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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center


Diane S. Keeney, Ph.D.

Assistant Professor of Medicine (Dermatology) and Biochemistry

Contact Information:

Vanderbilt University Medical Center
607 Light Hall
Nashville, TN 37232-0146
Fax: 615-322-4349

Research Specialty

We study roles for cytochrome P450 enzymes in the regulation of epithelial differentiation.

Research Description

Stratified squamous epithelia are self-renewing and directly interface the environment. In mammals, they comprise competent barriers that provide protection against hostile environmental elements; consequently, they are primary sites of disease, including cancer. Proliferating keratinocytes from different stratified squamous epithelia have many similarities, but their terminal differentiation programs are quite distinct. For example, the outer cell layer of the epidermis is anucleated, dry, and relatively impermeable; that in oral epithelium is nucleated, wet, and relatively permeable. Phenotype reversal at these sites would be fatal. We are studying mechanisms that regulate these disparate phenotypes during terminal differentiation and role for cytochrome P450-derived metabolites in these processes.

Skin expresses many cytochromes P450 (CYP genes) having critical roles in endogenous and exogenous substrate metabolism (e.g., therapeutic drugs, xenobiotics, fatty acids, eicosanoids, sterols, steroids, vitamins A & D). We characterized three homologous P450s in rodent skin (CYP2B19, 2B15, 2B12). Mouse CYP2B19 and rat CYP2B12 were found to be arachidonic acid epoxygenases, which generate epoxyeicosatrienoic (EET) acids. These P450 enzymes were detected only in differentiated keratinocytes comprising the outer epithelial cell layers, and this cell-specific transcriptional regulation suggested important roles for these enzymes in the production and/or disposition of molecules affecting keratinocyte differentiation and epidermal functions.

EETs are natural epoxy fatty acids formed in cutaneous tissues and in cultured keratinocytes. In keratinocyte cultures, the CYP2B19 metabolite 14,15-EET activated transglutaminase enzyme activities and promoted cell cornification. In present studies, we aim to understand the mechanisms how P450-derived epoxy fatty acids regulate these cellular processes, which are critical to establishing a competent epidermal barrier. In other ongoing projects, we aim to identify functional homologues in human epidermis responsible for generating epoxy fatty acids and to develop a Cyp2b19 null mouse. These in vitro and in vivo studies will generate new insight into how endogenously formed lipid mediators (EETs) regulate functions of epidermal keratinocytes that are responsible for forming the stratum corneum and the water permeability barrier in mammals.