Jean-Marie Botto

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

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.

Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation

In human skin, melanogenesis is a tightly regulated process. Indeed, several extracellular signals are transduced via dedicated signalling pathways and mostly converge to MITF, a transcription factor integrating upstream signalling and regulating downstream genes involved in the various inherent mechanisms modulating melanogenesis. The synthesis of melanin pigments occurs in melanocytes inside melanosomes where melanogenic enzymes (tyrosinase and related proteins) are addressed with the help of specific protein complexes. The melanosomes loaded with melanin are then transferred to keratinocytes. A more elaborate level of melanogenesis regulation comes into play via the action of non‐coding RNAs (microRNAs, lncRNAs). Besides this canonical regulation, melanogenesis can also be modulated by other non‐specific intrinsic pathways (hormonal environment, inflammation) and by extrinsic factors (solar irradiation such as ultraviolet irradiation, environmental pollution). We developed a bioinformatic interaction network gathering the multiple aspects of melanogenesis and skin pigmentation as a resource to better understand and study skin pigmentation biology.