Cutaneous Photobiology. The Melanocyte vs. the Sun: Who Will Win the Final Round?

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    Cutaneous Photobiology. The Melanocyte vs. the Sun: Who Will Win the

    Final Round?

    ANA LUISA KADEKARO1, RENNY J. KAVANAGH1, KAZUMASA WAKAMATSU2, SHOSUKE ITO2,

    MICHELLE A. PIPITONE1 and ZALFA A. ABDEL-MALEK1

    1Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 2Department of Chemistry, Fujita Health

    University School of Health Sciences, Toyoake, Aichi, Japan*Address reprint requests to Zalfa A. Abdel-Malek, Department of Dermatology, University of Cincinnati, 231 Albert Sabin Way, PO Box 670592,Cincinnati, OH 45267-0592, USA. E-mail: abdelmza@email.uc.edu

    Received 13 June 2003; in nal form 3 July 2003

    Solar ultraviolet radiation (UV) is a major environmental

    factor that dramatically alters the homeostasis of the skin as an

    organ by aecting the survival, proliferation and dierentiation

    of various cutaneous cell types. The eects of UV on the skin

    include direct damage to DNA, apoptosis, growth arrest, and

    stimulation of melanogenesis. Long-term eects of UV include

    photoaging and photocarcinogenesis. Epidermal melanocytes

    synthesize two main types of melanin: eumelanin and pheo-

    melanin. Melanin, particularly eumelanin, represents the major

    photoprotective mechanism in the skin. Melanin limits the

    extent of UV penetration through the epidermal layers, and

    scavenges reactive oxygen radicals that may lead to oxidative

    DNA damage. The extent of UV-induced DNA damage and

    the incidence of skin cancer are inversely correlated with total

    melanin content of the skin. Given the importance of the

    melanocyte in guarding against the adverse eects of UV and

    the fact that the melanocyte has a low self-renewal capacity, it

    is critical to maintain its survival and genomic integrity in order

    to prevent malignant transformation to melanoma, the most

    fatal form of skin cancer. Melanocyte transformation to

    melanoma involves the activation of certain oncogenes and the

    inactivation of specic tumor suppressor genes. This review

    summarizes the current state of knowledge about the role of

    melanin and the melanocyte in photoprotection, the responses

    of melanocytes to UV, the signaling pathways that mediate the

    biological eects of UV on melanocytes, and the most common

    genetic alterations that lead to melanoma.

    Key words: Human melanocytes, Ultraviolet radiation, Mel-anin, Photoprotection, DNA damage, Apoptosis, Melanoma

    SOLAR UV SPECTRA AND THE EFFECTSOF UV ON THE SKIN

    The skin is the largest and rst line of defense that protectsthe internal organs from various chemical and physicalenvironmental insults. Solar ultraviolet radiation (UV) is a

    major environmental factor that inuences the function,survival, and proliferation of many cell types. The predom-inant form of solar UV that reaches the earths surface is in

    the form of long wavelength ultraviolet A (UVA) (320400 nm) and only a minority (less than 10%) is in the form ofultraviolet B (UVB) (280320 nm) [Reviewed by Dillman (1)and Gilchrest et al. (2)]. The short wavelength ultraviolet C

    (UVC) (200280 nm) is highly energetic, but very little

    reaches the earths atmosphere. However, with the depletionof the ozone layer, more UVB and UVC can penetrate theearths atmosphere, increasing the risk for UV-induced

    mutagenesis and photocarcinogenesis (3). The UVA andUVB spectra differ in their biological effects and in theirdepth of penetration through the skin layers. The shorter

    wavelength UVB radiation is more energetic and mutagenicthan UVA. UVB rays are absorbed directly by DNA, andcan cause characteristic dipyrimidine sites in various criticalgenes (46). Similar effects have been found experimentally

    with UVC (6). UVB also induces the generation of oxygen

    Abbreviations 4-AHP, 4-amino-3-hydroxyphenylalanine; bFGF, basic broblast growth factor; BTCA, 6-(2-amino-2-carboxyethyl-2-carboxy-4-hydroxybenzothiazole); CREB, cAMP response element binding protein; ET-1, endothelin-1; MC1R, melanocortin 1 receptor; a-MSH, a-melanocortin;POMC, proopiomelanocortin; PTCA, pyrrole 2,3,5-tricarboxylic acid; RB, retinoblastoma protein; TNF-a, tumor necrosis factor-a; UV, ultravioletradiation

    PIGMENT CELL RES 16: 434447. 2003 Copyright Blackwell Munksgaard 2003Printed in UKall rights reserved ISSN 0893-5785

    434 Pigment Cell Res. 16, 2003

  • radicals, yet the impact of this effect on DNA damage hasnot been well explored. UVA, because of its longer wave-length, penetrates deeper through the epidermis, reaching the

    dermis. UVA causes DNA damage primarily by the genera-tion of reactive oxygen species that result in single-strandbreaks in DNA and in DNA-protein crosslinks (79).Oxygen radicals also cause lipid peroxidation that can result

    in membrane and protein damage.Exposure of the skin to UV aects the survival and

    proliferation of epidermal and dermal cells and alters various

    cutaneous functions. In general, the eects of UV exposureon the skin are detrimental, an exception being stimulation ofvitamin D synthesis, a hormone that is crucial for normal

    skeletal growth and development (10). Lack or inadequateexposure of the skin to UV results in rickets because ofvitamin D insufciency. Exposure of the skin to UV is critical

    for the isomerization of 7-dehydrocholesterol to pre-vitaminD, which is then converted to 1,25(OH)2 vitamin D3, theactive form of the hormone that is most efcient in calciumabsorption. 1, 25 (OH)2 vitamin D3 can be formed in the

    skin, as epidermal keratinocytes express the enzymes thatcatalyze the hydroxylation of vitamin D (11). The acuteeffects of UV on the skin are mostly adverse, and include

    DNA damage, apoptosis that is exemplied by the genera-tion of sunburn keratinocytes, erythema, immune suppres-sion that is evidenced by reduction in the number of

    Langerhans cells, and increased pigmentation (1217). Thedrastic long-term effects of UV on the skin include photo-aging, characterized histologically by solar elastosis due todegradation of collagen and the accumulation of abnormal

    elastin in the dermis, and skin cancers, including melanoma,the most deadly form (1823). The effects of UV on the skinare direct, as well as indirect. The direct effects of UV are

    exemplied by the generation of DNA photoproducts. Theindirect effects of UV, such as cell cycle arrest and melan-ogenesis, are mediated by a variety of UV-induced cytokines

    and growth factors that regulate the survival, proliferation,and function of different cell types in the epidermis and thedermis (2428).

    TANNING, A HALLMARK OF UV EXPOSURE

    Epidermal melanocytes play a central role in determining

    the responses of the skin to UV exposure. Melanocytesrepresent 810% of all epidermal cells, yet they serve acritical function in protecting the skin from UV-induced

    photodamage. The skin has developed two main defensemechanisms to guard against the damaging eects of UV:epidermal thickening and hyperkeratosis, and stimulation of

    melanin synthesis by epidermal melanocytes. Between thesetwo mechanisms, increased melanogenesis, a hallmark ofUV exposure evident as tanning, is the more photoprotec-

    tive. Increased skin pigmentation in response to UVexposure is a two-step process: immediate pigment darken-ing, which occurs within minutes of UV exposure, anddelayed tanning response, which becomes apparent

    23 days after sun exposure [reviewed in Pathak et al. (29)and Dillman (1)]. Immediate darkening is induced primarilyby UVA, and is due to photooxidation of preexisting

    melanin. This immediate effect involves reorganization of

    intermediate laments in melanocytes and keratinocytes, aswell as increased dendrite formation, in order to facilitatethe transfer of melanin-containing melanosomes from mel-

    anocytes to keratinocytes. The delayed tanning response isinduced by UVB and UVA, and involves an increase in thenumber of functional melanocytes, stimulation of melano-genesis, increased dendricity of melanocytes, and increased

    synthesis and transfer, as well as altered packaging, ofmelanosomes.The pigmentary response of the skin to UV is determined

    to a large extent by constitutive pigmentation. The classi-cation of skin phototypes IVI has been based on theability of individuals with dierent constitutive pigmenta-

    tion to tan in response to sun exposure (29). Skin phototypeI represents individuals with very fair skin who always burnand do not tan when exposed to the sun. Skin type II

    individuals tan slightly and often burn, and skin types IIIand IV individuals tan readily and rarely burn. Finally, skinphototypes V and VI represent individuals with very darkskin who never burn upon sun exposure. Melanocytes from

    different pigmentary phenotypes differ in their rate ofmelanin synthesis, their capacity to synthesize the brownblack eumelanin and the redyellow pheomelanin, and in

    the rate and manner of melanosome transfer from melano-cytes to keratinocytes. These variables account to a largeextent for the tremendous diversity of human pigmentation.

    Individuals with dark skin have a higher total melanincontent, and a higher amount of eumelanin than individualswith light skin color (3032). Recently, it was reported thatindividuals with ery or carroty hair color, who have alow minimal erythemal dose and a high tendency for actinicdamage, have a characteristic degradation product ofpheomelanin, namely 6-(2-amino-2-carboxyethyl-2-carboxy-

    4-hydroxybenzothiazole) (BTCA) in their hair (33, 34).Based on the association of BTCA with this phenotype, itwas proposed that the presence of BTCA may be a useful

    marker for skin cancer susceptibility. The size, number, andpackaging of melanosomes is another contributing factor tothe diversity of pigmentation, with larger size and more

    melanosomes present in dark skin than in fair skin (35)[reviewed by Pathak et al. (29)]. Ultrastructural studies haverevealed that in dark skin, melanosomes are mostly evidentas single entities, while in lightly pigmented skin, melano-

    somes are present as clusters, in keratinocytes in thesuprabasal layers of the epidermis.Individual variations in total melanin and in eumelanin

    and pheomelanin contents are not only evident in the skin insitu, but are also detectable in melanocytes cultured fromdierent pigmentary phenotypes (Table 1). Studies on cul-

    tured human melanocytes revealed that those derived fromdark skin consistently had higher total melanin and eumel-anin contents, as well as a higher ratio of eumelanin to

    pheomelanin, than those derived from light color skin.Furthermore, the activity of tyrosinase and the protein levelsof tyrosinase, TRP-1 and TRP-2 correlated directly withmelanin content, i.e. melanocytes derived from fair skin with

    a low melanin content consistently have lower tyrosinaseactivity and levels of tyrosinase, TRP-1 and TRP-2 thanmelanocytes derived from dark skin with a high melanin

    content (31, 3638).

    Pigment Cell Res. 16, 2003 435

  • COMPARISON OF THE PHOTOPROTECTIVECAPACITIES OF EUMELANIN ANDPHEOMELANIN

    Melanin, mainly eumelanin, is best known for its photopro-tective role in the skin. Photoprotection is aorded by theability of melanin to serve as a physical barrier that scattersincident UV, and as a lter that reduces the penetration of

    UV through the epidermis (39, 40). These effects are achievedby the localization of melanosomes in the perinuclear area ofepidermal melanocytes and keratinocytes, where they form

    supranuclear caps that protect nuclear DNA from impingingUV rays (41).In dark skin, large, heavily-melanized melanosomes,

    enriched in eumelanin and resistant to degradation bylysosomal enzymes, persist throughout the epidermal layers,and contribute considerably to photoprotection against

    UV-induced damage (35, 42, 43). In contrast, in fair skinthat contains a low eumelanin content, intact melanosomesare rare, or even absent, in the suprabasal layers of theepidermis, which accounts for the increased susceptibility of

    this skin type to the photodamaging effects of UV. Animportant property of melanin, particularly eumelanin, is itsability to scavenge free radicals, and to function as a

    superoxide dismutase that reduces reactive oxygen to hydro-gen peroxide (44, 45). In contrast to eumelanin, pheomelaninis photolabile and potentially phototoxic (4648). Studies on

    puried eumelanin and pheomelanin showed that irradiation

    of pheomelanin results in the generation of hydroxyl radicalsand superoxide anions that might contribute to oxidativeDNA damage. Additionally, pheomelanin increases the

    release of histamine, which contributes to the sun-inducederythema and edema in fair skinned individuals (49).Exposure of the skin to UV reduces the levels of glutathionereductase, which is important for pheomelanin synthesis, and

    is more prevalent in light-colored than in dark skin (5052).This observation implies that the response to UV involvesreduction in pheomelanin production, which is expected to

    limit the phototoxic effects of pheomelanin.The photoprotective role of melanin is supported by

    numerous epidemiological data demonstrating an inverse

    correlation between skin pigmentation and the incidence ofsun-induced skin cancers (18, 19) [reviewed in Gilchrest et al.(2)]. The incidence of all forms of skin cancer, basal and

    squamous cell carcinomas and melanoma, is by far higher inskin types I and II individuals, with fair skin who burn inresponse to UV exposure, than in skin types IIIVI individ-uals that have dark skin with a high eumelanin content and a

    good tanning ability. In the USA, the rates of basal andsquamous cell carcinoma are 50 times higher, and theincidence of melanoma is at least 10-fold higher in Cauca-

    sians than in African Americans (5357). Indeed, theincidence of melanoma worldwide is highest in the Celticpopulation of Australia (58). Further evidence for the

    photoprotective role of melanin comes from the observationthat albinos living in tropical regions are highly prone tophotoaging and non-melanoma skin cancer (59). The signi-cance of melanin in general, and of the relative amounts of

    eumelanin and pheomelanin in human skin, in determiningthe risk for skin cancer is supported by solid epidemiologicaland clinical evidence. However, more rigorous experimental

    evidence is needed to dene accurately the comparativeimpact of eumelanin and pheomelanin on photoprotectionin situ, in the context of the melanocyte and the skin.

    CONSTITUTIVE MELANIN CONTENT AND THERESPONSE OF CULTURED HUMANMELANOCYTES TO UV

    Clinical evidence for the photoprotective role of melanin iscorroborated by experimental data demonstrating that mel-

    anin content is an important determinant of the responses ofmelanocytes to UV. The feasibility of culturing humanmelanocytes from dierent pigmentary phenotypes and the

    demonstration that these cells respond in vitro to UV in amanner similar to their responses in the skin in situ havecontributed signicantly to the understanding of the photo-

    biological eects of UV. The rst study comparing theresponses of human melanocyte cultures derived fromdierent pigmentary phenotypes illustrated that melanocytes

    cultured from dark sk...

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