The tyrosinase enhancer is activated by Sox10 and Mitf in mouse melanocytes.
The terminal differentiation of melanocytes is associated with the transcriptional activation of genes responsible for pigment production such as tyrosinase. Pigment cell-specific transcription factors, such as Mitf, as well as specific proximal and distal regulatory elements (DRE) are implicated in the tight control of tyrosinase expression during development and adulthood. Proper tyrosinase expression in melanocytes depends upon the presence of a DRE that is located at -15 kb and provides enhancer activity via a central element termed core-enhancer. In this report, we show that the transcription factors Sox10, Mitf and USF-1 are able to activate the core-enhancer in luciferase reporter assays. Comparative sequence analysis identified evolutionarily motifs resembling Sox10 binding sites that were required for full enhancer activity in melanoma cells and in tyrosinase::lacZ transgenic mice. Sox10 was able to bind the DRE in vitro and mutation of the conserved motifs abolished the enhancer transactivation mediated by Sox10. In addition, two highly conserved CAGCTG E-box motifs were identified that were also required for enhancer activity and for transactivation by Mitf. The results suggest that Sox10 directly, and Mitf, most likely indirectly, activate the tyrosinase enhancer, underlining the contribution of Sox10 to tyrosinase gene regulation in melanocytes.
Murisier
Fabien
F
Swiss Institute for Experimental Cancer Research (ISREC), National Center of Competence in Research (NCCR) Molecular Oncology, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
Guichard
Sabrina
S
Beermann
Friedrich
F
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006609:High Mobility Group Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000502:physiology*; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D055757:SOXE Transcription Factors; D012689:Sequence Homology, Nucleic Acid; D012880:Skin Pigmentation / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation
D006609:High Mobility Group Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors; D014442:Monophenol Monooxygenase