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

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

The Viral Oncoprotein LMP1 Exploits TRADD for Signaling by Masking Its Apoptotic Activity

The tumor necrosis factor (TNF)-receptor 1–associated death domain protein (TRADD) mediates induction of apoptosis as well as activation of NF-κB by cellular TNF-receptor 1 (TNFR1). TRADD is also recruited by the latent membrane protein 1 (LMP1) oncoprotein of Epstein-Barr virus, but its role in LMP1 signaling has remained enigmatic. In human B lymphocytes, we have generated, to our knowledge, the first genetic knockout of TRADD to investigate TRADD's role in LMP1 signal transduction. Our data from TRADD-deficient cells demonstrate that TRADD is a critical signaling mediator of LMP1 that is required for LMP1 to recruit and activate I-κB kinase β (IKKβ). However, in contrast to TNFR1, LMP1-induced TRADD signaling does not induce apoptosis. Searching for the molecular basis for this observation, we characterized the 16 C-terminal amino acids of LMP1 as an autonomous and unique virus-derived TRADD-binding domain. Replacing the death domain of TNFR1 by LMP1′s TRADD-binding domain converts TNFR1 into a nonapoptotic receptor that activates NF-κB through a TRAF6-dependent pathway, like LMP1 but unlike wild-type TNFR1. Thus, the unique interaction of LMP1 with TRADD encodes the transforming phenotype of viral TRADD signaling and masks TRADD's pro-apoptotic function