TY  - JOUR
A1  - Hohenauer, Tobias
A1  - Berking, Carola
A1  - Schmidt, Andreas
A1  - Haferkamp, Sebastian
A1  - Senft, Daniela
A1  - Kammerbauer, Claudia
A1  - Fraschka, Sabine
A1  - Graf, Saskia Anna
A1  - Irmler, Martin
A1  - Beckers, Johannes
A1  - Flaig, Michael
A1  - Aigner, Achim
A1  - Höbel, Sabrina
A1  - Hoffmann, Franziska
A1  - Hermeking, Heiko
A1  - Rothenfusser, Simon
A1  - Endres, Stefan
A1  - Ruzicka, Thomas
A1  - Besch, Robert
T1  - The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival
JF  - EMBO Molecular Medicine
N2  - Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by Mre11/Rad50-containing nuclear foci. Activated DNA damage signalling caused stabilization of the tumour suppressor p53, which resulted in cell cycle arrest and apoptosis. When Brn3a was ectopically expressed in primary melanocytes and fibroblasts, anchorage-independent growth was increased. In tumourigenic melanocytes and fibroblasts, Brn3a accelerated tumour growth in vivo. Furthermore, Brn3a cooperated with proliferation pathways such as oncogenic BRAF, by reducing oncogene-induced senescence in non-malignant melanocytes. Together, these results identify Brn3a as a new factor in melanoma that is essential for melanoma cell survival and that promotes melanocytic transformation and tumourigenesis.
KW  - oncogene-induced senescence
KW  - BRN-3A
KW  - DNA
KW  - DNA damage
KW  - tumourigenesis
KW  - P53
KW  - in-vitro
KW  - neural crest factors
KW  - family
KW  - apoptosis
KW  - melanoma
KW  - BRAF mutations
KW  - domain
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122193
SN  - 1757-4676
VL  - 5
ER  - 
TY  - JOUR
A1  - Gewies, Andreas
A1  - Gorka, Oliver
A1  - Bergmann, Hanna
A1  - Pechloff, Konstanze
A1  - Petermann, Franziska
A1  - Jeltsch, Katharina M.
A1  - Rudelius, Martina
A1  - Kriegsmann, Mark
A1  - Weichert, Wilko
A1  - Horsch, Marion
A1  - Beckers, Johannes
A1  - Wurst, Wolfgang
A1  - Heikenwalder, Mathias
A1  - Korn, Thomas
A1  - Heissmeyer, Vigo
A1  - Ruland, Juergen
T1  - Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation
JF  - Cell Reports
N2  - The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-kappa B activation, and its proteolytic domain cleaves negative NF-kappa B regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-kappa B inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFN gamma) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation.
KW  - helper T-cells
KW  - combined immunodeficiency
KW  - messenger RNA
KW  - roquin
KW  - mice
KW  - NF-KAPPA-B
KW  - lymphoid-tissue
KW  - activation
KW  - cleavage
KW  - mutations
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114627
VL  - 9
IS  - 4
ER  -