Role of the retinoid X receptor a (RXRa) and its heterodimetric partners during skin carcinogenesis Rôle du recepteur X de rétinoïdes alpha (RXRalpha) et de ses partenaires de dimension dans les cancers cutanés Peau Pas de mots clés en anglais 571.9 Peau Thèses et écrits académiques Trétinoïne Thèses et écrits académiques Rétinoïdes Thèses et écrits académiques Interactions ADN-ligand Thèses et écrits académiques Pas de résumé Nuclear Receptors (NRs) are ligand-dependent transcription factors that play important roles during embryonic development and homoeostasis. Several NRs, including the retinoic acid receptors (RARa, band g), the retinoic X receptors (RXRa,b and g), the vitamin D receptor (VDR), the peroxisome proliferator activated receptors (PPARa, b and g) and the liver X receptors (LXRa and b), play key roles in the morphogenesis and homeostasis of the skin. RXRa is the predominant retinoid receptor in the epidermis and a obligatory heterodimeric partner for other non-steroidal NRs. Aberrant expression and function of several of these NRs have been found during skin carcinogenesis, both in mouse and human. Natural or synthetic ligands for RXRs, RARs, VDR and PPARs exhibit protective effects against tumor formation in human and mouse. To investigate the possiblerole of keratinocytic RXRa in skin caricnogenesis, we have subjected adult mice, in which RXRa was selectively ablated in keratinocytes (RXRaep-/- mice), to the chemical two-step tumorigenesis protocol. Upon DMBA/TPA treatment RXRaep-/- mice exhibited an increased tumor number, growth rate and a much higher frquency to malignant carcinoma, than control mice. DMBA/TPA-treated RXRaep-/- mice also develop melanocytic growths, which degenerate into melanoma. Furthermore, mice in which PPARg was selectively ablated in keratinocytes (PPARgep-/-), and mice bearing a PPARa-null mutation are also more susceptible to DMBA/TPA-induced epithelial tumors, than control mice. However, PPARgep-/- and PPARa-null mice did not develop melanocytic growth or melanoma upon DMBA/TPA treatment. We also showed that the susceptibility to epithelial tumors induced by DMBA/TPA is not affected in mice bearing a null mutation of the VDR gene. However, VDR null mice developed a large number of MGs in response to DMBA/TPA treatment, but in contrast to the MGs from RXRaep-/- mice, these MGs did not progress to malignant melanoma. Thus, keratinocytic RXRa/PPARg and RXRa/PPARa heterodimers may function as suppressor of epithelial tumors, whereas RXRa/VDR heterodimers may play a role in the formation of melanocytic growth. Further studies are required to identify the heterodimerc partner(s) of RXRa involved in the suppression of malignant melanoma. We also used Tg.AC mice as an alternative model to study the role of RXRa during skin carcinogenesis. Tg.AC transgenic mice carry an activated v-Ha-ras oncogene under the control of a partial -globin promoter and are highly sensitive to tumor formation in response to TPA treatment. Surprisingly, Tg.AC/RXRaep-/-(c) mice, carrying the Ha-ras oncogene and in which the selective ablation of the RXRa alleles occurred in epidermal keratinocytes during fetal epidermal morphogenesis, developed skin papillomas in the absence of any promotion agent, some of which progressed to carcinoma. Moreover, in response to a single topical application of DMBA, RXRaep-/-(c) mice, develop epithelial tumors. Thus, ablation of RXRa in keratinocytes during epidermal morphogenesis, is sufficient to promote the formation of Ha-ras initiated skin tumors. All together our results demonstrate that keratinocytic RXRa is a tumor suppressor of epithelial carcinogenesis (most probably within a heterodimer with PPARa and PPARg) and malignant melanoma, (most probably whitin a heterodimer with VDR and other NRs), via paracrine mechanisms. Electronic Thesis or Dissertation Text en France PDF https://publication-theses.unistra.fr/public/theses_doctorat/2004/CASTANEDA_SAUCEDO_Eduardo_2004.pdf Université de Strasbourg Strasbourg Castaneda Saucedo Eduardo 1973-01-01T00:00:00 FR 113462204 http://www.theses.fr/2004STR13059 2004STR13059 2004-01-01T00:00:00 Aspects moléculaires et cellulaires de la biologie Université Louis Pasteur (Strasbourg) 026404540 Doctorat Docteur es non oui Metzger Daniel 086804901 Chambon Pierre 061031127 École doctorale Sciences de la vie et de la santé (Strasbourg ; 2000-....) ED414 156502844 ddc:570