title: UBE3A regulates MC1R expression: a link to hypopigmentation in Angelman syndrome.
abstract: Angelman syndrome (AS) is a neurogenetic disorder caused by the lack of functional ubiquitin-protein ligase E3A (UBE3A) that acts as an E3 ligase in the ubiquitin-proteosomal degradation pathway and/or as a transcriptional coactivator. Besides neurological deficit, hypopigmentation is another phenotype associated with AS patients currently attributed to the hemizygosity of the type II oculocutaneous albinism (OCA2) gene. Here we show that the melanocortin-1-receptor (MC1R) is down-regulated in the skin of the Ube3a((-/-))  mice. Luciferase-reporter assay shows that UBE3A is able to induce MC1R promoter activity. Using chromatin immunoprecipitation assay, Ube3a was observed to be physically associated with the Mc1r promoter. Deletion of the E box/SP1 element in the MC1R minimal promoter abolishes the ability of UBE3A to elevate MC1R promoter-luciferase reporter activity. Ube3a((-/-))  mice also show relative skin hypopigmentation. These results demonstrate that UBE3A plays a role in MC1R transcriptional regulation which can contribute to the development of hypopigmentation in AS patients.
authors: School of Biological Sciences, Nanyang Technological University, Singapore.
authors: Daren
authors: D
authors: Low
authors: Ken-Shiung
authors: KS
authors: Chen
mesh_terms: D017204:Angelman Syndrome / Q000150:complications* / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D024721:E-Box Elements / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D017496:Hypopigmentation / Q000150:complications* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D012867:Skin / Q000473:pathology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D044102:Receptor, Melanocortin, Type 1; D016329:Sp1 Transcription Factor; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases