People with pale skin, red hair, freckles, and an inability to tan—the “redhair/fairskin” phenotype— are at highest risk of developing melanoma, compared to all other pigmentation types1. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the Melanocortin 1 receptor (MC1R) gene. MC1R encodes a cAMP stimulating G-protein coupled receptor that controls pigment production. Minimal receptor activity, as in redhair/fairskin polymorphisms, produces red/yellow pheomelanin pigment, while increasing MC1R activity stimulates production of black/brown eumelanin2. Pheomelanin has weak UV shielding capacity relative to eumelanin and has been shown to amplify UVA-induced reactive oxygen species (ROS) 3–5. Several observations, however, complicate the assumption that melanoma risk is completely UV dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and UV signature mutations are infrequently oncogenic drivers6. While linkage of melanoma risk to UV exposure is beyond doubt, UV-independent events are also likely to play a significant role1,7. Here, we introduced into mice carrying an inactivating mutation in the Mc1r gene (who exhibit a phenotype analogous to redhair/fairskin humans), a conditional, melanocyte-targeted allele of the most commonly mutated melanoma oncogene, BRafV600E. We observed a high incidence of invasive melanomas without providing additional gene aberrations or UV exposure. To investigate the mechanism of UV-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r e/e background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1re/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1re/e mouse skin. These data suggest that the pheomelanin pigment pathway produces UV-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. While UV protection remains important, additional strategies may be required for optimal melanoma prevention.

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With the increasing emphasis to replace fish meal (FM) with less expensive protein sources in aquaculture diets without reducing weight gains, an 8‐wk feeding trial was conducted with juvenile (15 g) sunshine bass Morone chrysops×M. saxatilis) to evaluate growth and body composition when fed diets with different levels of FM (0, 7.5, 15, and 30%). Six practical floating diets were formulated to contain 40% protein and similar energy levels, with various percentages of FM, meat‐and‐bone meal (MBM), soybean meal (SBM), poultry by‐product meal (PBM), and/or distillers grains with solubles (DGS). Ten fish were stocked into each of 24 110‐L aquaria and were fed twice daily ad libitum (0730 and 1600 h). At the conclusion of the feeding trial, final weights of fish fed diet 2 (0% FM, 29% SBM, 29% MBM, and 10% DGS), diet 3 (0% FM, 32% SBM, and 28% PBM), diet 5 (15% FM and 44% SBM), and diet 6 (30% FM and 26% SBM) were not significantly different (P > 0.05) and averaged 72 g. However, final weights of sunshine bass fed diet 1 (0% FM, 30% SBM, and 31% MBM) and diet 4 (7.5% FM and 54% SBM) were significantly lower and averaged 55 g. Specific growth rate (SGR) of sunshine bass fed diet 4 was significantly lower (2.14) than fish fed diet 2 (2.70), diet 3 (2.80), diet 5 (2.68), and diet 6 (2.84), while feed conversion ratio (FCR) of fish fed diet 4 was significantly higher than sunshine bass fed diets 2, 3, 5, and 6. Carcass (fish were decapitated) composition of sunshine bass fed diet 4 had a significantly higher percentage of moisture (70%) and protein (54% on a dry‐matter basis) than fish fed all other diets. Percentage lipid was similar among fish fed all diets and averaged 41% (dry‐matter basis). Results from the present study indicate that diets in which all of the FM is replaced with a combination of animal‐ and plant‐source proteins can be fed to sunshine bass without adverse effects on weight gain, growth rate, and body composition. Further feeding trials are needed to refine diet formulations used in the present study and should be conducted in aquaria and ponds.

Recently, we reported that melanoma risk in redheads is linked not only to pale skin, but also to the synthesis of the pigment – called pheomelanin – that gives red hair its color. We demonstrated that pheomelanin synthesis is associated with increased oxidative stress in the skin, yet we have not uncovered the chemical pathway between the molecule pheomelanin and the DNA damage that drives melanoma formation. Here, we hypothesize two possible pathways. On one hand, pheomelanin might generate reactive oxygen species (ROS) that directly or indirectly cause oxidative DNA damage. On the other hand, pheomelanin synthesis might consume cellular antioxidant stores and make the cell nucleus more vulnerable to other endogenous ROS. Uncovering the mechanistic pathway between pheomelanin and oxidative DNA damage will be an important step in developing strategies to lower melanoma risk in redheads.

MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1 alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.