The p53 tumor suppressor gene is responsible for producing the p53 protein, which works to repair the cell when DNA damage is detected. Some of its roles include arresting the cell cycle before replication, inducing apoptosis, or binding to promoter regions to prevent transcription of certain genes. There are about 100 proteins that p53 regulates, and the article I am going to discuss focuses on its relation to skin cancer and regulating UV-induced DNA damage. The article also looks at how p53 can serve as a biological endpoint to evaluate the efficacy of sunscreens in preventing UV-induced skin cancer.
A signature
mutation of UV-induced DNA damage is the C–>T
and CC–>TT
mutation, which are found in the p53 gene. The researchers in this article
conducted an experiment in which mice heterozygous (+/-) and homozygous (-/-) for the p53
gene, were exposed to UV in order to observe tumor development in relation to
presence of absence of the p53 gene. The study concluded that the order of
probability for developing tumors went from wildtype (+/+) mice being the least
at risk, to the heterozygous, and finally to the homozygous (-/-), which had
the highest risk. What I’m curious to know more about is how the researchers
ranked these “at risk” levels, and what measurement they used to quantify
likelihood of tumor development. The results imply that having the p53 gene is
better than not having it, because although p53 mutations can occur from the
UV, it’s better to have the gene so that non-mutants can continue to repair
damage.
Another experiment carried out studied
the effectiveness of sunscreen in inhibiting p53 mutations. The SPF of
sunscreen is determined by its ability to prevent sunburn, but is not
indicative of how well you are protected from other damages caused by UV
exposure. Because p53 mutations correlate with tumor development as studied in
the previous experiment I discussed, researchers looked at sunscreen’s ability
to inhibit these mutations from occurring. In one of the experiments, mice were
exposed with UVB from a sunlamp 5 times per week for 12 weeks. One group of
mice received UVB irradiation and sunscreen vehicle control, while another had
UVB absorbing sunscreen applied 30 minutes prior to exposure, and the last
group had UVB+UVA absorbing sunscreen applied 30 minutes prior. The results
showed that in comparison to the control, there was an 88% reduction in
mutation frequency for the UVB absorbing sunscreen, and a 92% reduction when
UVA+UVB sunscreen was used. But, as the study indicated, using sunlamps weren’t
as realistic as if the mice were to be exposed to actual sunlight, and so they
redid the experiment using solar simulator radiation (SSR). The results were
claimed to be extremely similar, although the exact numbers were not indicated. I question
whether it was necessary for them to initially use sunlamps if they knew it
wouldn’t be an accurate representation of real sunlight, and I also would like
to know more about what makes SSR better (i.e. how are the UV waves emitted
differently, how is its intensity different, etc.). The number of mice studied
was not indicated, but I find the results reliable because the experiment was
controlled in terms of type of mice, exposure amount, type of exposure, and treatment
of each group of mice. If all else besides type of product applied is the same,
I think it’s plausible to claim the mutation frequencies were due to the type of sunscreen
used. What I am curious to know more about is what the actual mutation rates
were like, and whether an 88% or 92% reduction meant that mutations were still
occurring, and tumors were still likely to develop, or if a reduction of those amounts were enough for the cell to later repair and avoid tumor development.
The article also discusses an
experiment done to examine the effect of sunscreen on human skin, by using skin
grafts of human skin used for breast reconstruction, which tested negative for
presence of p53. I think it was important for the researchers to make sure the
skin was not predisposed to having the gene expressed because that would have
indicated the skin was responding to DNA damage, and would have factored into
whether developing tumors were a result of the UVB exposure or to other
elements already in the skin. In the study, the skin was grafted onto mice, and
after the mice healed from the surgery, they were exposed to solar-simulated
UVB radiation 5 times per week, and p53 mutations were measured periodically by
AS-PCR, although the time points at which these measurements were taken are not
specified. The following table depicts the number of mutations occurring in
skin grafts out of the total number of mice irradiated.
As you can see, the number of mice tested was very small, and it is also questionable whether some mice had multiple mutations, and what combinations of mutations occurred. It is also strange that there are more mice irradiated by 12 weeks. But the overall trend shows that by week 12, all skin grafts had some sort of mutation when sunscreen was not used, and that in mice that were treated with sunscreen, there was 1 C-->T mutation, which leads me to question why it’s noted that for total skin grafts with mutations a zero is indicated. Although the sample size is too small to give an in depth analysis of the complete effect of sunscreen, it is apparent that there is a benefit of using sunscreen in regards to mutations arising based on the 10 fold difference in number of mutations by week 12.
Overall, I though
the article did a good job of analyzing its own experimental data, and noting
what they could do to improve upon, as well as the credibility of their
numbers. Several times, the article would discuss the results, and then
indicate the implications, and the error in their analysis. I am interested to
learn more about how sunscreen actually inhibits p53 gene mutations, and to
what extent sunscreen must be used in order to reduce mutation frequency and
likelihood of tumor development in the long run.
Sources:
1. Benjamin, C. L., Ullrich, S. E., Kripke, M. L. and Ananthaswamy, H. N. (2008), p53 Tumor Suppressor Gene: A Critical Molecular Target for UV Induction and Prevention of Skin Cancer. Photochemistry and Photobiology, 84: 55–62. doi: 10.1111/j.1751-1097.2007.00213.x
Sources:
1. Benjamin, C. L., Ullrich, S. E., Kripke, M. L. and Ananthaswamy, H. N. (2008), p53 Tumor Suppressor Gene: A Critical Molecular Target for UV Induction and Prevention of Skin Cancer. Photochemistry and Photobiology, 84: 55–62. doi: 10.1111/j.1751-1097.2007.00213.x