Sunday, May 4, 2014

The Role of Mc1r in UV-induced tanning


            Michelle Fat and I are doing our project on a topic regarding skin cancer, and so this blog post will focus on the role of melanin, and more specifically, the pathway for producing melanin involving the melanocortin 1 receptor (MC1R) and melanocyte stimulating hormone (MSH). The article, “Topical drug rescue strategy and skin protection based on the role of MC1R in UV-induced tanning,” discusses an experiment done on mice to examine the role of MSH-MC1R in producing melanin in response to UV exposure, as well as the effect of forskolin as a drug to protect skin.  
            Ultraviolet radiation from sun exposure is mostly Ultraviolet A, which can penetrate into the skin and cause indirect DNA damage through single-strand breaks and DNA-protein crosslinks. 5% of DNA photodamage is due to UVB, which is directly absorbed by the DNA and can cause structural damage. In response to UV exposure, melanin is produced in melanosomes (of melanocytes) and is transported to keratinocytes to be stored in the perinuclear area and act as a shield for DNA from UV rays. Melanin is made of lighter red/yellow pheomelanin and darker brown/black eumelanin. The difference in the color of people’s skin is based on how much melanin is produced, what type is produced, and the size and structure of it. 

The Experiment:
            The research article structured its experiment by using mice with a functional MSH-Mc1r pathway (Mc1rE/E), and mice with a mutated pathway (Mc1re/e). Weak MSH-Mc1r ligand coupling due to differences in sequencing accounts for fair skin in humans, and so in mice this mutation represents fair skinned mice. The mice were then treated 5 days per week with UV-B lamps for one month.

The ears of the mice were observed in this first experiment because they resemble human skin. The top row shows significantly darker skin color compared to the ears of the mice with a mutated pathway. The microscopic images show Fontana-Masson-stained skin to show melanin amounts. The wildtype mice have melanin accumulated as shown by the black spots, pointed at by the black arrows, whereas the mutated mice do not seem to have melanin. One aspect of this experiment that I would bring into question is the use of UVB light. We only absorb about 5% of UVB light from the sun, and it is much stronger than UVA, so much that you would need 1000x more exposure to UVA to get the same sunburn as UVB. Therefore, by using UVB, the effect on melanin was much more drastic, and I wonder if using UVA would have been a better way to realistically see the effects that were more relatable to the sun exposure we receive daily. The article also did not discuss the number of mice that were used in the experiment, so that could also play a factor if there were some mice that came out with different results, but the article implies that all mutant mice did not have melanin accumulation, while wildtype mice did.
            On the basis of observing the physical appearance of the mice, it is apparent that not only did the mutated mice not produce visible melanin, but they also did not change in color as did the wildtype mice. This is one aspect that appears to support the researchers’ statement that the MSH-MC1R pathway does play a role in melanin production. But, there are other pathways involved in the production of melanin, and I wonder if the reason why a mutation in the MSH-MC1R pathway not only prevented the pathway from working, but also had an effect on related pathways, which could also contribute to not forming melanin.
            Overall, for this section of the research article, I think they briefly supported their hypothesis that the MSH-MC1R pathway plays a role in melanin production, but if they had numerical measurements (I’m not completely sure how it would be quantified though), it might make their claims more concrete. I also think that using UVB light might have made their data somewhat biased because it is a much stronger form of radiation that we don’t experience in high amount in reality, but on the other hand, it amplifies the effect so that its more observable. I think their experimental set up was effective in that they made sure the mice that were mutated were only different for the MSH-MC1R pathway, and so there were no other presumable contributing factors besides that one difference.

1.     D'Orazio J, Nobuhisa T, Fisher D, et al. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature [serial online]. September 21, 2006;443(7109):340-344. Available from: Academic Search Complete, Ipswich, MA. Accessed May 2, 2014.
2.     Brenner M, Hearing VJ. The protective role of melanin against UV damage in human skin. Photochem Photobiol. 2008;13:539–549. doi: 10.1111/j.1751-1097.2007.00226.x.