A vitamin D analogue KH 1060 activates the protein kinase C-c-fos signalling pathway to stimulate epidermal proliferation in murine skin.
The cellular signalling pathways of a potent 20-epi-22-oxa vitamin D3 analogue (KH 1060) were examined in vivo in a hairless mouse model. Seventy two hours after a single topical application of KH 1060 a thickening of the epidermis (from 24.8 +/- 1.2 microns at 0.01 pmol/cm2 KH 1060 to 124.2 +/- 6 microns at 5 pmol/cm2 KH 1060, P < 0.001) was elicited due to epidermal hyperproliferation. This effect could be blocked by topical 2.5 mumol/cm2 sphingosine, an inhibitor of protein kinase C. Two hours after topical application of 2.5 pmol/cm2 KH 1060 a translocation of protein kinase C activity from cytoplasm to the membrane fractions was observed. Moreover, using a reverse-transcription polymerase chain reaction technique, a transient upregulation of c-fos gene expression was seen 2 hours after topical treatment with KH 1060. The expression of c-fos was dependent on protein kinase C activation, since after pretreatment with the protein kinase C blocker sphingosine, c-fos messenger RNA was not detected. These findings strongly suggest that KH 1060 stimulates epidermal growth through activation of the protein kinase C-c-fos signalling axis in vivo.
Department of Dermatological Research, Leo Pharmaceutical Products, Ballerup, Denmark.
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Gniadecki
D000818:Animals; D001483:Base Sequence; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D004817:Epidermis / Q000254:growth & development* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000494:pharmacology
D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C074279:KH 1060; D011493:Protein Kinase C; D002117:Calcitriol; D013110:Sphingosine