77 research outputs found
An RNAi-based system for loss-of-function analysis identifies Raf1 as a crucial mediator of BCR-ABL - Driven leukemogenesis
Genetic loss-of-function studies in murine tumor models have been essential in the analysis of downstream mediators of oncogenic transformation. Unfortunately, these studies are frequently limited by the availability of genetically modified mouse strains. Here we describe a versatile method allowing the efficient expression of an oncogene and simultaneous knockdown of targets of interest (TOI) from a single retroviral vector. Both oncogene and TOI-specific miR30-based shRNA are under the control of the strong viral long terminal repeat promoter, resulting in a single shared RNA transcript. Using this vector in a murine syngeneic BM transplantation model for BCR-ABL - induced chronic myeloid leukemia, we find that oncogene expression andtargetknockdownin primary hematopoietic cells with this vector is efficient both in vitro and in vivo, and demonstrate that Raf1, but not BRAF, modulates BCR-ABL - dependent ERK activation and transformation of hematopoietic cells. This expression system could facilitate genetic loss-of-function studies and allow the rapid validation of potential drug targets in a broad range of oncogene-driven murine tumor models. © 2011 by The American Society of Hematology
Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides
The disruption of proteostasis in neurodegenerative diseases
Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio
"Histologisch nicht in toto" ist nach endoskopischer Abtragung von malignen kolorektalen Polypen speziell bei breitbasiger Polypenmorphologie ein wichtiger Risikofaktor fĂĽr Lymphknotenmetastasen
A Single Retroviral Vector Design for the Simultaneous Expression of a Mir30 Based Shrna with An Oncogene - Identification of Raf 1 but Not BRAF as a Crucial Mediator for BCR ABL Mediated Leukemogenesis
Targeted inactivation of nuclear interaction partner of ALK (NIPA) disrupts meiotic prophase
NIPA (nuclear interaction partner of ALK) is an F-box like protein that monitors the timing of mitotic entry. Constitutively active
NIPA delays mitotic entry by preventing accumulation of nuclear cyclin B1. Here, we have investigated the consequences of Nipa
inactivation by using a conditional knockout strategy. Nipa-deficient animals are viable, but show a lower birth rate and a reduced
body weight. Furthermore, Nipa-deficient males are sterile owing to a block of spermatogenesis during meiotic prophase. Whereas
Nipa–/– mouse embryonic fibroblasts show no severe phenotype, Nipa–/– spermatocytes arrest during stage IV of the epithelial cycle
with subsequent TUNEL-positive apoptosis resulting from improper synapsis, defects in the repair of DNA double-stranded breaks
and synaptonemal complex formation. Moreover, we show nuclear accumulation of cyclin B1 with a subsequent premature increase
in G2/M kinase activity in Nipa–/– spermatocytes. Together, these results show a new unsuspected role for NIPA in meiosis
Erste Erfahrungen und Ergebnisse des Molekularen Tumorboards in der Uroonkologie - bizentrische Auswertung von 120 Patientinnen und Patienten
Inhibition of Aurora Kinase B Is Important for Biologic Activity of the Dual Inhibitors of BCR-ABL and Aurora Kinases R763/AS703569 and PHA-739358 in BCR-ABL Transformed Cells
<div><p>ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/AS703569 in Ba/F3- cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.</p></div
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