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2 The Melanocyte and Sunlight: A Cooperative but High-Risk Relationship

2 The Melanocyte and Sunlight: A Cooperative but High-Risk Relationship

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L. Marrot

Fig. 8.1 Stressors targeting melanocyte: melanogenesis constitutes a peculiar additional source of

stress compared to other epidermal cells

(i) cell cycle arrest and DNA repair are mobilized in order to prevent genomic

degradation or (ii) apoptosis, programmed cell death, eliminates highly damaged

cells. In the epidermis for instance, sunburn cells are apoptotic (for review see

Marrot and Meunier 2008). Cui et al. demonstrated that p53 stimulates the POMC

promoter and secretion by keratinocytes in response to UV. In fact, the tanning

response to UVB exposure is only minimally present in p53 knockout mice, thus

p53 functions as a sensor and effector of UV-induced pigmentation (Cui et al. 2007)

(Fig. 8.1).

The peptide endothelin-1 (EDN1) was also shown to be upregulated in murine

skin following UVB irradiation, and it interacts with specific G protein-coupled

receptors (endothelin receptor: ENDR). END1 stimulates melanogenesis, proliferation, dendricity and MC1R expression in melanocytes. It was recently shown that

UV-induced END1 expression in keratinocytes was directly and positively controlled by p53 transcriptional activity. In fact, END1 was significantly downregulated in the epidermis of p53 knockout mice (Hyter et al. 2012). Thus, END1 and

POMC/α-MSH may have a synergistic effect aiming at increasing melanocyte

activity in order to protect the epidermis from sunlight-induced genotoxic stress.

P53 may drive this pigmentary adaptive response (Fig. 8.2).

8 The Cutaneous Melanocyte as a Target of Environmental Stressors


Fig. 8.2 Melanogenic paracrine pathways from keratinocytes in response to UV stress. Induction

of photodamage (CPD) activates p53 in keratinocytes, and p53 stimulates secretion of POMC

(which is cleaved to produce α-MSH) and endothelin-1 ET-1. ET-1/ENDR interaction triggers

signaling pathways inside melanocyte leading to differentiation (melanogenesis, dendricity).

α-MSH/MC1R interaction activates production of cAMP which in turn stimulates transcriptional

activity of MITF. MITF upregulates the expression of melanogenic enzymes: melanogenesis takes

place in melanosomes which are transferred to keratinocytes and protect their genomic DNA from

further UV exposures (tanning process)

Melanogenesis: A Response also Directly Linked to DNA

Damage in Melanocytes

Melanogenesis can be upregulated in cultured melanocytes exposed to UV, even in

the absence of keratinocytes. In fact, intracellular signaling also contributes to the

pigmentary response and an unexpected link between DNA damage and melanin

production was reported some years ago. For instance, treatment of irradiated

melanocytes with a liposome-encapsulated DNA repair enzyme which accelerated

CPD excision stimulated melanogenesis (Gilchrest et al. 1993). The same team

observed that addition of the dinucleotide pTpT to culture medium was associated

with a pro-pigmenting effect which was confirmed in vivo after its application to

guinea pig skin (Eller et al. 1996). Since pTpT was able to mimic the DNA segment

excised during the repair of TT pyrimidine dimers, the authors speculated about the

influence of DNA damage on melanogenesis. They finally demonstrated that pTpT

targeted and disrupted structures of telomeres, leading to an artificial DNA damage

response in which p53 was activated. The tanning response was thus largely

mediated by p53: as proof, UV-induced pigmentation is reduced in p53 knockout


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mice. Melanogenesis together with improved DNA repair can thus be considered a

SOS response by the skin against environmental genotoxicity and here again, p53

has a crucial influence (for review see Gilchrest et al. 2009).


Melanin: A Two-Edged Sword for Melanocytes

This concept of a two-edged sword was first proposed a few decades ago by Hill

et al. when they observed that melanin could generate a significant oxidative stress

under UV exposure (Hill et al. 1997). Several papers were published on this

paradoxical behavior of our natural sunscreen. Reports were first based on in vitro

experiments, but recent in vivo data confirmed that melanin could exacerbate UV

stress. A scientific consensus seems to emerge and it reconciles the Janus face of

pigmentation: cutaneous protection as a global process but a risk to the melanocyte

itself, particularly in fair skin exposed to UV.

Intrinsic Pro-oxidant Potential of Melanin and Its Precursors

Melanogenesis involves several oxidation reactions, which potentially produce

adverse biochemical effects (Fig. 8.3 and for review see Denat et al. 2014). For

instance, tyrosinase oxidizes tyrosine firstly into dopa and then into dopaquinone,

and this orthoquinone can react with nucleophilic compounds such as thiols or

amino groups. Moreover, the generation of superoxide anions in association with

tyrosinase activity has been reported in the literature (Koga et al. 1992; Tomita et al.

1984). Dihydroxy-indole (5,6-DHI) is oxidized into indolequinone and

dihydroxy-indole carboxylic acid (5,6-DHICA). DHICA is converted into the

corresponding quinone. Redox cycling from indoles to quinones can generate ROS

(ultimately hydrogen peroxide H2O2) as reported by Nappi and Vass (1996).

Polymerization of these quinones results finally in a black or brown eumelanin

pigment whereas production of the reddish-brown pheomelanin requires the

incorporation of cysteine: the resulting cysteinyldopa is converted into benzothiazine derivatives. It was suggested that cysteine consumption in

pheo-melanogenesis may compete with glutathione synthesis and affect redox

homeostasis in melanocytes (Morgan et al. 2013). Melanogenesis takes place inside

melanosomes which ensures that toxic chemical intermediates are contained.

However, melanosomes displaying structural abnormalities with partial leakage of

their content were observed in dysplastic nevi and melanoma cells (Borovanský

et al. 1991; Meyskens et al. 2001). Similarly, the diffusion of H2O2 into cytoplasm

is highly probable, enabling the production of genotoxic hydroxyl radicals ÁOH.

Miranda et al. showed that the rate of chromosomal aberrations (sister chromatid

exchange) correlated with the concentration of tyrosine supplied to cultured melanocytes: stimulation of melanogenesis could thus damage chromosomes (Miranda

et al. 1997). In line with this, Maresca et al. reported that catalase activity

8 The Cutaneous Melanocyte as a Target of Environmental Stressors


Fig. 8.3 The mammalian melanogenic pathway. Tyrosine-hydroxylase and dopa-oxidase activities of tyrosinase transform tyrosine into dopaquinone. Dopaquinone either react with cysteine to

enter pheo-melanogenic pathway (red melanin) or is transformed into indole-quinone moieties to

enter eu-melanogenic pathway (black or brown melanin). TRP2/DCT tautomerase activity

prevents spontaneous decarboxylation of dopachrome which is converted into

dihydroxy-indole-carboxylic acid. Possible contributions to oxidative stress generation or to

impairment of redox homeostasis are mentioned in red in this scheme

(enzymatic protection against H2O2) correlated with melanogenic intensity. This

natural protection against oxidative stress was thus required together with melanin

production (Maresca et al. 2008). In dysplastic nevi in which melanocytes are

hyperpigmented, melanosome sulphur and iron content was much higher than in

normal melanocytes and an oxidative imbalance was observed using a specific

probe for oxidative stress (Pavel et al. 2004). Smit et al. obtained similar results in

melanocytes from pigmented dysplastic nevi, where an unusually high level of

oxidative DNA damage was detected (Smit et al. 2008). Interestingly, a protective

role was proposed for the melanogenic enzyme dopachrome tautomerase

DCT/TRP2. TRP2 favors the production of DHICA (see Fig. 8.3), which is less

toxic than DHI and TRP2 was reported to increase glutathione levels in amelanotic

melanoma cells, providing protection against oxidative DNA damage and H2O2induced cytotoxicity (Michard et al. 2008). TRP2, as a direct player in melanogenesis, could thus be the first “line of defense” against oxidative stress associated

with pigmentation.


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Melanin Photoreactivity: A Significant Source of Stress

in Melanocytes Exposed to Sunlight

Early studies indicated that tanning confers only limited sun protection (a protection

factor of less than 3 as reported by Cripps 1981), suggesting that melanin is not a

perfect sunscreen. Moreover, melanin photochemistry is intriguing and appears

sometimes to contradict its photoprotective role.

In Vitro Data

The phototoxicity of pheomelanin and its instability in the presence of UV light

were reported in the literature some time ago. These properties are consistent with

the vulnerability of individuals with red hair to sun damage (for review see

Napolitano et al. 2014). However, the production of ROS by synthetic or natural

black and brown pigments exposed to UV radiation has also been observed in vitro

(Tomita et al. 1984; Korytowski et al. 1987; Kipp and Young 1999). These

unexpected results were confirmed in cultured melanocytes irradiated with different

UV spectra, using DNA damage as a marker. Noz et al. used the comet assay,

which quantifies DNA breaks in individual cells, to compare the sensitivity of

melanocytes from dysplastic nevi, common nevi and normal skin to UVB-induced

DNA damage. The highest level of DNA damage (in the dark or under UVB) was

observed in dysplastic nevus cells, the most highly pigmented cell type used in the

experiments (Noz et al. 1996). Wenczl et al. obtained comparable data in

UVA-exposed cells in which melanogenesis had been previously increased by

adding tyrosine to the culture medium (Wenczl et al. 1998). Marrot et al. compared

DNA damage in human fibroblasts, in melanocytes from different donors and in

melanocytes activated by tyrosine. Here again, DNA damage induction correlated

with melanin content (Marrot et al. 1999). Kvam and Tyrrell showed enhanced

induction of 8-OHdG oxidative damage in the DNA of murine or human melanoma

cells, when melanogenesis was activated prior to UVA exposure (Kvam and Tyrrell


In Vivo Data

Whether those in vitro data reflect an in vivo reality has been a matter of debate,

since constitutive skin pigmentation unquestionably determines the incidence of

skin cancer. In fact, squamous cell carcinomas and melanomas are respectively 50

or 13 times more common in Caucasians than in African Americans (Halder and

Bridgeman-Shah 1995). In vivo, induction of DNA damage in the form of

pyrimidine dimers is inversely correlated with ethnic pigmentation (Bykov et al.

2000; Kobayashi et al. 2001) or with skin color as assessed by individual typology

angle (ITA) (Del Bino et al. 2006). However, could the resistance of dark skin to

DNA photodamage be attributable solely to pigmentation? A 2005 review

8 The Cutaneous Melanocyte as a Target of Environmental Stressors


discussed the prevention of DNA photodamage by melanogenesis and concluded

that the repair of DNA damage could correlate with skin phototype, i.e. repair

would occur more rapidly in the dark-skinned type IV than in the fair-skinned type

II (Agar and Young 2005). More recently, Miyamura et al. reported that

UVA-induced tanning did not confer significant protection against UVB-induced

pyrimidine dimers, and that other protective factors such as DNA repair might be

linked to skin pigmentation (Miyamura et al. 2011). The deleterious impact of

melanin in vivo was addressed by some results obtained using the Platyfish

Xiphophorus. The action spectra of UV and visible light in the induction of melanoma were studied, and heavily pigmented hybrids appeared very sensitive to

tumor induction in the UVA spectrum. The authors considered that the photoreactivity of melanin may play a role in increasing the risk of UV-induced cancer

(Setlow et al. 1993). The action spectra of radical species generation by melanin in

Xiphophorus assessed by EPR and that of melanoma induction were comparable,

suggesting that ROS produced by pigment photoreactivity contributed to tumor

formation (Wood et al. 2006). Takeushi et al. compared the impact of UVB/UVA

radiation on the skin of black, yellow and albino mice (the hair follicles and the

inter-follicular epidermis). Although the level of pyrimidine dimers was similar in

the three mouse strains, UV-induced apoptosis was higher in the upper portion of

the hair follicles in most pigmented animals, suggesting that melanin acts as a

photocatalyst of ROS production in hair bulbs (Takeuchi et al. 2004). Yamaguchi

et al. compared levels of apoptotic cells in the epidermis of fair-skinned and

dark-skinned human volunteers exposed to erythemal UV doses. Seven-fold more

apoptotic cells were detected in dark skin, although DNA damage induction

(CPD) was lower than in fair skin (Yamaguchi et al. 2006). Recently, Noonan et al.

confirmed the capacity of melanin to increase the risk of melanoma in vivo through

generation of oxidative stress in melanocytes exposed to UVA. Using a HGF

transgenic mouse previously developed as a model for UV induced melanoma

(Noonan et al. 2001), they compared tumorigenesis in black and albino animals.

Melanoma induction by UVA required the presence of melanin (i.e. the frequency

of UVA-induced melanoma was higher in black mice than in albino ones) and UVA

exposure of pigmented animals was followed by significant formation of 8-oxo-dG

in melanocyte DNA (Noonan et al. 2012). Interestingly, in the skin of these

transgenic mice, melanocytes were not confined to hair follicles but were scattered

within the epidermis and dermis, and melanin transfer to keratinocytes was relatively inefficient. Therefore, the UV protection provided by the upper epidermis

was limited, while melanin accumulated within melanocytes, where its presence

probably promoted the generation of a significant oxidative stress on exposure to

UVA. In a way, data obtained by Noonan et al. constituted an in vivo proof of

concept for in vitro experiments conducted on UVA-irradiated cultured melanocytes. Premi et al. recently reported the induction of CPD in melanocytes, in the

dark and several hours after exposure to UVA. This a priori improbable process

relies on a chemiexcitation pathway which begins with the generation of peroxynitrite from UVA-induced ROS and RNS (reactive nitrogen species). Melanin

precursors (or melanin degradation products) associated with peroxynitrite critically


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influence this process by catalyzing the formation of excited-state triplet carbonyl

residues in the vicinity of nuclear DNA. These carbonyl entities can then transfer

the required energy to pyrimidines for the formation of pyrimidine dimers in the

absence of light (Premi et al. 2015). UVA and melanin can thus also contribute to

the induction of UVB-like mutagenic lesions in melanocytes.

In conclusion, accumulating evidence suggests that melanogenesis combined

with exposure to sunlight may constitute a serious risk factor for the development of

skin cancer. Although this phenomenon mainly concerns lightly pigmented skin, it

may not be neglected in photoprotection strategies.



Melanocytes as Targets of (Bio) Chemical Toxicity

AhR Activators

The Aryl hydrocarbon Receptor (AhR) is a cytoplasmic transcription factor which is

activated by various chemical ligands (Fig. 8.4). It controls expression of some

cytochrome P450 enzymes including CYP1A1 and CYP1B1 which are involved in

the metabolism of compounds such as dioxin (TCCD), Polycyclic Aromatic

Hydrocarbons (PAH, e.g. benzopyrene), indocarbinols, flavonoids. As monooxygenases, CYP1A1 and B1 reduce the hydrophobicity of chemicals but can also

generate reactive metabolites (e.g. epoxides) which are either transformed into diols

and glucuronides or are conjugated to glutathione before excretion. UVB radiation

produces a tryptophan photoproduct, FICZ, which is also a very potent AhR activator

at concentrations in the picomolar range (Fritsche et al. 2007). Since AhR is present in

the epidermis, FICZ may constitute a chemical link between sunlight and skin

metabolism. AhR activation produces reactive and potentially mutagenic intermediates, it is thus suspected that this pathway may promote tumorigenesis. AhR is

expressed in all skin cells and may increase the development of carcinoma: the

incidence of benzopyrene-induced skin cancer is lower in AhR-/- knockout mice

(Shimizu et al. 2000). AhR is also expressed in melanocytes and may be responsible

for the hypermelanosis that is generally reported in individuals exposed to dioxin, a

powerful AhR activator. Dioxin or FICZ may stimulate melanin production in vitro

by increasing the activity of melanogenic enzymes (TYR and TRP1) in an

AhR-dependent process involving MITF (Luecke et al. 2010). Moreover,

UVB-induced pigmentation was reduced in AhR-/- mice compared to wild type

animals, confirming a possible involvement of AhR in tanning (Jux et al. 2011).

Pigmentation was also increased in melanocytes treated with cigarette smoke extracts

which contain PAH as potential AhR ligands (Nakamura et al. 2013) and in vivo,

smoking is associated with lip and gingival hyperpigmentation (Haresaku et al. 2007).

A paradoxical stress-induced depigmentation was reported in pityriasis versicolor, a

skin disease caused by Malassezia furfur, a lipophilic yeast which is one of the flora

resident on human skin. M furfur produces indole derivatives such as pityriacitrin,

8 The Cutaneous Melanocyte as a Target of Environmental Stressors


Fig. 8.4 AhR and Nrf2 pathways. Cytoplasmic AhR is maintained inactive in a multiprotein

complex. Interaction with chemical ligands modifies AhR structure and facilitates its nuclear

translocation where it binds the specific sequence XRE (xenobiotic responsive element). As a

transcription factor, AhR controls expression of genes involved in phase I metabolism such as

CYP1A1/B1 (for review see Denison et al. 2011). Nrf2 is repressed by Keap1, which contains

thiol residues as redox sensors. After alteration of Keap1 conformation or after phosphorylation,

Nrf2 translocates into the nucleus and binds the specific sequence ARE (antioxidant responsive

element). Nrf2 controls and coordinates expression of a battery of genes encoding antioxidant and

detoxifying enzymes (for review see Niture et al. 2014). Coordination of both AhR and Nrf2

activations ensures safe metabolism of xenobiotics since toxic metabolites are neutralized and

excreted by Nrf2 pathway. In fact, a biochemical crosstalk between AhR and Nrf2 was recently

described (Kalthoff et al. 2010)

indirubin or malassezin, some of which are potential AhR ligands (for review see

Gaitanis et al. 2013). However, instead of triggering AhR-induced pigmentation,

malassezin displayed a potent melanocytotoxicity in vitro (mainly apoptosis) which

explains the occurrence of white spots in infected skin (Krämer et al. 2005). Zinc

pyrithione (ZnPT) is a microbiocidal agent used as a topical antimicrobial. It targets

Malassezia and thus behaves as an efficient antidandruff compound. Strikingly ZnPT

also displayed toxic effects in melanocytes in vitro: it induced high expression of the

stress marker HSP70, damaged genomic DNA and could finally trigger apoptosis

(Lamore et al. 2010).



L. Marrot

Phenol Compounds as Chemicals

with Melanocyte-Specific Cytotoxicity

Melanocytes are generally resistant to the apoptosis induced by different kinds of

stress; however some phenol compounds can produce a targeted toxicity leading to

leukoderma, a vitiligo-like disease. Leukoderma symptoms include partial to

complete depigmentation of the skin areas in contact with damaging products due to

a significant decrease in the melanocyte population. Phenolic structures involved in

this toxic process can be found in pharmaceutical products, cosmetic ingredients

and food additives, such as for instance rhododenol (4-(4-hydroxyphenyl)2-butanol) and the corresponding raspberry ketone, 4-tertiary-butylphenol, hydroquinone monomethyl-ether. These compounds may penetrate melanosomes and

interfere with the melanogenic process as their structures resemble that of tyrosine.

They are transformed by tyrosinase/TRP1 into quinones which then generate a

strong oxidative stress through redox cycling and ROS production: in fact, the

stimulation of melanogenesis aggravates this cytotoxic process. Moreover, these

quinones bind protein thiol residues, some of which are essential for enzymatic

activities. This cytotoxic process further highlights the possibility of specific risks

associated with the melanogenic pathway (Manga et al. 2006; Ito et al. 2015;

Nagata et al. 2015).


Mediators of Inflammatory Stress Can Lead

to Hyperpigmentation

Post-inflammatory hyperpigmentation (PIH) appears as the hypermelanosis often

associated with acne, contact dermatitis or atopic dermatitis, but also results from

stresses such as phototoxic drug eruption, burns and even mechanical irritation. PIH

is manifested more commonly in dark skin as pigmented macules involving the

epidermis and sometimes the dermis. PIH can be stimulated by inflammatory

mediators such as endothelin-1 or stem cell factor, in addition to ROS or nitric

oxide released by inflammatory cells. Oxidation of arachidonic acid, a well-known

by-product of the inflammatory process, generates the leukotrienes LTC4 and

LTD4, the thromboxane TXB2 and the prostaglandins PGE1, PGE2 and PGF2α.

These factors stimulate melanocytes in vitro: dendricity is increased in treated cells

which transfer more melanin to surrounding keratinocytes. Various messengers

(cAMP, cGMP, diacylglycerol) and effectors (MAPK, PKC, PKA) are mobilized

and this complex network reflects the exquisite connection of melanocyte physiology with general skin status (Lamel et al. 2013; for review Costin and Hearing

2007). Solar lentigo (SL) is sometimes considered an interesting PIH paradigm

exemplifying the connection between pigmentation and skin health (for review see

8 The Cutaneous Melanocyte as a Target of Environmental Stressors


Cardinali et al. 2012). SL appears as pigmented lesions in photodamaged skin,

which increase with chronological aging. The number of melanocytes in SL is

comparable to that in healthy skin, however hyperpigmentation affects the epidermal basal layer. Pigmentary proteins/peptides (tyrosinase, POMC, endothelin-1

(ET-1) and its receptor (ETRB), stem cell factor (SCF)) as well as keratinocyte

growth factor (KGF) are locally upregulated. It is considered by experts that

melanogenesis is stimulated by local damage to skin resulting in the overproduction

of ET-1, SCF or KGF. SCF and KGF may constitute soluble factors secreted by

fibroblasts: sun-damaged dermis may thus contribute directly to hypermelanosis in

SL (Kovacs et al. 2010). Recently, UVA-mediated bystander stress produced in

melanocytes by keratinocytes or fibroblasts was shown to further increase oxidative

effects in pigment cells (Redmond et al. 2014). More generally, the influence of

dermis status on pigmentation is now well established and for instance photoaged

fibroblasts can contribute to local hyperpigmentation (Hedley et al. 2002; Duval

et al. 2014).


Drug-Induced Hyperpigmentation

A recent systematic review of 306 publications stated that it appears likely that

drug-induced hyperpigmentation is caused by only a limited number of compounds

(Krause 2013). The use of prostaglandin agonists in ocular treatment leads to

hyperpigmentation of periorbital skin, consistent with the pro-pigmenting impact of

prostaglandins in inflammation-induced hyperpigmentation. In line with this,

PGF2α analogs, such as for instance Latanoprost, were shown to stimulate skin

pigmentation after topical application in guinea pigs (Anbar et al. 2009). Some

other chemicals which do not produce harmful effects in the dark can be photoactivated by UVA, and their phototoxicity sometimes triggers hyperpigmentation.

Psoralens have been extensively studied in this regard as 8-methoxy-psoralen (8MOP) and in particular 5-methoxy-psoralen (5-MOP) are used in combination with

UVA exposure (PUVA therapy) to repigment vitiligo lesions. This pigmentary

response is probably linked to skin damage through genotoxic activation of p53. In

fact, under UVA exposure, 8MOP or 5MOP induce DNA adduct formation

(mono-adducts and crosslinks) leading to p53 mutation: moreover p53 regulates

tyrosinase gene expression (Gasparro 2000; Khlgatian et al. 2002). There is

insufficient space to cite all the data published on modulation of pigmentation by

various drugs (antibiotics such as fluoroquinolones or minocycline; amiodarone,

phenothiazine), particularly on exposure to sunlight: here again, pigmentation

appears closely linked to skin stress (for review see Dereure 2001).



L. Marrot

Melanocyte-Specific Defensive Capabilities

Despite the limited number of melanocytes in the epidermis and their low mitotic

index, and despite chronic exposures to sunlight and to other environmental

stressors, skin pigmentation generally persists throughout life. A resistance to

apoptosis may be one explanation for this striking longevity, which carries an

associated risk of damage accumulation ultimately leading to senescence or

transformation. Moreover, recent data suggest that pigment cells can improve their

ability to repair DNA damage and to manage oxidative stress.


αMSH/MC1R Improves Anti-genotoxic Protection

MC1R activates the main pathway controlling UV-induced pigmentation.

Fortunately, the MC1R-cAMP response also facilitates repair of DNA photodamage by enhancing nucleotide excision repair in melanocytes. Stimulation of MC1R

contributes to p53 serine-15 phosphorylation mediated by the cAMP/PKA pathway.

The resulting stabilization and activation of p53 improves DNA repair within

melanocytes (Kadekaro et al. 2012). It was recently proposed that MC1R-cAMP

signaling could even act upstream of the repair process by allowing PKA-mediated

phosphorylation of ATR. ATR interacts with the XP repair factor to form a complex at sites of DNA photolesions and this accelerates excision repair of damaged

DNA (Jarrett et al. 2014). In order to maintain the melanocyte population in skin,

α-MSH also inhibits UV-induced cell death by increasing levels of the

anti-apoptotic protein Bcl2. In fact, Bcl2 is a target for the transcription factor MITF

which is activated by the MC1R-cAMP pathway. This mechanism could explain

why melanocytes can survive acute UV doses and persist in photoexposed skin for

decades (Böhm et al. 2005; Kadekaro et al. 2005). Overexposure to sun is generally

associated with increased melanoma genesis but the molecular mechanisms

involved remain unclear. Some oncogenes are frequently mutated in melanoma

caused by chronic irradiation or non-chronic acute UV exposures (C-KIT and

BRAF respectively). The risk of melanoma increased for BRAF mutants in a

context of MC1R variants (Fink and Fisher 2013) or when p53 was also mutated

(Viros et al. 2014). These results further highlight the influence of MC1R and p53

in the prevention of melanocyte transformation.


Adjustment of Endogenous Antioxidants

In the last decade, the transcription factor Nrf2 has aroused increasing interest

because of its central role in controlling cellular redox homeostasis. In normal

conditions, Nrf2 is maintained inactive as a protein complex with its repressor

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