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• W2058973334 abstract "The allure of the sun's warm embrace. A tan, its by-product, a sign of health, wealth and leisure. But is there a hidden cost? For over a hundred years, it has been suspected that too much exposure to sunlight, and in particular the ultraviolet (UV) component, carries a risk of developing skin cancer, including its most deadly manifestation, melanoma. UV is the most prominent carcinogen in our environment. Conjugated bonds in biomolecules strongly absorb UV radiation (UVR) and become chemically reactive. This is deleterious when it results in cyclobutane pyrimidine dimers, which are mutagenic and can directly cause the oncoprotein activation and tumour suppressor inactivation that fuel skin tumorigenesis. Skin can adapt to seasonal increases in UVR by upregulating melanin production. Increased risk of melanoma due to UVR exposure occurs; however, when Caucasians inhabit low latitudes and experience UVR levels for which their skin is not adapted, and when untanned skin is suddenly exposed to intense UVR, as invariably occurs with the annual migration of high-latitude dwellers towards the equator (aka the summer vacation). However, the link between intermittent exposure to intense UVR and melanoma and the presumed protective effect of sunscreen are still controversial. A recent publication from the group of Richard Marais has now established that intermittent UVR mimicking mild sunburn will accelerate melanomagenesis. Further, they demonstrate that this can be mitigated but not entirely negated by application of sunscreen, which absorbs UVA and UVB (Viros et al., 2014). Previously, the Pritchard and Marais groups created a recombinant mouse model, whereby treatment with tamoxifen can induce melanocyte-specific Cre-mediated rearrangement of the Braf locus, permitting expression of a V600E mutant form of the BRAF protein (Dhomen et al., 2009), which in humans is detected in about 50% of cutaneous melanoma cases. BRAFV600E-expressing mice develop multiple naevi and ~50% typically develop melanoma by around 12 months. In the study by Viros et al., 3-month old BRAFV600E-expressing mice were exposed to ultraviolet radiation mimicking mild sunburn (160 mJ/cm2 UVA/UVB) weekly up to 6 months. A cloth was used to shield one-half of each mouse from UVR and this non-exposed skin served as an internal control. UV irradiation accelerated melanoma formation: all irradiated mice developed melanoma by 7 months at a median latency of 5.3 months with on average 3.5 tumours each; 98% of tumours were within the UV-irradiated area. These striking observations confirm epidemiological findings that UVR, sufficient to induce mild sunburn, can act as a carcinogen for BRAFV600E-expressing melanocytes. When sun protection factor (SPF) 50 sunscreen was applied to the skin of the mice prior to UV irradiation, this protected from immediate skin damage, preventing apoptosis of keratinocytes, induction of TP53 (TRP53, P53) protein, epidermal hypertrophy and dermal thickening. Remarkably, Viros et al. demonstrated that the application of sunscreen-protected mice also from melanoma formation, increasing the median latency to 7.5 months and decreasing the tumour burden to 1.5 tumours each. However, melanoma formation was still above base-line in sunscreen-protected mice. Thus, the authors conclude that sunscreen offers some protection against melanoma but must be combined with other sun avoidance strategies (such as covering up) to completely neutralize the effects of UVR. Array comparative genome-hybridization (aCGH) analysis – a technique whereby genomic DNA prepared from normal and tumour material is differentially labelled and hybridized to an array of probes spanning the genome; a ratio of normal: tumour signal < or >1 indicates DNA amplification or deletion respectively – revealed that compared to spontaneous melanoma, UVR-induced melanoma contained significantly fewer recurrent copy number changes in known melanoma oncogenes and tumour suppressors, suggesting that UVR-induced nucleotide substitutions rather than deletion or amplification renders these genes oncogenic. Nevertheless, there were still a couple of tumours that showed alterations in Cdkn2a, Mitf and Braf copy numbers, highlighting their relevance for melanomagenesis. Sequencing genomic DNA of tumours from UV-irradiated skin revealed a ~30-fold increase in single nucleotide substitutions compared to tumours from non-UVR-exposed skin, with the majority of lesions being C>T transitions occurring in CC dinucleotides (a hallmark of UVR). Such nucleotide substitutions can cause amino acid substitutions and when they are found in the same gene multiple times this is evidence for the gene concerned contributing to melanomagenesis. 6 of 15 (40%) UVR-exposed melanomas harboured non-synonymous substitutions in the Trp53 gene coding region, far more than anticipated by chance and bearing the UVR hallmark C>T transitions. Moreover, the mutations uncovered corresponded to those frequently detected in common human neoplasms including melanoma. To prove that mutation of TRP53 could interact with BRAFV600E and drive melanoma formation, BRAFV600E-expressing mice were crossed with mice expressing a TRP53R127H mutant protein. Double mutant mice developed even more melanoma than UV-irradiated BRAFV600E-expressing mice. This finding is consistent with the observation that the benign naevi which ordinarily develop in brafV600E-expressing zebrafish progress to melanoma when a trp53 carrying a M214K mutation is expressed in these fish (Patton et al., 2005). Both mutations, R127H and M214K, lead to a TRP53 that is compromised as a transcription factor, resulting in defective target gene expression, and the mutant protein failing to elicit cellular functions such as cell cycle arrest or apoptosis. The TRP53 mutations identified in the UVR-induced BRAFV600E melanomas can lead to stabilized mutant proteins, which can interfere with residual wild-type protein. Moreover, increased TRP53 protein can gain functions (such as inducing cellular invasion) through perturbing the action of other proteins (such as p63 and p73) within the TRP53 interactome. The fact that no deletions in Trp53 were involved in this model suggests that a mixture of lost and gained functions of mutant TRP53 can co-operate with BRAFV600E to drive UVR-induced melanoma. On the other hand, melanoma formation in BRAFV600E mice can also be accelerated in a Trp53 deficient background (Goel et al., 2009), suggesting that in the absence of UVR and hence reduced DNA damage, loss of TRP53 is sufficient to facilitate BRAFV600E-driven melanomagenesis. TRP53 is mutationally inactivated in 10–20% of human melanoma, but additional mechanisms exist to inactivate TRP53 that are encountered in melanoma. Thus, amplification of the gene encoding either MDM2 or more often MDM4 and consequent overexpression of these proteins (which bind the N-terminus of TRP53 and antagonize transcriptional transactivation) occur in up to 65% of cases. Deletion of p14ARF which inhibits MDM2/4 (encoded by CDKN2A, which also encodes the CDK4/6 inhibitor p16INK4A) occurs in ~40% of cases. Thus, inactivation of TRP53 is expected to occur in the great majority of melanoma cases. As MDM2/4 can be targeted by small molecule inhibitors, this might be a viable strategy for restoring TRP53 function in melanoma with wild-type TRP53. “The model established by the Marais group reflects a more ‘real-life’ situation, in which adult individuals are exposed to repeated doses of UVR mimicking mild sunburn.”" @default.
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• W2058973334 date "2014-09-02" @default.
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• W2058973334 title "TP53 in the UV spotlight: abona fidedriver of melanoma" @default.
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• W2058973334 doi "https://doi.org/10.1111/pcmr.12302" @default.
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