Delta Np63 intronic miR-944 is implicated in the Delta Np63-mediated induction of epidermal differentiation

摘要

Delta Np63 is required for both the proliferation and differentiation of keratinocytes, but its role in the differentiation of these cells is poorly understood. The corresponding gene, TP63, harbors the MIR944 sequence within its intron. However, the mechanism of biogenesis and the function of miR-944 are unknown. We found that miR-944 is highly expressed in keratinocytes, in a manner that is concordant with that of Delta Np63 mRNA, but the regulation of miR-944 expression under various conditions did not correspond with that of Delta Np63. Bioinformatics analysis and functional studies demonstrated that MIR944 has its own promoter. We demonstrate here that MIR944 is a target of Delta Np63. Promoter analysis revealed that the activity of the MIR944 promoter was markedly enhanced by the binding of Delta Np63, which was maintained by the supportive action of AP-2 during keratinocyte differentiation. Our results indicated that miR-944 biogenesis is dependent on Delta Np63 protein, even though it is generated from Delta Np63 mRNA-independent transcripts. We also demonstrated that miR-944 induces keratin 1 and keratin 10 expression by inhibiting ERK signaling and upregulating p53 expression. Our findings suggested that miR-944, as an intronic miRNA and a direct target of Delta Np63, contributes to the function of Delta Np63 in the induction of epidermal differentiation.