K5 and K14 are interesting in that they are broadly expressed in most stratified epithelial tissues (45). In these tissues, the pair is expressed in mitotically active basal keratinocytes, as judged by in situ hybridizations and/or immunohistochemical localization of epidermis (32, 42, 51), rodent forestomach (60), tongue (11), and various other stratified and pseudo-stratified epithelia (42). In addition, K5 has been detected histologically in a number of epithelial cells, including human thymic reticulum, the ORS, sebaceous glands, and both basal and myoepithelial cells of eccrine sweat glands and salivary glands (42). Indeed, an important and unifying feature of basal keratinocytes appears to be their unique ability to express K5 and K14, irrespective of body location (45). Given that cell-typespecific expression of KS and K14 genes appears to be at the transcriptional level (33, 69), the promoters of these genes * Corresponding author. seem to display an insensitivity to the varied environments of keratinocytes.Little is known about the molecular mechanisms which govern the complex expression of genes in the keratinocyte. Given that (i) K5 and K14 account for up to 30% of total protein of mitotically active keratinocytes and (ii) the tissuespecific expression of these proteins is regulated transcriptionally (33, 69), K5 and K14 genes provide ideal tools for investigating these regulatory mechanisms. The human KS and K14 genes have been cloned and sequenced (33,37). Cell type specificity of the KS promoter has been suggested from tissue culture studies (22,46), although the K14 promoter is promiscuously expressed in a number of cell types in vitro (30,75). While the in vivo behavior of the K5 promoter has not yet been explored, 2,100 bp of the K14 promoter is sufficient to direct expression of heterologous genes to the basal cells of stratified epithelia in transgenic mice (7,73,74).A number of recent studies have begun to focus on identifying putative regulatory domains and transcription factors that may be involved in expression of either endogenous or viral genes in keratinocytes (3,4,8,9,20,22,24,29,30,35,37,46,52,54,65,66,72,75). Thus far, only a few nuclear factors that both are restricted in their tissue specificity and appear to participate in conferring keratinocytespecific gene expression have been identified. One of these, AP2, has been implicated broadly in the regulation of endogenous and viral genes that are typically expressed in keratinocytes (29,30,40,54,65,66). However, AP2 does not appear to be sufficient for keratinocyte specificity on its own (29).The aim of this work was to explore the regulatory mechanisms involved in controlling keratinocyte-specific gene expression in culture and in transgenic animals. We 3176