Protein kinase D distribution in normal human epidermis, basal cell carcinoma and psoriasis.

Abstract

Keratinocytes undergo a defined programme of proliferation and differentiation during normal stratification of the epidermis. Anomalies in the signalling pathways controlling this process probably contribute to the pathogenesis of hyperproliferative dermatological diseases, including psoriasis and basal cell carcinoma (BCC). We have previously proposed that protein kinase D (PKD) is a proproliferative signalling enzyme in keratinocytes and have speculated that abnormalities in its levels or regulation may contribute to hyperproliferative disorders of the skin. To determine if hyperproliferative human skin disorders are characterized by abnormal protein expression or distribution of PKD, normal human epidermis was compared with BCC and uninvolved and involved psoriatic epidermis. To examine protein expression, immunohistochemical analysis of human samples and Western blotting of neoplastic mouse keratinocytes was performed. Western analysis of neoplastic mouse cells using a phosphospecific PKD antibody allowed estimation of PKD activation status. Normal human epidermis demonstrated predominant PKD protein expression in the stratum basalis, the proliferative epidermal compartment, with decreased relative expression throughout the suprabasal strata. Uninvolved psoriatic skin showed a similar pattern, but in contrast, psoriatic lesions demonstrated a diffuse distribution of PKD staining throughout all strata. The majority of BCCs examined showed significant PKD protein levels and, in those biopsies in which the levels could be compared, elevated PKD levels relative to normal epidermis. PKD levels and activation status were also increased in a neoplastic mouse keratinocyte cell line. PKD was elevated or misdistributed in the hyperproliferative human skin disorders, BCC and psoriasis, as well as neoplastic mouse keratinocytes. We speculate that PKD exerts proproliferative and/or antidifferentiative effects in the epidermis, and that anomalous distribution and/or activation of PKD may be involved in precipitating or sustaining the disease process in BCC and psoriasis.