The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin

The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV-induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV-protective effects against DNA damage in UVB-tanned skin (but not in UVA-tanned skin) were significantly higher. UVA-induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up-regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB-exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV-induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis.     

Skin and hair pigmentation variation in Island Melanesia

Skin and hair pigmentation are two of the most easily visible examples of human phenotypic variation. Selection-based explanations for pigmentation variation in humans have focused on the relationship between melanin and ultraviolet radiation, which is largely dependent on latitude. In this study, skin and hair pigmentation were measured as the melanin (M) index, using narrow-band reflectance spectroscopy for 1,135 individuals from Island Melanesia. Overall, the results show remarkable pigmentation variation, given the small geographic region surveyed. This variation is discussed in terms of differences between males and females, among islands, and among neighborhoods within those islands. The relationship of pigmentation to age, latitude, and longitude is also examined. We found that male skin pigmentation was significantly darker than females in 5 of 6 islands examined. Hair pigmentation showed a negative, but weak, correlation with age, while skin pigmentation showed a positive, but also weak, correlation with age. Skin and hair pigmentation varied significantly between islands as well as between neighborhoods within those islands. Bougainvilleans showed significantly darker skin than individuals from any other island considered, and are darker than a previously described African-American population. These findings are discussed in relation to prevailing hypotheses about the role of natural selection in shaping pigmentation variation in the human species, as well as the role of demographic processes such as admixture and drift in Island Melanesia.     

Melanogenesis: a photoprotective response to DNA damage?

Exposure to ultra violet radiation (UVR) is associated with significant long-term deleterious effects such as skin cancer. A well-recognised short-term consequence of UVR is increased skin pigmentation. Pigmentation, whether constitutive or facultative, has widely been viewed as photoprotective, largely because darkly pigmented skin is at a lower risk of photocarcinogenesis than fair skin. Research is increasingly suggesting that the relationship between pigmentation and photoprotection may be far more complex than previously assumed. For example, photoprotection against erythema and DNA damage has been shown to be independent of level of induced pigmentation in human white skin types. Growing evidence now suggests that UVR induced DNA photodamage, and its repair is one of the signals that stimulates melanogenesis and studies suggest that repeated exposure in skin type IV results in faster DNA repair in comparison to skin type II. These findings suggest that tanning may be a measure of inducible DNA repair capacity, and it is this rather than pigment per se which results in the lower incidence skin cancer observed in darker skinned individuals. This evokes the notion that epidermal pigmentation may in fact be the mammalian equivalent of a bacterial SOS response. Skin colour is one of most conspicuous ways in which humans vary yet the function of melanin remains controversial. Greater understanding of the role of pigmentation in skin is vital if one is to be able to give accurate advice to the general public about both the population at risk of skin carcinogenesis and also public perceptions of a tan as being healthy.     

Unravelling UVA-induced mutagenesis

Ultraviolet A (UVA) radiation represents more than 90% of the solar UV radiation reaching Earth's surface. Exposure to solar UV radiation is a major risk in the occurrence of non-melanoma skin cancer. Whole genome sequencing data of melanoma tumors recently obtained makes it possible also to definitively associate malignant melanoma with sunlight exposure. Even though UVB has long been established as the major cause of skin cancer, the relative contribution of UVA is still unclear. In this review, we first report on the formation of DNA damage induced by UVA radiation, and on recent advances on the associated mechanism. We then discuss the controversial data on the UVA-induced mutational events obtained for various types of eukaryotic cells, including human skin cells. This may help unravel the role of UVA in the various steps of photocarcinogenesis. The connection to photocarcinogenesis is more extensively discussed by other authors in this issue.     

Catch me if you can--predation affects divergence in a polyphenic species

Predation is a major driving force in evolution. Predation has been shown to select for size, morphology, and camouflage. Many animals use camouflage to reduce predation risk. In some cases, individuals can adjust their pigmentation, enabling them a higher survival in a heterogeneous environment. Here, we show that the difference in pigmentation between juvenile perch individuals (Perca fluvuiatilis) occupying different environments (open water and vegetated habitats of lakes) is likely a consequence of predator selection. Lightly pigmented individuals have a higher chance of survival in open water whereas darker pigmented individuals survive better in vegetation. As a response to predators, individuals forced into the vegetation by predators developed darker skin whereas the skin of individuals forced into open water became lighter. In a common garden experiment, in the absence of predation, we found that pigmentation in juvenile perch is only due to plasticity and not to genetic variation. However, contrary to predictions, individuals raised in open water developed darker skin compared to individuals raised in vegetation. This may be a response to UV-stress. Overall, our results suggest that predation can be a strong selective agent on pigmentation differences among conspecifics occupying different habitats.     

Chemoprevention of photocarcinogenesis by selected dietary botanicals.

Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer. It may be because of inadequate use, incomplete spectral protection and toxicity. Therefore new chemopreventive methods are necessary to protect the skin from photodamaging effects of solar UV radiation. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis. In recent years, considerable interest has been focused on identifying naturally occurring botanicals, specifically dietary, for the prevention of photocarcinogenesis. A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties. This review summarizes chemopreventive effects of some selected botanicals, such as apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against photocarcinogenesis in in vitro and in vivo systems. Attention has also been focused on highlighting the mechanism of chemopreventive action of these dietary botanicals. We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation.     

Visible Light Induces Melanogenesis in Human Skin through a Photoadaptive Response

Visible light (400–700 nm) lies outside of the spectral range of what photobiologists define as deleterious radiation and as a result few studies have studied the effects of visible light range of wavelengths on skin. This oversight is important considering that during outdoors activities skin is exposed to the full solar spectrum, including visible light, and to multiple exposures at different times and doses. Although the contribution of the UV component of sunlight to skin damage has been established, few studies have examined the effects of non-UV solar radiation on skin physiology in terms of inflammation, and limited information is available regarding the role of visible light on pigmentation. The purpose of this study was to determine the effect of visible light on the pro-pigmentation pathways and melanin formation in skin. Exposure to visible light in ex-vivo and clinical studies demonstrated an induction of pigmentation in skin by visible light. Results showed that a single exposure to visible light induced very little pigmentation whereas multiple exposures with visible light resulted in darker and sustained pigmentation. These findings have potential implications on the management of photo-aggravated pigmentary disorders, the proper use of sunscreens, and the treatment of depigmented lesions.     

The evolution of human skin coloration

Skin color is one of the most conspicuous ways in which humans vary and has been widely used to define human races. Here we present new evidence indicating that variations in skin color are adaptive, and are related to the regulation of ultraviolet (UV) radiation penetration in the integument and its direct and indirect effects on fitness. Using remotely sensed data on UV radiation levels, hypotheses concerning the distribution of the skin colors of indigenous peoples relative to UV levels were tested quantitatively in this study for the first time. The major results of this study are: (1) skin reflectance is strongly correlated with absolute latitude and UV radiation levels. The highest correlation between skin reflectance and UV levels was observed at 545 nm, near the absorption maximum for oxyhemoglobin, suggesting that the main role of melanin pigmentation in humans is regulation of the effects of UV radiation on the contents of cutaneous blood vessels located in the dermis. (2) Predicted skin reflectances deviated little from observed values. (3) In all populations for which skin reflectance data were available for males and females, females were found to be lighter skinned than males. (4) The clinal gradation of skin coloration observed among indigenous peoples is correlated with UV radiation levels and represents a compromise solution to the conflicting physiological requirements of photoprotection and vitamin D synthesis. The earliest members of the hominid lineage probably had a mostly unpigmented or lightly pigmented integument covered with dark black hair, similar to that of the modern chimpanzee. The evolution of a naked, darkly pigmented integument occurred early in the evolution of the genus Homo. A dark epidermis protected sweat glands from UV-induced injury, thus insuring the integrity of somatic thermoregulation. Of greater significance to individual reproductive success was that highly melanized skin protected against UV-induced photolysis of folate (Branda & Eaton, 1978, Science201, 625-626; Jablonski, 1992, Proc. Australas. Soc. Hum. Biol.5, 455-462, 1999, Med. Hypotheses52, 581-582), a metabolite essential for normal development of the embryonic neural tube (Bower & Stanley, 1989, The Medical Journal of Australia150, 613-619; Medical Research Council Vitamin Research Group, 1991, The Lancet338, 31-37) and spermatogenesis (Cosentino et al., 1990, Proc. Natn. Acad. Sci. U.S.A.87, 1431-1435; Mathur et al., 1977, Fertility Sterility28, 1356-1360).As hominids migrated outside of the tropics, varying degrees of depigmentation evolved in order to permit UVB-induced synthesis of previtamin D(3). The lighter color of female skin may be required to permit synthesis of the relatively higher amounts of vitamin D(3)necessary during pregnancy and lactation. Skin coloration in humans is adaptive and labile. Skin pigmentation levels have changed more than once in human evolution. Because of this, skin coloration is of no value in determining phylogenetic relationships among modern human groups.     

Sunless skin tanning with dihydroxyacetone delays broad-spectrum ultraviolet photocarcinogenesis in hairless mice

Sunless tanning with dihydroxyacetone (DHA) is not considered to be a sunscreen although it does absorb parts of the ultraviolet (UV) spectrum. We investigated the protection with topical application of DHA against solar UV-induced skin carcinogenesis in lightly pigmented hairless hr/hr C3H/Tif mice. Broad-spectrum UV radiation, simulating the UV part of the solar spectrum was obtained from one Philips TL12 and five Bellarium-S SA-1-12 tubes. Three groups of mice were UV-exposed four times a week to a dose-equivalent of four times the standard erythema dose (SED), without or with application of 5 or 20% DHA only twice a week. Similarly, three groups of mice were treated with DHA and irradiated with a high UV dose (8 SED), simulating a skin burn. Two groups (controls) were not irradiated, but either left untreated or treated with 20% DHA alone. The UV-induced skin pigmentation by melanogenesis could easily be distinguished from DHA-induced browning and was measured by a non-invasive, semi-quantitative method. Application of 20% DHA reduced by 63% the pigmentation produced by 4 SED, however, only by 28% the pigmentation produced by 8 SED. Furthermore, topical application of 20% DHA significantly delayed the time to appearance of the first tumor >or=1mm (P=0.0012) and the time to appearance of the third tumor (P=2 x 10(-6)) in mice irradiated with 4 SED. However, 20% DHA did not delay tumor development in mice irradiated with 8 SED. Application of 5% DHA did not influence pigmentation or photocarcinogenesis.In conclusion, this is the first study to show that the superficial skin coloring generated by frequent topical application of DHA in high concentrations may delay skin cancer development in hairless mice irradiated with moderate UV doses.     

Sunless skin tanning with dihydroxyacetone delays broad-spectrum ultraviolet photocarcinogenesis in hairless mice

Sunless tanning with dihydroxyacetone (DHA) is not considered to be a sunscreen although it does absorb parts of the ultraviolet (UV) spectrum. We investigated the protection with topical application of DHA against solar UV-induced skin carcinogenesis in lightly pigmented hairless hr/hr C3H/Tif mice. Broad-spectrum UV radiation, simulating the UV part of the solar spectrum was obtained from one Philips TL12 and five Bellarium-S SA-1-12 tubes. Three groups of mice were UV-exposed four times a week to a dose-equivalent of four times the standard erythema dose (SED), without or with application of 5 or 20% DHA only twice a week. Similarly, three groups of mice were treated with DHA and irradiated with a high UV dose (8 SED), simulating a skin burn. Two groups (controls) were not irradiated, but either left untreated or treated with 20% DHA alone. The UV-induced skin pigmentation by melanogenesis could easily be distinguished from DHA-induced browning and was measured by a non-invasive, semi-quantitative method. Application of 20% DHA reduced by 63% the pigmentation produced by 4 SED, however, only by 28% the pigmentation produced by 8 SED. Furthermore, topical application of 20% DHA significantly delayed the time to appearance of the first tumor ≥1 mm (P=0.0012) and the time to appearance of the third tumor (P=2×10⁻⁶) in mice irradiated with 4 SED. However, 20% DHA did not delay tumor development in mice irradiated with 8 SED. Application of 5% DHA did not influence pigmentation or photocarcinogenesis.In conclusion, this is the first study to show that the superficial skin coloring generated by frequent topical application of DHA in high concentrations may delay skin cancer development in hairless mice irradiated with moderate UV doses.     

Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis

Ultraviolet (UV) radiation causes inflammation, gene mutation and immunosuppression in the skin. These biological changes are responsible for photocarcinogenesis. UV radiation in sunlight is divided into two wavebands, UVB and UVA, both of which contribute to these biological changes, and therefore probably to skin cancer in humans and animal models. Oxidative damage caused by UV contributes to inflammation, gene mutation and immunosuppression. This article reviews evidence for the hypothesis that UV oxidative damage to these processes contributes to photocarcinogenesis. UVA makes a larger impact on oxidative stress in the skin than UVB by inducing reactive oxygen and nitrogen species which damage DNA, protein and lipids and which also lead to NAD+ depletion, and therefore energy loss from the cell. Lipid peroxidation induces prostaglandin production that in association with UV-induced nitric oxide production causes inflammation. Inflammation drives benign human solar keratosis (SK) to undergo malignant conversion into squamous cell carcinoma (SCC) probably because the inflammatory cells produce reactive oxygen species, thus increasing oxidative damage to DNA and the immune system. Reactive oxygen or nitrogen appears to cause the increase in mutational burden as SK progress into SCC in humans. UVA is particularly important in causing immunosuppression in both humans and mice, and UV lipid peroxidation induced prostaglandin production and UV activation of nitric oxide synthase is important mediators of this event. Other immunosuppressive events are likely to be initiated by UV oxidative stress. Antioxidants have also been shown to reduce photocarcinogenesis. While most of this evidence comes from studies in mice, there is supporting evidence in humans that UV-induced oxidative damage contributes to inflammation, gene mutation and immunosuppression. Available evidence implicates oxidative damage as an important contributor to sunlight-induced carcinogenesis in humans.     

Are there mechanistic differences between ultraviolet and visible radiation induced skin pigmentation?

Most of the studies on sunlight-induced pigmentation of skin are mainly focused on ultraviolet (UV) radiation-induced pigmentation and ways to prevent it. Recent studies have shown that the visible component of sunlight can also cause significant skin pigmentation. In the current study, the extent of pigmentation induced by UV and visible regions of sunlight in subjects with Fitzpatrick skin type IV-V was measured and compared with pigmentation induced by total sunlight. The immediate pigment darkening (IPD) induced by the visible fraction of sunlight is not significantly different from that induced by the UV fraction. However, the persistent pigment darkening (PPD) induced by visible fraction of sunlight in significantly lower than that induced by the UV fraction. The dose responses of IPD induced by UV, visible light and total sunlight suggest that both UV and visible light interact with the same precursor although UV is 25 times more efficient in inducing pigmentation per J cm(-2) of irradiation compared to visible radiation. The measured diffused reflection spectra and decay kinetics of UV and visible radiation-induced pigmentation are very similar, indicating that the nature of the transient and persistent species involved in both the processes are also likely to be same.     

Short-term and long-term cellular and molecular events following UV irradiation of skin: implications for molecular medicine

Acute ultraviolet (UV) irradiation of normal human skin results in several clinical effects, including sunburn inflammation (erythema) and tanning, histological changes such as thickening of the epidermis, and local or systemic immunosuppression. Chronic UV irradiation leads to photoaging, sustained immunosuppression and photocarcinogenesis. Photocarcinogenesis involves the accumulation of genetic changes, as well as immune system modulation, and ultimately leads to the development of skin cancers. Recent advances in molecular and cellular biology have clarified the mechanisms of photocarcinogenesis, including the formation of DNA photoproducts, DNA repair, the mutation of proto-oncogenes and tumour suppressor genes, and UV-induced immunosuppression. Further investigation and a better understanding of photocarcinogenesis are critical to the development of effective prevention and intervention strategies for human skin cancer.     

Genomic ancestry, self-reported "color" and quantitative measures of skin pigmentation in Brazilian admixed siblings

A current concern in genetic epidemiology studies in admixed populations is that population stratification can lead to spurious results. The Brazilian census classifies individuals according to self-reported "color", but several studies have demonstrated that stratifying according to "color" is not a useful strategy to control for population structure, due to the dissociation between self-reported "color" and genomic ancestry. We report the results of a study in a group of Brazilian siblings in which we measured skin pigmentation using a reflectometer, and estimated genomic ancestry using 21 Ancestry Informative Markers (AIMs). Self-reported "color", according to the Brazilian census, was also available for each participant. This made it possible to evaluate the relationship between self-reported "color" and skin pigmentation, self-reported "color" and genomic ancestry, and skin pigmentation and genomic ancestry. We observed that, although there were significant differences between the three "color" groups in genomic ancestry and skin pigmentation, there was considerable dispersion within each group and substantial overlap between groups. We also saw that there was no good agreement between the "color" categories reported by each member of the sibling pair: 30 out of 86 sibling pairs reported different "color", and in some cases, the sibling reporting the darker "color" category had lighter skin pigmentation. Socioeconomic status was significantly associated with self-reported "color" and genomic ancestry in this sample. This and other studies show that subjective classifications based on self-reported "color", such as the one that is used in the Brazilian census, are inadequate to describe the population structure present in recently admixed populations. Finally, we observed that one of the AIMs included in the panel (rs1426654), which is located in the known pigmentation gene SLC24A5, was strongly associated with skin pigmentation in this sample.     

A trade‐off between overheating and camouflage on shorebird eggshell colouration

In ground‐nesting birds egg colour and appearance may have evolved due to opposite selection pressures. Pigmentation and spottiness make the eggs darker and have been suggested to improve camouflage. However darker and more spotted eggs may reach higher temperatures when not attended by adults and receiving direct sunlight, which may be lethal for embryos. Some authors suggested that this trade‐off may not exist because eggshell pigments mainly reflect in the infrared region of the solar spectrum, but have not considered that wavelengths in the visible part of the spectrum may also contribute to overheating. To test the occurrence of a trade‐off between camouflage and overheating of eggs, we took digital images to analyse colour and camouflage in 93 nests of four shorebird species (two stilts and two plovers) in two regions (tropical and mediterranean sites). We predicted that these species (closely related) may have evolved different eggshell designs depending on solar radiation, which is supposed to be stronger in the Tropics. To record egg temperatures, we placed Japanese quail eggs in natural nests of shorebirds, and registered temperatures using a datalogger. We found that darker and more spotted eggs reached higher temperatures than lighter ones, and that after controlling for environmental temperatures, eggs overheated more in the Tropics, likely because of a more intense solar radiation. We also found that tropical shorebirds’ eggshells have darker spots and lighter backgrounds. Overall, darker eggs were better camouflaged. Taken together, our results show that the benefits of increasing pigmentation of eggshell backgrounds and spottiness for a better camouflage are counteracted by the increased risks of overheating when eggs remain exposed to direct solar radiation.     

Mechanism of skin pigmentation

Melanin is a pigment that plays an important role in providing coloration and protecting human skin from the harmful effects of UV light radiation. Human skin color is determined by the type and amount of melanins that are synthesized and deposited within the melanosomes. In addition, the transfer of these specialized membrane-bound organelles from melanocytes to surrounding keratinocytes also plays a role in dictating human skin color. In order to investigate the principle features of skin pigmentation, the origin, function, and production ability of melanin should be highly understood in terms of biological and pathophysiological aspects. Furthermore, a deep understanding of melanin synthesis will also contribute to cosmetics and drugs development. In this review, the processes of melanin biosynthesis, such as survival, proliferation, and differentiation of melanin cells, as well as the biological regulation of human pigmentation were described.     

Chemical analysis of constitutive pigmentation of human epidermis reveals constant eumelanin to pheomelanin ratio

The skin constitutive pigmentation is given by the amount of melanin pigment, its relative composition (eu/pheomelanin) and distribution within the epidermis, and is largely responsible for the sensitivity to UV exposure. Nevertheless, a precise knowledge of melanins in human skin is lacking. We characterized the melanin content of human breast skin samples with variable pigmentations rigorously classified through the Individual Typology Angle (ITA) by image analysis, spectrophotometry after solubilization with Soluene‐350 and high‐performance liquid chromatography (HPLC) after chemical degradation. ITA and total melanin content were found correlated, ITA and PTCA (degradation product of DHICA melanin), and TTCA (degradation product of benzothiazole‐type pheomelanin) as well but not 4‐AHP (degradation product of benzothiazine‐type pheomelanin). Results revealed that human epidermis comprises approximately 74% of eumelanin and 26% pheomelanin, regardless of the degree of pigmentation. They also confirm the low content of photoprotective eumelanin among lighter skins thereby explaining the higher sensitivity toward UV exposure.     

Antagonizing Effects and Mechanisms of Afzelin against UVB-Induced Cell Damage

Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human keratinocytes, resulting in skin inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effects of UV irradiation is essential. Therefore, in this study, we investigated the protective effects of afzelin, one of the flavonoids, against UV irradiation in human keratinocytes and epidermal equivalent models. Spectrophotometric measurements revealed that the afzelin extinction maxima were in the UVB and UVA range, and UV transmission below 376 nm was <10%, indicating UV-absorbing activity of afzelin. In the phototoxicity assay using the 3T3 NRU phototoxicity test (3T3-NRU-PT), afzelin presented a tendency to no phototoxic potential. In addition, in order to investigate cellular functions of afzelin itself, cells were treated with afzelin after UVB irradiation. In human keratinocyte, afzelin effectively inhibited the UVB-mediated increase in lipid peroxidation and the formation of cyclobutane pyrimidine dimers. Afzelin also inhibited UVB-induced cell death in human keratinocytes by inhibiting intrinsic apoptotic signaling. Furthermore, afzelin showed inhibitory effects on UVB-induced release of pro-inflammatory mediators such as interleukin-6, tumor necrosis factor-α, and prostaglandin-E₂ in human keratinocytes by interfering with the p38 kinase pathway. Using an epidermal equivalent model exposed to UVB radiation, anti-apoptotic activity of afzelin was also confirmed together with a photoprotective effect at the morphological level. Taken together, our results suggest that afzelin has several cellular activities such as DNA-protective, antioxidant, and anti-inflammatory as well as UV-absorbing activity and may protect human skin from UVB-induced damage by a combination of UV-absorbing and cellular activities.     

Skin color variation in orang asli tribes of peninsular malaysia

Pigmentation is a readily scorable and quantitative human phenotype, making it an excellent model for studying multifactorial traits and diseases. Convergent human evolution from the ancestral state, darker skin, towards lighter skin colors involved divergent genetic mechanisms in people of European vs. East Asian ancestry. It is striking that the European mechanisms result in a 10–20-fold increase in skin cancer susceptibility while the East Asian mechanisms do not. Towards the mapping of genes that contribute to East Asian pigmentation there is need for one or more populations that are admixed for ancestral and East Asian ancestry, but with minimal European contribution. This requirement is fulfilled by the Senoi, one of three indigenous tribes of Peninsular Malaysia collectively known as the Orang Asli. The Senoi are thought to be an admixture of the Negrito, an ancestral dark-skinned population representing the second of three Orang Asli tribes, and regional Mongoloid populations of Indo-China such as the Proto-Malay, the third Orang Asli tribe. We have calculated skin reflectance-based melanin indices in 492 Orang Asli, which ranged from 28 (lightest) to 75 (darkest); both extremes were represented in the Senoi. Population averages were 56 for Negrito, 42 for Proto-Malay, and 46 for Senoi. The derived allele frequencies for SLC24A5 and SLC45A2 in the Senoi were 0.04 and 0.02, respectively, consistent with greater South Asian than European admixture. Females and individuals with the A111T mutation had significantly lighter skin (p = 0.001 and 0.0039, respectively). Individuals with these derived alleles were found across the spectrum of skin color, indicating an overriding effect of strong skin lightening alleles of East Asian origin. These results suggest that the Senoi are suitable for mapping East Asian skin color genes.     

A caspase-resistant mutant of PKC-delta protects keratinocytes from UV-induced apoptosis

Keratinocyte apoptosis induced by UV radiation is a major protective mechanism from skin photocarcinogenesis. The induction of apoptosis by UV radiation, as well as a variety of genotoxic stimuli, involves the activation of PKC-delta by caspase-3-mediated cleavage in its hinge region, thus generating a constitutively active catalytic fragment. To determine the role of PKC-delta cleavage in UV apoptosis signaling, we introduced a caspase-resistant PKC-delta mutant (D330A) into human keratinocytes by retrovirus transduction. Overexpression of PKC-delta(D330A) protected keratinocytes from UV-induced apoptosis and enhanced long-term survival. PKC-delta(D330A) partially prevented the release of cytochrome c from the mitochondria and the loss of Mcl-1, a key antiapoptotic protein downregulated during UV apoptosis. Thus, the cleavage and activation of PKC-delta are critical components of UV-induced apoptosis in human keratinocytes, and the inactivation of PKC-delta can promote the survival of keratinocytes exposed to UV radiation.