Protein kinase C-dependent upregulation of miR-203 induces the differentiation of human keratinocytes.
Terminal differentiation of keratinocytes is a multistep process that requires a coordinated program of gene expression. We aimed to explore the possible involvement of a previously unreported class of non-coding RNA genes, microRNAs (miRNAs) in keratinocyte differentiation by using miRNA expression profiling. Out of 365 miRNAs tested, 7 showed significant change between keratinocytes cultured in low or high calcium concentration. The highest-ranked upregulated gene was miR-203, whose expression was significantly upregulated in response to calcium and other inducers of keratinocyte differentiation such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and vitamin D(3). Differentiation-induced upregulation of miR-203 expression was blocked by treatment with specific inhibitors of protein kinase C (PKC), GF109203X, and Ro31-8220. Moreover, our results showed that the activator protein-1 (AP-1) proteins c-Jun and JunB regulate miR-203 expression in keratinocytes. In contrast to inducers of keratinocyte differentiation, epidermal growth factor and keratinocyte growth factor suppressed miR-203 expression in keratinocytes below the basal level. Overexpression of miR-203 in keratinocytes resulted in enhanced differentiation, whereas inhibition of miR-203 suppressed calcium-induced terminal differentiation as judged by involucrin expression. These results suggest that upregulation of miR-203 in human keratinocytes is required for their differentiation and is dependent on the activation of the PKC/AP-1 pathway.
Sonkoly
Enikö
E
Molecular Dermatology Research Group, Unit of Dermatology and Venerology, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. eniko.sonkoly@ki.se
Wei
Tianling
T
Pavez Loriè
Elizabeth
E
Suzuki
Hiroyuki
H
Kato
Mitsuyasu
M
Törmä
Hans
H
Ståhle
Mona
M
Pivarcsi
Andor
A
D000328:Adult; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D014807:Vitamin D / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
C496453:FGF7 protein, human; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D018808:Transcription Factor AP-1; D014815:Vitamins; D051523:Fibroblast Growth Factor 7; D014807:Vitamin D; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D002118:Calcium