Visit our Expo - Redox and Inflammation signaling 2012

Session XIV : Transcriptional and translational control Poster XIV, 35
Finding crossroads of signal transduction pathways targeting promoters of “disease”
genes involved in pathological calcification.
Alexander Kel1, Nico Voss1, Olga Kel-Margoulis1, Evelin Katona3, Gerd Schmitz3 and
Edgar Wingender1,4
1 BIOBASE GmbH, Halchtersche Str. 33, D-38304 Wolfenbüttel, Germany; 3 Institute
for Clinical Chemistry and Laboratory Medicine University Hospital Regensburg
Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany; 4 Dept. Bioinformatics,
UKG/Univ. Göttingen, Goldschmidstr. 1, 37077 Göttigne, Germany
E-mail : alexander.kel@biobase-international.com
Different signal transduction pathways converge at key molecules that master the regulation
of certain cellular processes. Such crossroads of signal networks are often their “Achilles
Heels” causing a disease when not functioning properly. We have developed a computational
method for analysis microarray gene expression data and identification the key transcription
factors and “upstream” signaling molecules that might be the causes of the observed change
in gene expression. There are two steps of analysis (using TRANSFAC® and
TRANSPATH® databases): 1) CMFinder analyzes 5’-upstream regions of coexpressed
genes and applies a genetic algorithm to reveal composite modules (CMs) consisting of cooccurring
single TF binding sites and composite elements; 2) ArrayAnalyzer is a fast
network search engine that analyzes signal transduction networks controlling the activities of
the corresponding TFs and finds the key signaling molecules. The method was applied to
micrarray data on Pseudoxanthoma elasticum (PXE) (a disease linked to the monogenic
defects of ABCC6 transporter and characterized by alterations of elastic fibers and dystrophic
calcification). We provided evidence that the SOX9-related transcriptional pathway and the
IL-1#-linked signaling route are defective in PXE. We have identified PKAc kinase and
TRAF-6 as important key nodes in the signaling pathways that are pathologically altered.
They can be considered as prospective drug targets. We hypothesized that impaired activity of
the transporter may change a lipid balance in extracellular matrix resulting in activation of
certain signal transduction mechanism leading to the disease symptoms.
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