Cloning, chromosomal localization and expression pattern of the POU domain gene Oct-11.

POU domain genes encode a family of highly conserved transacting factors that influence the transcriptional activity of several cell type-specific and ubiquitous genes. We have cloned and sequenced cDNAs encoding a novel mouse POU domain protein, Oct-11, that is closely related within the POU domain to the POU class II proteins, Oct-1 and Oct-2. Recombinant Oct-11 protein binds specifically to an octamer sequence in vitro. The Oct-11 gene is expressed during mouse embryogenesis and in the adult thymus and testis. In addition, it is abundant in the myeloma cell line P3/NS-1/1-Ag4.1. We describe the structure of Oct-11 and its chromosomal localization, and discuss the evidence that the POU class II gene family has evolved by duplication and divergence of a common ancestral gene

Antioxidant properties of small proline-rich proteins : from epidermal cornification to global ROS detoxification and wound healing

The small proline-rich (SPRR) proteins are generally known for their involvement in the formation and adaptation of the skin__s barrier. During the cornification process, they are cross-linked within the cornified cell envelope (CE) and as such they are responsible for the physical and permeability barrier function of our skin. In this thesis, the novel antioxidant properties of the SPRR proteins are described. As part of the CE, these proteins provide a natural antioxidant shield to our skin and act as our first line of defence against reactive oxygen species (ROS). Also during wound healing, SPRR proteins can directly reduce toxic ROS levels. This activity is directly related to their ability to promote cell migration and is essential in order to allow wound closure. A literature-based meta-analysis revealed their up-regulation in various forms of tissue injury, ranging from heart infarction and commensal-induced gut responses to nerve regeneration and burn injury. Apparently, SPRR proteins have a far more widespread role in wound healing and tissue remodelling than their established function in skin cornification. Likely, SPRR proteins provide all tissues with an efficient, finely tuneable antioxidant barrier, specifically adapted to the tissue involved and the damage inflicted.UBL - phd migration 201

EGFR Regulation of Epidermal Barrier Function

Keratinocyte terminal differentiation is the process that ultimately forms the epidermal barrier that is essential for mammals to survive in the ex utero environment. This process is tightly controlled by the expression of many well-characterized genes. Although a few of these genes are known to be regulated by the epidermal growth factor receptor (EGFR), an important regulator of multiple epidermal functions, neither the genome-wide scale of EGFR-mediated regulation nor the mechanisms by which EGFR signaling controls keratinocyte differentiation are well understood. Using microarray analysis we identified 2,676 genes that are regulated by EGF, a ligand of the EGFR. We further discovered, and separately confirmed by functional assays, that EGFR activation abrogates all essential metabolic processes of keratinocyte differentiation by (1) decreasing the expression of lipid matrix biosynthetic enzymes, (2) regulating numerous genes forming the cornified envelope, and (3) suppressing the expression of tight junction proteins. In organotypic cultures of skin, the collective effect of EGF impaired epidermal barrier integrity, evidenced by increased transepidermal water loss. As defective epidermal differentiation and disruption of the epidermal barrier are primary features of many human skin diseases, we used bioinformatics analysis to identify genes that are known to be associated with human skin diseases. In comparison to non-EGF-regulated genes, the EGF-regulated gene list was significantly enriched for disease genes. Further validation of the expression profiles of many of the 114 identified skin disease genes included the transcription factors GATA binding protein 3 (GATA3) and Kruppel-like factor 4 (KLF4), both required for establishing the barrier function of the skin in developing mice. These results provide a new systems level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation. As the overall effect of this inhibition is to impair epidermal barrier integrity, this study clarifies how dysregulation of the EGFR and its ligands may contribute to diseases of the skin