Mechanismen der GSK-3-Beta-vermittelten Regulation des onkogenen Transkriptionsfaktors NFATc2 im Pankreaskarzinom
Loading...
Files
Date
Authors
Publisher
Philipps-Universität Marburg
Supervisors
Abstract
GSK-3-Beta is a multifunctional kinase which is deregulated in many diseases, such
as diabetes, Alzheimers’s disease or cancer. It was originally considered to be a
tumor suppressor due to its implication in the Wnt/-catenin signaling pathway.
Recent studies however revealed a crucial pro-proliferative role in pancreatic
cancer which is accompanied by an aggressive phenotype. GSK-3 is
moreover a main modulator of the Calcineurin/NFAT signaling pathway.
Thereby, it serves to phosphorylate NFAT proteins in the nucleus in order to
induce their nuclear export. Own previous works could identify several crucial
NFATc2-mediated mechanisms of pancreatic tumor growth stimulation.
However, there is rare evidence about upstream regulatory pathways targeting
NFATc2 metabolism in cancer. The aim of this study was to assess a potential
GSK-3-Beta-NFATc2 interaction in pancreatic cancer and to evaluate the use of
GSK-3-Beta inhibitors to specifically target NFATc2. Herein, we identified a novel
phosphorylation-dependent GSK-3-Beta-NFATc2 stabilization pathway which
significantly contributes to pancreatic cancer growth. Mechanistically, we found
that GSK-3-Beta phosphorylates three conserved serines in the SP2 region of
NFATc2 and thereby preserves a rapid degradation in the nucleus. By sitedirected
mutagenesis, we could furthermore show that constitutive
phosphorylation of NFATc2 accelerates tumor growth in vitro and in vivo. In
addition, we identified STAT3 as a partner of NFATc2 and showed for the first
time, that GSK-3-Beta stabilizes the interaction of NFATc2 with the oncogenic
transcription factor and that this in turn enhances transcriptional activity on an
NFAT-responsive promoter. Taken together this study reveals an oncogenic
role of GSK-3-Beta in pancreatic cancer which is carried by a multi-faceted
regulation of the transcription factor NFATc2. On the one hand, NFATc2 protein
stability is strengthened by SP2 phosphorylation and on the other hand,
transcriptional activity is stabilized independent of SP2 phosphorylation by
recruiting a nuclear NFATc2-STAT3 complex. In summary, this novel oncogenic
pathway provides further mechanistic insights into pancreatic cancer and opens
new therapeutic prospects.
Review
Metadata
Contributors
Supervisor:
Dates
Created: 2011Issued: 2011-06-28Updated: 2011-08-08
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
transcription factor
DFG-subjects
Transkriptionsfaktor
DDC-Numbers
570
show more
Dobes, Sandra: Mechanismen der GSK-3-Beta-vermittelten Regulation des onkogenen Transkriptionsfaktors NFATc2 im Pankreaskarzinom. : Philipps-Universität Marburg 2011-06-28. DOI: https://doi.org/10.17192/z2011.0370.
License
This item has been published with the following license: In Copyright