Papers of the Week

Epidermal keratinocytes express semaphorin (Sema) 3A, which is involved in the regulation of cutaneous innervation. However, the mechanisms underlying the intracellular signaling of Sema3A expression in keratinocytes remain unknown. We herein investigated signaling mechanisms for the induction of Sema3A expression in normal human epidermal keratinocytes (NHEKs). Sema3A expression transiently increased in calcium-stimulated NHEKs, but markedly decreased in terminally differentiated NHEKs. Sema3A mRNA mainly localized in the stratum basale and stratum suprabasale of the epidermis. The 5'-flanking region of the Sema3A gene was cloned, and a critical region for Sema3A promoter activity within -134 bp of the start codon was identified. Transcription factor binding sites, including that for activator protein (AP)-1, were found in this region. Sema3A expression was increased by the co-overexpression of JunB and Fra-2 in the presence of 0.1 or 1.4 mM calcium. The calcium-mediated transient up-regulation of Sema3A expression was significantly suppressed by mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK] (MEK) 1/2 or AP-1 inhibitors. These results demonstrate that the calcium-mediated transient up-regulation of Sema3A in NHEKs is involved in the MEK/ERK and AP-1 signaling axis. Therefore, Sema3A mRNA may be expressed in the lower epidermis under controlled conditions by calcium via the MAPK-AP1 axis.