The applicant has recently discovered a novel monooxygenase enzyme expressed in mouse skin during embryonic and postnatal development. The long-term goal of this research is to elucidate the endogenous substrates and products of this enzyme and its significance to development of normal skin function. DNA sequence analyses of partial cDNA clones identify the gene encoding this enzyme as a new member of the cytochrome P450 gene (CYP,Cyp for murine) superfamily--2B subfamily by standardized nomenclature. CYP genes encode heme-containing monooxygenases that oxidatively metabolize a vast array of small hydrophobic ligands like sterols, steroids, vitamins (A,D) or fatty acids. The first partial cDNA was discovered by reverse-transcription and PCR amplification (RT-PCR) of RNA from a mouse embryo at embryonic day 15.5 (E15.5; term = 18.5 days). In situ hybridization localized Cyp2b mRNA to suprabasal epidermal cells at E16.5, a time when the epidermis is undergoing rapid differentiation. Subsequently, Cyp2b transcripts have been identified by RT-PCR in RNA from whole skin (embryonic and postnatal mice), which may represent multiple Cyp2b gene subfamily members. Proposed specific aims are to: 1) use in situ hybridization and RT-PCR to identify the cell-type(s) expressing this enzyme and to characterize spatial and temporal expression patterns from embryonic to adult life; 2) obtain a full-length cDNA encoding this enzyme and express it in E. coli; and 3) functionally characterize the recombinant protein in vitro, to elucidate its metabolic potential in vivo. Of primary interest is whether this enzyme metabolizes retinoids, steroids or lipids that function as signalling molecules or lipids that are structural components of the epidermal water permeability barrier. By characterizing Cyp2b monooxygenase(s) in murine skin and the metabolic pathway(s) in which it functions in vivo, it will become possible to identify regulatory steps in biochemical processes that can be exploited to treat skin diseases.
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