Rôle du facteur de transcription HIF-1 dans la physiologie cutanée et dans la réponse à l'exposition UV

Abstract : The transcription factor HIF-1 is a heterodimer composed of an and ß subunit. HIF-1 is capable of recognizing a consensus sequence called HRE (hypoxia Response Element) and regulate the expression of more than 200 target genes involved in various cellular mechanisms. We are interested in studying the role of HIF-1 in the skin physiology.Our results show that HIF-1 regulates the expression of two main factors (XPC and XPD) involved in nucleotide excision repair through binding on HRE in their promoter regions. Quantitative chromatin immunoprecipitation assays further revealed putative HREs in the genes encoding other DNA repair proteins (XPB, XPG, CSA and CSB), suggesting that HIF-1 is a key regulator of the DNA repair machinery. We proved that HIF-1 is essential for keratinocyte adhesion through its regulation exerted on laminin-332 and integrins (6, ß1). The lack of HIF-1 expression also prevents the reconstruction of epidermis by human keratinocytes. Our results showed that mice constitutively depleted for HIF-1 in their epidermis develop with age a phenotype of inflammation in several regions. These mice are very sensitive to the stress resulting from wound injury and UVB irradiation. HIF-1 depletion in the epidermis of inducible mice using tamoxifen results in a detachment of the epidermis in suprabasal layers. These mice die within two weeks after injection of tamoxifen
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Nsrein Ali. Rôle du facteur de transcription HIF-1 dans la physiologie cutanée et dans la réponse à l'exposition UV. Autre. Institut National Polytechnique de Lorraine, 2010. Français. ⟨NNT : 2010INPL041N⟩. ⟨tel-01748832⟩

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