Search

Sox transcription factors are members of the Sry-related protein family that play multiple roles mainly during development. Sox18 has been implicated in the development of hair follicles as well as the blood and lymphatic vasculature, due to the identification of mutations that result in the ragged phenotype in mice, and in the hypotrichosis lymphedema telangiectasia syndrome in humans. Sox18 consists of an N-terminal high-mobility group DNA binding and a central transactivation domain, followed by a C-terminal region of unknown function. We show here that this C-terminal domain consists of three blocks that are highly conserved within a subgroup of the Sox family, and that the central so-called charged block comprises an additional strong transactivating domain. This activity can be pinpointed to a recently described 9aa transactivation motif that mediates the interaction with the transcriptional cofactor TAF9. These result can explain previously controversial data on the functional consequences of Sox18 mutations in mice and humans.

Abstract —A variety of pathophysiological situations that affect cells of the vasculature, including endothelial and smooth muscle cells, leads to the expression of genes such as adhesion molecules and chemokines that are dependent on members of the nuclear factor (NF)-κB family of transcription factors. The corresponding gene products mediate important biological functions such as immune and inflammatory reactions, smooth muscle cell proliferation, and angiogenesis. The beneficial and usually transient NF-κB–dependent gene expression may be exaggerated in pathological situations and results in damage to the vessel wall and impaired vascular cell function. In this review, we will capitalize on the favorable and adverse roles of NF-κB in the context of vascular disease, eg, chronic and localized inflammation, arteriosclerosis, and neoangiogenesis.

Transcription factors (TFs) have been difficult to identify by bioinformatics, due to the heterogenous nature of the domains they are composed of. Therefore, we have developed a simple and generally applicable screening system for the identification of transcriptional activators, based on the presence of a functional transactivation domain (TAD). The system utilizes a retroviral vector to express a cDNA library as fusion genes with the yeast gal4 DNA-binding domain. This retroviral library is transduced into a murine NIH3T3-based reporter cell line carrying a stable integrated gal4 promoter–green fluorescent protein reporter gene. cDNA inserts encoding a functional TAD reconstitute a chimeric TF that activates the reporter gene. After fluorescence activated cell sorting (FACS) and expansion of GFP-positive cells, the responsible cDNA inserts are retrieved. From a cDNA library of cytokine-stimulated human umbilical vein endothelial cells (HUVEC), a number of known as well as potentially novel TFs were isolated, demonstrating the suitability of the system. The identification of other factors that are currently not associated with transcriptional regulation suggest additional functions for these proteins. Moreover, our results have focused attention on signaling pathways that have not been recognized previously in the context of endothelial cell biology.