Transcriptional Control of K5, K6, K14, and K17 Keratin Genes by AP-1 and NF-kappaB Family Members

The expression of keratins K5 and K14 is restricted to the basal layers of the healthy epidermis, whereas the expression of K6 and K17 is induced in response to proliferative and inflammatory signals, respectively. The control of keratin expression occurs primarily at the transcriptional level. We studied the effects of transcription factors of the AP-1 and NF-kappaB families on the expression of those four keratin genes. We chose AP-1 and NF-kappaB proteins because they are activated by many extracellular signals, including those in hyperproliferative and inflammatory processes. DNA constructs expressing the transcription factors were, in various combinations, cotransfected with constructs containing keratin gene promoters and the CAT reporter gene into HeLa cells or keratinocytes. We found that the K5 and K14 promoters, which are coexpressed in vivo, are regulated in parallel by the cotransfected genes. Both were activated by the c-Fos and c-Jun components of AP-1, but not by Fra1. On the other hand, the NF-kappaB proteins, especially p65, suppressed these two promoters. The K17 promoter was specifically activated by c-Jun, whereas the other transcription factors tested had no significant effect. In contrast, the K6 promoter was very strongly activated by all AP-1 proteins, especially by the c-Fos + c-Jun and Fra1 + c-Jun combinations. It was also strongly activated by the p65 NF-kappaB protein. AP-1 and NF-kappaB acted synergistically in activating the K6 promoter, although the AP-1 and the NF-kappaB responsive sites could be separated physically. These results suggest that the interplay of AP-1 and NF-kappaB proteins regulates epidermal gene expression and that the activation of these transcription factors by extracellular signaling molecules brings about the differential expression of keratin genes in epidermal differentiation, cutaneous diseases, and wound healing.