Microarray profiling of gene expression in human keratinocytes suggests a new protective activity against UV-induced DNA damage for a compound previously known to interact with SCF-KIT signalling pathway

• Published in: International journal of cosmetic science 2011-10, Vol.33 (5), p.398-407
• Main Authors: Serre, C., Lebleu, A., Bergeron, L., Plantivaux, A., Botto, J. M., Dal Farra, C., Domloge, N.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Cell Line; DNA Damage; Female; Gene Expression Profiling; Humans; keratinocytes; Keratinocytes - metabolism; Keratinocytes - radiation effects; Medical sciences; melanocytes; microarray; Middle Aged; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-kit - metabolism; Real-Time Polymerase Chain Reaction; SCF/KIT pathway; Signal Transduction; Skin, nail, hair, dermoskeleton; Stem Cell Factor - metabolism; Ultraviolet Rays; UVB protection
• ISSN: 0142-5463; 1468-2494
• DOI: 10.1111/j.1468-2494.2011.00641.x

Synopsis The stem cell factor (SCF) and its protein–tyrosine kinase receptor KIT are together implicated in the regulation of diverse biological processes and particularly in melanogenesis. Indeed, this signalling pathway controls melanoblast migration from the neural crest during embryogenesis and allows the communication between keratinocytes and melanocytes in the adult. In melanocytes, the binding of SCF to its transmembrane receptor leads to the activation of signalling pathways implicating protein kinases which finally control the expression of pigmentation‐related genes. We have developed a biological compound called IV09.007, which we previously described as a modulator of the SCF/KIT signalling pathway with a pro‐pigmenting effect. In the present work, we have studied the expression and localization of both SCF and KIT mRNAs and proteins in the skin or skin‐derived cell lines. Then, we explored with a microarray approach the ability of IV09.007 to modulate the expression of genes in human keratinocytes and melanocytes in culture. Thereby, we observed the regulation of genes implicated in DNA repair, mainly related to base/nucleotides excision pathways. A modulated transcriptional response was also observed for some genes implicated in the response against oxidative stress, in apoptosis inhibition and in lowering inflammatory immune response. These microarray results predicted a conferred protective effect of IV09.007 and we verified this hypothesis by performing comet assays on UVB‐irradiated keratinocytes or melanocytes, to demonstrate the efficacy of IV09.007 on preventing DNA damage. Résumé Le stem cell factor (SCF) et son récepteur à activité tyrosine–kinase, nommé KIT, sont impliqués dans divers processus biologiques et en particulier dans la mélanogenèse. En effet, cette voie de signalisation contrôle la migration des mélanoblastes depuis la crête neurale durant le développement embryonnaire et participe à l’âge adulte, à la communication entre les kératinocytes et les mélanocytes. Au niveau des mélanocytes, la liaison de SCF à son récepteur membranaire entraîne l’activation de voies de signalisation impliquant des protéines kinases qui, au final, vont réguler l’expression de gènes impliqués dans les processus de pigmentation. Nous avons développé un composé nommé IV09.007, que nous avons précédemment décrit comme présentant des propriétés de modulation de la voie SCF/KIT de transduction du signal, avec un effet pro‐pigmentant. Dans la prése