Abstract
The multifunctional protein E4F1 is an essential regulator of skin homeostasis. More precisely, E4F1 is involved in the maintenance of epidermal stem cells and regulates keratinocyte differentiation. However, it seems that its functions extend beyond the epidermal cells but its roles in other skin cell types remain poorly investigated. Therefore, I studied the role of E4F1 in the melanocyte lineage. Melanocytes are epidermal cells, responsible for melanogenesis. This physiological process, controlled by the MITF transcription factor, allows the synthesis of melanin, a pigment essential to protect the skin against ultraviolet induced-DNA damages.To identify the functions of E4F1 in melanocytes, I generated genetically engineered mouse models allowing the specific inactivation of E4f1 in these cells. I demonstrated that the loss of E4f1 causes severe pigmentation defects, without affecting melanocytes survival. This phenotype was linked to a strong decrease in the expression of MITF and of melanin synthesis enzymes. At the molecular level, E4f1 depletion reduces the expression of its target genes, including Elp3, encoding the catalytic subunit of the Elongator complex. This complex is involved in the modification of a subset of transfer RNAs and contributes to the fidelity of translation. Therefore, E4f1 depletion induces an unfolded protein stress response (ER stress response), which results in the repression of Mitf.Interestingly, MITF expression has been shown to be deregulated in melanoma, a cancer type arising from melanocytes. A low expression of MITF has been associated with an aggressive tumor profile and resistance to targeted therapies. Thus, I characterized the E4F1 functions in melanoma development, progression, and resistance to therapies. My data, obtained from genetically engineered mouse models of melanoma, suggest that E4f1 inactivation in melanoma cells delays tumor development.Altogether, my PhD work has enabled the identification, for the first time, of a role of E4F1 in the melanocyte lineage, both in melanocyte homeostasis and in melanoma development.