Characterization of Neurofibromatosis 2 (NF2) Tumor : Suppreor Binding Proteins

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder that is characterized by the occurrence of vestibular schwannomas, meningiomas and other nervous system tumors. Both the familial tumors of NF2, and equivalent sporadic tumors in the general population, are caused by inactivation of a tumor suppressor gene located on chromosome band 22q12. The NF2 gene product has been named merlin (moesin, ezrin and radixin like protein) because of its striking similarity to ezrin, radixin and moesin (ERM). Regulation of the merlin and ERM proteins (MERM) involves intramolecular and intermolecular head-to-tail associations between family members. The next step is to further analyze the normal function of merlin and its role as a growth regulator. Towards this end the MERM binding protein, NHE-RF, was further characterized and other merlin binding proteins were sought. Analyses of NHE-RF expression in various tumor cell lines revealed a significant upregulation of NHE-RF expression in ER- positive breast carcinoma cell lines. In addition, 90% of the analyzed primary ER-positive breast tumors express high levels of NHE-RF. NHE-RF appears to be involved in many cellular signaling pathways, and it is likely that its regulation through estrogen plays a role in breast neoplasia. To isolate further merlin binding proteins, a yeast two-hybrid screen was conducted and revealed that a novel protein (merintA) interacts directly with merlin. The gene for human merintA lies on chromosome 4 where the predicted four exons encode a 178 amino acid protein with the Grb2 binding motif (p)YVNG. MerintA associates and co-localizes with merlin and F-actin in cultured cells and in addition, merintA binds to Grb2 directly. These findings reveal that merintA is a specific and relevant merlin binding protein and could link merlin to Grb2 signaling pathways that might reveal clues to the tumor suppressor function of merlin

Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers

A study on the transition between seniority-type and collective excitations in 204Po and 206Po

Low-lying yrast states in 204Po and 206Po have been investigated by the γ-γ fast timing technique with LaBr3(Ce) detectors. Excited states of these nuclei were populated in the 197Au(11B,4n) and the 198Pt(12C,4n) fusion-evaporation reactions, respectively, at the FN-Tandem Facility at the University of Cologne. The lifetimes of the 4+1 states in both nuclei were measured, along with an upper limit for the 2+1 state in 204Po. The preliminary results are discussed in the scope of the systematic behavior of the transition strengths between yrast states in polonium isotopes

Ein Wirtschaftsführer im Dienste des Nationalsozialismus

Teilw. zugl.: Kassel, Universität Kassel, Staatsexamensarbeit, 200

Memory Enhancement by Targeting CDK5 Regulation of NR2B

SummaryMany psychiatric and neurological disorders are characterized by learning and memory deficits, for which cognitive enhancement is considered a valid treatment strategy. The N-methyl-D-aspartate receptor (NMDAR) is a prime target for the development of cognitive enhancers because of its fundamental role in learning and memory. In particular, the NMDAR subunit NR2B improves synaptic plasticity and memory when overexpressed in neurons. However, NR2B regulation is not well understood and no therapies potentiating NMDAR function have been developed. Here, we show that serine 1116 of NR2B is phosphorylated by cyclin-dependent kinase 5 (Cdk5). Cdk5-dependent NR2B phosphorylation is regulated by neuronal activity and controls the receptor’s cell surface expression. Disrupting NR2B-Cdk5 interaction via a small interfering peptide (siP) increases NR2B surface levels, facilitates synaptic transmission, and improves memory formation in vivo. Our results reveal a regulatory mechanism critical to NR2B function that can be targeted for the development of cognitive enhancers.Video Abstrac

Search for Isovector Valence-Shell Excitations in 140Nd and 142Sm via Coulomb excitation reactions of radioactive ion beams

Projectile Coulomb excitation experiments were performed at HIE-ISOLDE at CERN with the radioactive ion beams of 140Nd and 142Sm. Ions with an energy of 4:62 MeV/A were impinging on a 1.45 mg/cm2 thick 208Pb target. The γ-rays depopulating the Coulomb-excited states were recorded by the HPGe-array MINIBALL and scattered particles were detected by a double-sided silicon strip detector. Experimental intensities were used for the determination of electromagnetic transition matrix elements. A preliminary result of the B(M1; 2+3 → 2+1) of 140Nd and an upper limit for the case of 142Sm are revealing the main fragments of the proton-neutron mixed-symmetry 2+1;ms states

Search for Isovector Valence-Shell Excitations in Nd-140 and Sm-142 via Coulomb excitation reactions of radioactive ion beams

Projectile Coulomb excitation experiments were performed at HIE-ISOLDE at CERN with the radioactive ion beams of 140Nd and 142Sm. Ions with an energy of 4.62 MeV/A were impinging on a 1.45 mg/cm2 thick 208Pb target. The γ-rays depopulating the Coulomb-excited states were recorded by the HPGe-array MINIBALL and scattered particles were detected by a double-sided silicon strip detector. Experimental intensities were used for the determination of electromagnetic transition matrix elements. A preliminary result of the B(M1; 2+ 3→2+ 1 ) of 140Nd and an upper limit for the case of 142Sm are revealing the main fragments of the proton-neutron mixed-symmetry 2+ 1,ms states.peerReviewe

Coulomb Excitation of Proton-rich N = 80 Isotones at HIE-ISOLDE

A projectile Coulomb-excitation experiment was performed at the radioactive ion beam facility HIE-ISOLDE at CERN. The radioactive 140Nd and 142Sm ions were post accelerated to the energy of 4.62 MeV/A and impinged on a 1.45 mg/cm2-thin 208Pb target. The γ rays depopulating the Coulomb-excited states were recorded by the HPGe-array MINIBALL. The scattered charged particles were detected by a double-sided silicon strip detector in forward direction. Experimental γ-ray intensities were used for the determination of electromagnetic transition matrix elements. Preliminary results for the reduced transition strength of the B(M1 23+ to 21+)=0.35(19) μN2 of 140Nd and a first estimation for 142Sm have been deduced using the Coulomb-excitation calculation software GOSIA. The 23+ states of 140Nd and 142Sm show indications of being the main fragment of the proton-neutron mixed-symmetry 21, ms+ state.peerReviewe