TY  - JOUR
A1  - Keller, Andreas
A1  - Leidinger, Petra
A1  - Vogel, Britta
A1  - Backes, Christina
A1  - ElSharawy, Abdou
A1  - Galata, Valentina
A1  - Mueller, Sabine C.
A1  - Marquart, Sabine
A1  - Schrauder, Michael G.
A1  - Strick, Reiner
A1  - Bauer, Andrea
A1  - Wischhusen, Jörg
A1  - Beier, Markus
A1  - Kohlhaas, Jochen
A1  - Katus, Hugo A.
A1  - Hoheisel, Jörg
A1  - Franke, Andre
A1  - Meder, Benjamin
A1  - Meese, Eckart
T1  - miRNAs can be generally associated with human pathologies as exemplified for miR-144*
JF  - BMC MEDICINE
N2  - Background: miRNA profiles are promising biomarker candidates for a manifold of human pathologies, opening new avenues for diagnosis and prognosis. Beyond studies that describe miRNAs frequently as markers for specific traits, we asked whether a general pattern for miRNAs across many diseases exists. 
Methods: We evaluated genome-wide circulating profiles of 1,049 patients suffering from 19 different cancer and non-cancer diseases as well as unaffected controls. The results were validated on 319 individuals using qRT-PCR. 
Results: We discovered 34 miRNAs with strong disease association. Among those, we found substantially decreased levels of hsa-miR-144* and hsa-miR-20b with AUC of 0.751 ( 95% CI: 0.703-0.799), respectively. We also discovered a set of miRNAs, including hsa-miR-155*, as rather stable markers, offering reasonable control miRNAs for future studies. The strong downregulation of hsa-miR-144* and the less variable pattern of hsa-miR-155* has been validated in a cohort of 319 samples in three different centers. Here, breast cancer as an additional disease phenotype not included in the screening phase has been included as the 20th trait. 
Conclusions: Our study on 1,368 patients including 1,049 genome-wide miRNA profiles and 319 qRT-PCR validations further underscores the high potential of specific blood-borne miRNA patterns as molecular biomarkers. Importantly, we highlight 34 miRNAs that are generally dysregulated in human pathologies. Although these markers are not specific to certain diseases they may add to the diagnosis in combination with other markers, building a specific signature. Besides these dysregulated miRNAs, we propose a set of constant miRNAs that may be used as control markers.
KW  - peripheral blood
KW  - microna profiles
KW  - disease
KW  - signature
KW  - expression
KW  - miRNA
KW  - microarray
KW  - biomarker
KW  - bioinformatics
KW  - lung-cancer
KW  - multiple sclerosis
KW  - gene
KW  - serum
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114349
SN  - 1741-7015
VL  - 12
ER  - 
TY  - JOUR
A1  - Bernt, Alexander
A1  - Rangrez, Ashraf Y.
A1  - Eden, Matthias
A1  - Jungmann, Andreas
A1  - Katz, Sylvia
A1  - Rohr, Claudia
A1  - Müller, Oliver J.
A1  - Katus, Hugo A.
A1  - Sossalla, Samuel T.
A1  - Williams, Tatjana
A1  - Ritter, Oliver
A1  - Frank, Derk
A1  - Frey, Norbert
T1  - Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy
JF  - Scientific Reports
N2  - The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.
KW  - Calcineurin-NFATsignaling
KW  - activation
KW  - SUMO2
KW  - cardiac hypertrophy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167525
VL  - 6
IS  - 35758
ER  -