hanenberg. The shRNA sequence against mouse Map3k4 (5′-TTACGTCATCTGGACTAAT-3′) was ... Dr. Helmut Hanenberg. Flow cytometry analysis For analyzing mice erythroblasts, BM cells from P38α+/− and P38α−/− mice were collected and washed with staining buffer (PBS + 5% FBS). Then cells were

Effects of novel HDAC inhibitors on urothelial carcinoma cells

BackgroundHistone deacetylase inhibitors (HDACi) are promising anti-cancer drugs that could also be employed for urothelial carcinoma (UC) therapy. It is unclear, however, whether inhibition of all 11 zinc-dependent HDACs or of individual enzymes is more efficacious and specific. Here, we investigated the novel HDACi 19i (LMK235) with presumed preferential activity against class...

Effects of novel HDAC inhibitors on urothelial carcinoma cells

Histone deacetylase inhibitors (HDACi) are promising anti-cancer drugs that could also be employed for urothelial carcinoma (UC) therapy. It is unclear, however, whether inhibition of all 11 zinc-dependent HDACs or of individual enzymes is more efficacious and specific. Here, we investigated the novel HDACi 19i (LMK235) with presumed preferential activity against class IIA HDAC4...

FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

Microsatellite DNAs that form non-B structures are implicated in replication fork stalling, DNA double strand breaks (DSBs) and human disease. Fanconi anemia (FA) is an inherited disorder in which mutations in at least nineteen genes are responsible for the phenotypes of genome instability and cancer predisposition. FA pathway proteins are active in the resolution of non-B DNA...

The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling

Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). Expression and...

Characterization of an Additional Splice Acceptor Site Introduced into CYP4B1 in Hominoidae during Evolution

CYP4B1 belongs to the cytochrome P450 family 4, one of the oldest P450 families whose members have been highly conserved throughout evolution. The CYP4 monooxygenases typically oxidize fatty acids to both inactive and active lipid mediators, although the endogenous ligand(s) is largely unknown. During evolution, at the transition of great apes to humanoids, the CYP4B1 protein...

Peptide-independent stabilization of MHC class I molecules breaches cellular quality control

Tolba Abualrous Sunil Kumar Saini Linda Janen Andy Van Hateren Constanze Wiek Helmut Hanenberg Frank Momburg Adnane Achour Tim Elliott ) Sebastian Springer ( Denise Boulanger The intracellular

A Novel MCPH1 Isoform Complements the Defective Chromosome Condensation of Human MCPH1-Deficient Cells

Biallelic mutations in MCPH1 cause primary microcephaly (MCPH) with the cellular phenotype of defective chromosome condensation. MCPH1 encodes a multifunctional protein that notably is involved in brain development, regulation of chromosome condensation, and DNA damage response. In the present studies, we detected that MCPH1 encodes several distinct transcripts, including two...

Multimodality Imaging Methods for Assessing Retinoblastoma Orthotopic Xenograft Growth and Development

Genomic studies of the pediatric ocular tumor retinoblastoma are paving the way for development of targeted therapies. Robust model systems such as orthotopic xenografts are necessary for testing such therapeutics. One system involves bioluminescence imaging of luciferase-expressing human retinoblastoma cells injected into the vitreous of newborn rat eyes. Although used for...

AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia

Institute for Cell Signalling by the Wellcome Trust strategic award grant 097945/B/11/Z (to A.A.). Helmut Hanenberg is supported by the Lilly Foundation Physician/Scientist initiative and the Walther Cancer

Analysis of Prototype Foamy Virus particle-host cell interaction with autofluorescent retroviral particles

Background The foamy virus (FV) replication cycle displays several unique features, which set them apart from orthoretroviruses. First, like other B/D type orthoretroviruses, FV capsids preassemble at the centrosome, but more similar to hepadnaviruses, FV budding is strictly dependent on cognate viral glycoprotein coexpression. Second, the unusually broad host range of FV is...

Bcr/Abl Interferes with the Fanconi Anemia/BRCA Pathway: Implications in the Chromosomal Instability of Chronic Myeloid Leukemia Cells

Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. Although it is well known that CML cells are genetically unstable, the mechanisms accounting for this genomic instability are still poorly understood. Because the Fanconi anemia (FA) pathway is believed to control several mechanisms of...

Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA

Ilaria Dalla Rosa Steffi Goffart Melanie Wurm Constanze Wiek Frank Essmann Stefan Sobek Peter Schroeder Hongliang Zhang Jean Krutmann Helmut Hanenberg Klaus Schulze-Osthoff Christian Mielke Yves

Genetic inactivation of the Fanconi anemia gene FANCC identified in the hepatocellular carcinoma cell line HuH-7 confers sensitivity towards DNA-interstrand crosslinking agents

Background Inactivation of the Fanconi anemia (FA) pathway through defects in one of 13 FA genes occurs at low frequency in various solid cancer entities among the general population. As FA pathway inactivation confers a distinct hypersensitivity towards DNA interstrand-crosslinking (ICL)-agents, FA defects represent rational targets for individualized therapeutic strategies...

Shared Genetic Susceptibility to Breast Cancer, Brain Tumors, and Fanconi Anemia

, Khedoudja Nafa, Sat Dev Batish, Raffaella Diotti, Hildegard Schneider, Amie Deffenbaugh , Thomas Scholl, Virginia K. Proud , Mark Robson, Larry Norton, Nathan Ellis, Helmut Hanenberg, Arleen D. Auerbach