{'fraction_non_alphanumeric': 0.024822047818945064, 'fraction_numerical': 0.010403358277057857, 'mean_word_length': 5.095661846496107, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Agouti signal protein: crossing the ‘yellow’ signal and arriving to pathways that affect tumorgenesis

Two major advancements in pigment cell research in the 1990’s were cloning of the human melanocortin 1 receptor (MC1R) gene and defining the role of its product, the MC1R, in regulating human pigmentation. The MC1R is a Gs protein-coupled receptor with seven transmembrane domains. It is one of few receptors that have physiological agonists (a-MSH and ACTH) and antagonist (agouti signal protein; ASP). Since decades, mouse studies showed that activation of the Mc1r by a-MSH increased eumelanin synthesis by follicular melanocytes, resulting in a black coat color. This was substantiated by the finding that loss of function mutations in the Mc1r (recessive yellow) resulted in a yellow coat color due to reduced ability to produce melanin in response to a-MSH and the predominance of pheomelanin. It is also known that temporal expression of the agouti gene resulted in the agouti phenotype, characterized by a yellow band due to interruption of eumelanin synthesis, allowing only for production of pheomelanin. Mutations that result in over expression of ASP resulted in yellow coat color, in addition to obesity and increased tumorgenicity. While the mechanisms for the effects of ASP on coat color and body weight have been elucidated, the increase in tumor formation remained elusive. Interest in the human MC1R was sparked by the demonstration that human melanocytes express functional MC1R, and the compelling epidemiological evidence for the role of this gene as a major contributor to the diversity of human pigmentation and a melanoma susceptibility gene. The MC1R is highly polymorphic, with the wild type allele predominant in Africa, in populations with high eumelanin content in their skin and hair, and the so-called RHC alleles R151C, R160W, and D294H, associated strongly with red hair phenotype in populations in northern latitudes that do not receive much sun exposure, and in the Celtic population in Australia. It turned out that the latter alleles code for a non-functional receptor, resulting in reduced ability of melanocytes to synthesize eumelanin, and the predominance of pheomelanin. Epidemiologists also found that the RHC alleles are strongly associated with increased melanoma risk. As in mouse follicular melanocytes, binding of the MC1R by its agonists activated cAMP production and eumelanin synthesis. It is known that ASP is an antagonist of human MC1R; however, the physiological function of ASP in human melanocytes is elusive. Given that ASP acts as a competitive inhibitor of a-MSH, it is expected that the effects of ASP should mimic those of a non-functional MC1R due to blocking the biological effects of a-MSH. The Hearing laboratory has been instrumental in elucidating the effects of ASP on melanogenesis, and showed that ASP inhibited the expression of the melanogenic enzymes tyrosinase, TRP1, and TRP-2 (Sakai et al., 1997).The downstream events triggered by activation of the MC1R by a-MSH are by far better understood than those resulting from blocking the receptor by ASP. To fill this gap in knowledge about the effects of ASP on melanocytes, Le Pape et al. compared the effects of a-MSH and ASP on gene expression profiles of murine melan-a melanocytes (Le Pape et al., 2009). The results of gene array analysis showed that a-MSH and ASP generally had opposite effects on gene expression, and in accordance with previous reports, they had opposing effects on melanogenic enzymes and proteins, such as Mitf, Tyrosinase, TRP-1, DCT, and Silver. The authors further found that ASP suppressed the expression of genes involved in various aspects of pigmentation, including melanosome biogenesis, melanin synthesis and intracellular transport. Of importance is the up regulation by ASP of genes that inhibit PKA activity, such as Prkar1a and b, Cri, and Pkia and Pkib2, which in turn inhibit induction of Mitf and Tyrosinase, and thus result in dedifferentiation of melanocytes. Additionally, ASP up regulated the expression of genes involved in development of the nervous system, further contributing to melanocyte dedifferentiation. Novel findings included identification of genes involved in translation, alcohol metabolism, DNA replication, and ion transport. Of particular importance and relevance to tumorgenesis is the suppression by ASP of genes that regulate oxidative stress, such as those that regulate glutathione synthesis, reduction and transfer, which are expected to affect the redox state of melanocytes, as well as a panel of DNA repair genes, including BRCA1‘ and Ddit2. Genes that were up regulated by ASP included those involved in differentiation and development, cell adhesion and motility and in ECM-receptor interactions, which affect migration and invasion of cells. Interestingly, many of the genes regulated by ASP have been associated with cancer and oncogenesis, which provides an explanation for the increased susceptibility of ASP-over expressing mice to develop malignant tumors. The results reported by Le Pape et al. are consistent with the recently described functions of a-MSH in promoting DNA repair and reducing the generation of reactive oxygen species in UV-irradiated human melanocytes Coverage on: Le Pape et al. (2009) Microarray analysis sheds light on the de-differentiating role of agouti signal protein in murine melanocytes via the Mc1r. Proc. Natl. Acad. Sci. 106: 1802– 1807.