Differential regulation of karyopherin alpha 2 expression by TGF-beta1 and IFN-gamma in normal human epidermal keratinocytes: evident contribution of KPNA2 for nuclear translocation of IRF-1.

Despite a number of studies on signal transduction in epidermal keratinocytes, very little is known about how signals move from the cytosol to the nucleus during the course of keratinocyte proliferation and differentiation. In this study, we first compared the expression patterns of the karyopherin alpha (KPNA) subtypes, and found that KPNA2, KPNA3, and KPNA4 were the major subtypes in both normal human epidermal keratinocytes (NHEKs) and normal human dermal fibroblasts (NHDFs). Stimulation with either transforming growth factor (TGF)-beta1 or IFN-gamma for 24 hours resulted in the downregulation of KPNA2 expression specifically in NHEK at both the mRNA and protein levels. Interestingly, IFN-gamma, but not TGF-beta1, specifically downregulated KPNA2 expression at the promoter level, suggesting differential regulation of KPNA2 expression by IFN-gamma and TGF-beta1. We then demonstrated that KPNA2 physically bound to IFN regulatory factor-1 (IRF-1), a transcription factor induced by IFN-gamma, and induced nuclear translocation of IRF-1 in NHEKs. We finally performed microarray and quantitative real-time PCR analysis for the mRNA expression pattern of NHEK with either overexpression or knockdown of KPNA2, and indicated KPNA2 involvement for various epidermal gene regulations such as involucrin. Our data suggest that KPNA2 may play an important role in the signal-transduction pathways that regulate epidermal proliferation and differentiation.