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Liefold, Nicola (2007): A new role of transcription factor SOX17 as potential interaction partner of KLF4 and EGR-1 in human coronary artery smooth muscle cells and in differentiating mouse ES-cells. Dissertation, LMU München: Faculty of Biology
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Abstract

The development of the vascular network comprises tightly regulated processes, involving vasculogenesis and angiogenesis. The cells, which are mainly participating in these processes, are endothelial cells and vascular smooth muscle cells, the latter ones especially being important for the stability of blood vessels. Uncontrolled proliferation of VSMCs contributes crucially to the development of vascular disease, e.g. in the case of atherosclerosis. Two main initiator factors of these processes are Low Densitiy Lipoprotein (LDL) and Platelet Derived Growth Factor-BB (PDGF-BB). For this reason, the VSMCs and the transcriptional regulation of their proliferation, in response to LDL and PDGF-BB, build an important target for therapeutical interventions. Sox17, a member of subgroup F of the Sox family proteins, was for the first time detected in vascular smooth muscle cells in different mouse tissues, like liver, brain, heart, lung, spleen and kidney in vivo and in human coronary artery smooth muscle cells in vitro. Moreover, a new possible protein complex, consisting of SOX17, KLF4 and EGR-1, was found in human coronary artery smooth muscle cells, as well as in 4 day old embryoid bodies. All members of this complex are induced by PDGF-BB, a growth factor which becomes activated in angiogenesis and pathological vascular conditions, stimulating the migration and proliferation of vascular SMCs. By this the complex might be involved in migration and proliferation of vascular SMCs, and moreover in pathological vascular conditions, like the progression of atherosclerosis. EGR-1 is known to be the key player in mediating the transcriptional responses to PDGF-BB and LDL and has already been implicated in progression of atherosclerosis. Because of the fact, that a complex, consisting of Sox17, Klf4 and Egr-1, was also observed to be formed in differentiating ES-cells (day 4), supports a broader role of this protein complex in the differentiation of cell-specific lineages during development, in particular vascular smooth muscle cells and endoderm lineages. The complex might have an inhibitory, as well as an activating role, as Sox17, Klf4, and Egr-1 are known to behave bifunctional. Besides, Sox17 seems to bind to -catenin during EB formation. At least this could be an indication for an involvement of the complex in modulating the wnt-signaling pathway during embryonic development.