TY  - JOUR
A1  - Saint Fleur-Lominy, Shella
A1  - Maus, Mate
A1  - Vaeth, Martin
A1  - Lange, Ingo
A1  - Zee, Isabelle
A1  - Suh, David
A1  - Liu, Cynthia
A1  - Wu, Xiaojun
A1  - Tikhonova, Anastasia
A1  - Aifantis, Iannis
A1  - Feske, Stefan
T1  - STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia
JF  - Cell Reports
N2  - T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.
KW  - T cell acute lymphoblastic leukemia
KW  - T-ALL
KW  - Notch1
KW  - STIM1
KW  - STIM2
KW  - calcium
KW  - Ca2+
KW  - CRAC
KW  - channel
KW  - inflammation
KW  - interferon
KW  - anemia
KW  - macrophages
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227259
VL  - 24
IS  - 11
ER  - 
TY  - JOUR
A1  - Atak, Sinem
A1  - Langlhofer, Georg
A1  - Schaefer, Natascha
A1  - Kessler, Denise
A1  - Meiselbach, Heike
A1  - Delto, Carolyn
A1  - Schindelin, Hermann
A1  - Villmann, Carmen
T1  - Disturbances of ligand potency and enhanced degradation of the human glycine receptor at affected positions G160 and T162 originally identified in patients suffering from hyperekplexia
JF  - Frontiers in Molecular Neuroscience
N2  - Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GIyR) undergoes direct interaction with the incoming ligand via a cation-π interaction. Recently, we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GIyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GIyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER toward the ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is delivered to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, 1162 affects primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.
KW  - mutations
KW  - trafficking
KW  - domain
KW  - hyperekplexia
KW  - loop B
KW  - side chain properties
KW  - ligand potencies
KW  - Cys-loop receptor
KW  - glycine receptor
KW  - site
KW  - activation
KW  - binding
KW  - channel
KW  - mechanisms
KW  - dominant
KW  - startle
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144818
VL  - 8
IS  - 79
ER  -