Visit our Expo - Redox and Inflammation signaling 2012

Session XIV : Transcriptional and translational control Poster XIV, 62
JUNB-DEPENDENT VEGF TRANSCRIPTION AND TUMOR ANGIOGENESIS
Dirk Schmidt1, Oliver Pein1, Björn Textor1, Alexander Licht1, Norbert E. Fusenig2,
Peter Angel1 and Marina Schorpp-Kistner1
1,2Deutsches Krebsforschungszentrum (DKFZ), 1Division of Signal Transduction and
Growth Control and 2Division of Differentiation and Carcinogenesis, Im Neuenheimer
Feld 280, D-69120 Heidelberg, Germany. E-mail: marina.schorpp@dkfz.de
The JunB subunit of the AP-1 transcription factor complex mediates gene regulation in
response to a plethora of extracellular stimuli. Previously, we showed that the complete
ablation of JunB resulted in an early embryonic lethal phenotype due to vascular defects. In
order to elucidate the underlying molecular mechanisms we analyzed various JunB-deficient
cell systems and targeted deletion of the junB gene to endothelial cells. Endothelial-cell
specific ablation of junB resulted in a similar embryonic lethal phenotype and confirmed the
absolute requirement of JunB for vasculogenic and angiogenic processes in the developing
embryo.
Analysis of JunB-deficient embryonic stem cells, endothelioma cells and fibroblasts revealed
that JunB itself is upregulated in response to hypoxia. This induction is independent of HIF
and MAPK signaling but requires NF-kB, as junB mRNA induction is lost in fibroblasts with
suppressed NF-kB activity. JunB, in turn, is directly required for basal and hypoxia-induced
transcription of VEGF as demonstrated by independent experimental approaches such as
QRT-PCR, EMSA and coexpression studies. VEGF regulation by JunB is also of
physiological relevance in tumor angiogenesis, as teratocarcinomas derived from junB-/- ES
cells exhibit a pale and growth retarded phenotype with significantly reduced amounts of
midsize and large blood vessels. The failure of host-derived vessels to recolonise the tumor
tissue correlates with a reduced capacity of JunB null tumor cells to release the angiogenic
factor VEGF due to the absence of JunB. Yet, other typically hypoxia-induced genes as such
of the glycolytic pathway are not governed by JunB. Consistently, JunB is dispensable for the
early maximal induction of VEGF in response to hypoglycemia which requires the JunB
sibling c-Jun.
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