The stratum corneum, composed of tough, rigid, interlocking keratinocytes, serves as an essential barrier between terrestial organisms and their environment. At the transition from the living layers of the epidermis to the stratum corneum, the cells of the epidermis lose their nuclei and other organelles, rearrange their cytoskeletal network, and cease metabolic activity. The regulatory and proteolytic events that coordinate the tightly controlled process of epidermal terminal differentiation are poorly understood. Caspases are conserved proteases with a vast repertoire of substrates including structural elements (nuclear lamin, actin, fodrin, keratin 18, plectin), repair elements (polyadenyl ribophosphorylase, DNA protein kinase C), and regulatory elements (sterol regulatory element binding proteins, Rb, NF-κB), to list a few.1 Caspases have been shown to participate in lens epithelial differentiation2 and erythropoiesis,3 two tissues in addition to the epidermis where the anucleate terminally differentiated cell serves an important function before being shed or phagocytized.

To examine a potential role for caspases in epidermal terminal differentiation, we first determined which caspases are expressed in the epidermis. RNase protection assays (RPAs) were performed on total RNA isolated from mouse skin and cultured mouse epidermal keratinocytes (MEKs). Mouse epidermis and MEKs express caspase-2, -3, -6, -8, and -14, but not caspase-1, -7, -11, or -12. Caspase-9 was detected in epidermis and cultured keratinocytes by RT–PCR. To compare levels of caspase expression between basal and differentiating keratinocytes, we utilized RNA from MEKs grown in low and high calcium medium respectively.4 Caspase-14 displayed high mRNA levels in low calcium conditions and appeared to be downregulated after growth for 48 h in high calcium medium. The other caspase members showed no difference in mRNA levels between basal and differentiating keratinocytes. Northern analysis of cultured MEKs confirmed these findings, demonstrating abundant caspase-14 mRNA in low calcium conditions which increased in the first 16 h after switching to high calcium, and then decreased over the next 48 h. Caspase-14 is a newer member of the caspase family, and was identified independently by three groups,5,6,7 two of which suggested that caspase-14 may be skin specific. Because caspase-14 was the only caspase expressed in epidermis that showed differential expression, and because of reports suggesting that caspase-14 may be skin specific, we proceeded to further investigate this interesting caspase.

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