Identification of Aim-1 as the underwhiteMouse Mutant and Its Transcriptional Regulation by MITF

Abstract

Animal pigmentation mutants have provided rich models for the identification of genes modulating pathways from melanocyte development to melanoma. One mouse model is the underwhite locus, alleles of which manifest altered pigmentation of both eye and fur, sometimes in an age-dependent fashion. Here we show that the mouse homolog of a recently identified gene whose mutation produces Japanese gold-colored fish, medaka b, maps to the mouse underwhite locus. We identify distinct mutations of this gene, known as Aim-1, in three underwhite mouse alleles and find that structure/function differences correlate with recessive versus dominant inheritance. The human ortholog of AIM-1 was originally identified as a melanocyte-restricted antigen that is recognized by autologous T cells from a patient with melanoma. We also provide evidence that AIM-1 is transcriptionally modulated by MITF, a melanocyte-specific transcription factor essential to pigmentation and a clinical diagnostic marker in human melanoma. Although AIM-1 appears to reside downstream of MITF, chromatin immunoprecipitations do not reveal binding of MITF to a 5-flanking region containing histone 3 acetylation, indicating that MITF either acts indirectly on AIM-1 or it binds to a remote regulatory sequence. Nevertheless, MITF links AIM-1 expression and the underwhite phenotype to a transcriptional network central to pigmentation in mammals.

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

“…This is what we found with two antimelanoma CTL clones, including a CTL recognizing the immunodominant peptide Melan-A/MART1 [26][27][28][29][30][31][32][33][34][35] , presented by HLA-A2. In a previous study, IFN-c was shown to reduce by up to 78% the cytotoxicity of anti-Melan-A/MART-1 26-35 CTL, despite the stimulatory effect of IFN-c on MHC class I expression and antigen presentation.…”

“…26,27 We, therefore, quantified MITF-M expression in two melanoma cell lines, LB2259-MEL and CP50-MEL, treated with IL-1b (Fig. 1).…”

Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail

“…SLC45A2 transcription is thought to be indirectly regulated by the melanocyte-specific transcription factor MITF (Du and Fisher 2002) and SLC45A2 ESTs have not been found in chicken brain cDNA libraries (http://www.genome.ucsc.edu). Surprisingly, we could amplify SLC45A2 59 and 39 cDNA sequences from a RACE-ready first-strand brain cDNA library.…”

“…SLC45A2 mutations have been found in medaka (Fukamachi et al 2001), humans (Newton et al 2001), mouse (Newton et al 2001;Du and Fisher 2002), and horse (Mariat et al 2003). Oculocutaneous albinism type IV (OCA4) in humans is caused by mutations in SLC45A2 (Newton et al 2001).…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…Pigmentation-associated transcriptional targets of MITF include the pigment enzyme genes tyrosinase, TRP1, TRP2/Dct, which were recognized to contain an evolutionarily conserved consensus promoter/enhancer element that matches the MITF recognition sequence (Bentley et al 1994;Hemesath et al 1994;Yasumoto et al 1994). Additional differentiation-associated genes include Pmel17/silver/gp100 (which encodes the melanoma diagnostic epitope HMB45) (Halaban et al 1996;Baxter and Pavan 2003;Du et al 2003), MelanA/Mart1 , Melastatin (TRPM1) (Miller et al 2004;Zhiqi et al 2004), AIM1 (ocular albinism 4 gene) (Du and Fisher 2002), Ocular albinism 1 gene (OA1) (Vetrini et al 2004), VMD2 (Esumi et al 2004), HIF1␣ (Busca et al 2005), Plasminogen activator inhibitor-1 (Murakami et al 2006), numerous mast cell targets of MITF including Prostaglandin D2, multiple mast cell genes including proteases, various adhesion molecules and others (see Ito et al 2004;Morii et al 2004;Takeda et al 2006 and references therein), and melanocortin 1 receptor (MC1R) in mast cells and possibly in melanocytes (Adachi et al 2000;Smith et al 2001;Aoki and Moro 2002). Numerous additional genes are being identified through expression microarrays, and are liable to reflect the multiple steps involved between signaling, expressing, packaging, and exporting pigment.…”