Role of JunB in hypoxia-mediated cell response and tumour angiogenesis

The AP-1 transcription factor, consisting of the Jun, Fos and ATF protein families, exerts changes in gene expression in response to multiple extracellular signals. As loss of functional JunB results in embryonic lethality the aim of this work was to elucidate molecular mechanisms underlying this phenotype. Therefore, a comparative analysis of wildtype and junB-/- cells was performed using in vitro systems such as mouse Embryonic Stem (ES) cells differentiated towards Embryoid Bodies (EBs), endothelioma cells, fibroblasts and ES cell derived teratocarcinomas. Analysis of junB-/- EBs revealed that vascular defects of JunB null embryos can be mimicked by this in vitro system in that these EBs fail to form a higher organised vascular network and exhibit a strongly reduced VEGFR-1 expression, both reflecting the phenotype described for yolk sacs of junB-/- embryos. In addition, expression of proteinases known to be involved in angiogenic processes, such as uPA and MMP-9, was completely abolished, while mRNA levels for MMP-13 were reduced. Culturing EBs under normoxic and hypoxic conditions revealed that VEGF is expressed to a less extent under normoxia in junB-/- EBs whereas expression of its receptor VEGFR-1 is reduced under normoxia as well as hypoxia. Similar gene expression studies in the tissue-specific in vitro system of endothelioma cell lines as well as in mouse embryonic fibroblasts both lacking JunB confirmed the data obtained from the EB differentiation. In line with these data I was able to restore the vascular phenotype of junB-/- EBs by the ectopic application of VEGF. 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 tumour tissue correlates with a reduced capacity of junB null tumour cells to release the angiogenic factor VEGF due to the absence of JunB. <br>In summary, the analysis of the dif

Author dc:creator

• Schmidt, Dirk

Contributors dc:contributor

• Neuhaus, Gunther

• tumour
• angiogenesis
• transcription factor

Repository record source_url

https://freidok.uni-freiburg.de/data/327

OAI identifier oai:identifier

oai:freidok.uni-freiburg.de:327