Skip to main content
SpringerLink
Log in

Human Cutaneous Pigmentation

A Collaborative Act in the Skin, Directed by Paracrine, Autocrine, and Endocrine Factors and the Environment

  • Chapter
From Melanocytes to Melanoma

Abstract

Cutaneous pigmentation is the outcome of exquisite interactions among various cell types in the skin, the best described of which are the interactions between epidermal melanocytes and keratinocytes, and between melanocytes and dermal fibroblasts. Melanocytes are the site of melanin synthesis, and keratinocytes are the recipients of melanosomes, melanin-containing organelles. The wide variation in constitutive pigmentation among humans is caused by enormous differences in the rate of synthesis of the two forms of melanin, eumelanin and pheomelanin, and the rate of transfer of melanosomes to keratinocytes. Cutaneous pigmentation is regulated by a wide array of factors, some of which are endocrine, and many are paracrine and/or autocrine. Many of those factors regulate constitutive pigmentation and also participate in the ultraviolet radiation (UVR)- or inflammation-induced hyperpigmentation. There is convincing evidence that the tanning response to UVR exposure is mediated by a spectrum of locally produced cytokines and growth factors, such as α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH), and endothelin-1 (ET-1). Currently, more is known about the regulation of melanin synthesis than about the control of melanosome transfer. Only in the past few years was significant progress made in defining some of the molecular aspects and genes involved in the latter process. The significance of cutaneous pigmentation lies in its principal role in photoprotection against the carcinogenic effects of UVR. Numerous epidemiological and clinical studies have concluded that the incidence of UVR-induced skin cancer correlates inversely with constitutive pigmentation and the ability to tan. An important role of some of the paracrine/autocrine factors, such as nerve growth factor (NGF), stem cell factor (SCF), ET-1, α-MSH, or ACTH, is to protect melanocytes from stress-induced apoptosis, e.g., that induced by exposure to UVR. This survival effect is of tremendous importance given the significance of the melanocyte in photoprotection and its limited capacity to proliferate and self-renew. It is plausible that at least some of those factors might link the survival pathways to the DNA repair pathways in melanocytes. If this is the case, then the ability of melanocytes to respond to those survival factors might be a determinant of skin cancer, particularly melanoma, susceptibility.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Pathak MA, Jimbow K, Fitzpatrick T. Photobiology of pigment cell. In: Seiji M, ed. Phenotypic Expression in Pigment Cells. University of Tokyo Press, Tokyo, Japan, 1980, pp. 655–670.

    Google Scholar 

  2. Fitzpatrick TB, Szabo G, Seiji M, Quevedo WC. Biology of the melanin pigmentary system. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freeberg IM, Austen KF, eds. Dermatology in General Medicine. McGraw-Hill, New York, NY, 1979, pp. 131–163.

    Google Scholar 

  3. Fuchs E. Epidermal differentiation: the bare essentials. J Cell Biol 1990;111:2807–2814.

    Article  PubMed  CAS  Google Scholar 

  4. Dillman AM. Photobiology of skin pigmentation. In: Levine N, ed. Pigmentation and Pigmentary Disorders. CRC, Boca Raton, FL, 1993, pp. 61–94.

    Google Scholar 

  5. Gilchrest BA, Zhai S, Eller MS, Yarosh DB, Yaar M. Treatment of human melanocytes and S91 melanoma cells with the DNA repair enzyme T4 endonuclease V enhances melanogenesis after ultraviolet irradiation. J Invest Dermatol 1993;101:666–672.

    Article  PubMed  CAS  Google Scholar 

  6. Kadekaro AL, Kavanagh RJ, Wakamatsu K, Ito S, Pipitone MA, Abdel-Malek ZA. Cutaneous photobiology. The melanocyte vs. the sun: who will win the final round? Pigment Cell Res 2003;16:434–47.

    Article  PubMed  CAS  Google Scholar 

  7. Hunt G, Kyne S, Ito S, Wakamatsu K, Todd C, Thody AJ. Eumelanin and pheomelanin contents of human epidermis and cultured melanocytes. Pigment Cell Res 1995;8:202–208.

    Article  PubMed  CAS  Google Scholar 

  8. Szabo G. Racial differences in the fate of melanosomes in human epidermis. Nature 1969;222:1081.

    Article  PubMed  CAS  Google Scholar 

  9. Halaban R, Pomerantz SH, Marshall S, Lambert DT, Lerner AB. Regulation of tyrosinase in human melanocytes grown in culture. J Cell Biol 1983;97:480–488.

    Article  PubMed  CAS  Google Scholar 

  10. Abdel-Malek Z, Swope V, Collins C, Boissy R, Zhao H, Nordlund J. Contribution of melanogenic proteins to the heterogeneous pigmentation of human melanocytes. J Cell Sci 1993;106:1323–1331.

    PubMed  CAS  Google Scholar 

  11. Abdel-Malek ZA, Swope VB, Nordlund JJ, Medrano EE. Proliferation and propagation of human melanocytes in vitro are affected by donor age and anatomical site. Pigment Cell Res 1994;7:116–122.

    Article  PubMed  CAS  Google Scholar 

  12. Iwata M, Corn T, Iwata S, Everett MA, Fuller BB. The relationship between tyrosinase activity and skin color in human foreskins. J Invest Dermatol 1990;95:9–15.

    Article  PubMed  CAS  Google Scholar 

  13. Halaban R, Langdon R, Birchall N, et al. Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. J Cell Biol 1988;107:1611–1619.

    Article  PubMed  CAS  Google Scholar 

  14. Kock A, Schwarz T, Kirnbauer R, et al. Human keratinocytes are a source for tumor necrosis factor α: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 1990;172:1609–1614.

    Article  PubMed  CAS  Google Scholar 

  15. Imokawa G, Yada Y, Miyagishi M. Endothelins secreted from human keratinocytes are intrinsic mitogens for human melanocytes. J Biol Chem 1992;267:24,675–24,680.

    PubMed  CAS  Google Scholar 

  16. Chakraborty AK, Funasaka Y, Slominski A, et al. Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B. Biochim Biophys Acta 1996;1313:130–138.

    Article  PubMed  Google Scholar 

  17. Wakamatsu K, Graham A, Cook D, Thody AJ. Characterization of ACTH peptides in human skin and their activation of the melanocortin-1 receptor. Pigment Cell Res 1997;10:288–297.

    Article  PubMed  CAS  Google Scholar 

  18. Abdel-Malek Z, Swope VB, Suzuki I, et al. Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci U S A 1995;92:1789–1793.

    Article  PubMed  CAS  Google Scholar 

  19. Pathak MA, Hori Y, Szabo G, Fitzpatrick TB. The photobiology of melanin pigmentation in human skin. In: Kawamura T, Fitzpatrick TB, Seiji M, eds. Biology of Normal and Abnormal Melanocytes. University Park Press, Baltimore, MD, 1971, pp. 149–169.

    Google Scholar 

  20. Kobayashi N, Nakagawa A, Muramatsu T, et al. Supranuclear melanin caps reduce ultraviolet induced DNA photoproducts in human epidermis. J Invest Dermatol 1998;110:806–810.

    Article  PubMed  CAS  Google Scholar 

  21. Nordlund JJ, Abdel-Malek ZA. Mechanisms for post-inflammatory hyperpigmentation and hypopigmentation. In: Bagnara J, ed. Advances in Pigment Cell Research Proceedings of the XIII International Pigment Cell Society. Alan R. Liss, New York, NY, 1988, pp. 219–236.

    Google Scholar 

  22. Gilchrest BA, Eller MS. DNA photodamage stimulates melanogenesis and other photoprotective responses. J Investig Dermatol Symp Proc 1999;4:35–40.

    Article  PubMed  CAS  Google Scholar 

  23. Menon IA, Persad S, Ranadive NS, Haberman HF. Photobiological effects of eumelanin and pheomelanin. In: Bagnara JT, Klaus SN, Paul E, Schartl M, eds. Biological, Molecular and Clinical Aspects of Pigmentation. University of Tokyo Press, Tokyo, Japan, 1985, pp. 77–86.

    Google Scholar 

  24. Bustamante J, Bredeston L, Malanga G, Mordoh J. Role of melanin as a scavenger of active oxygen species. Pigment Cell Res 1993;6:348–353.

    Article  PubMed  CAS  Google Scholar 

  25. Pathak MA, Fitzpatrick TB. The role of natural photoprotective agents in human skin. In: Fitzpatrick TB, Pathak MA, Haber LC, Seiji M, Kukita A, eds. Sunlight and Man. University of Tokyo Press, Tokyo, Japan, 1974, pp. 725–750.

    Google Scholar 

  26. Kaidbey KH, Poh Agin P, Sayre RM, Kligman AM. Photoprotection by melanin—a comparison of black and Caucasian skin. J Am Acad Dermatol 1979;1:249–260.

    PubMed  CAS  Google Scholar 

  27. Sober AJ, Lew RA, Koh HK, Barnhill RL. Epidemiology of cutaneous melanoma. An update. Dermatol Clin 1991;9:617–629.

    PubMed  CAS  Google Scholar 

  28. Pathak MA. Ultraviolet radiation and the development of non-melanoma and melanoma skin cancer: clinical and experimental evidence. Skin Pharmacol 1991;4(suppl 1):85–94.

    PubMed  Google Scholar 

  29. Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 1999;340:1341–1348.

    Article  PubMed  CAS  Google Scholar 

  30. Levine N, Hori Y, Kubota Y. Acquired hypermelanotic disorders. In: Levine N, ed. Pigmentation and Pigmentary Disorders. CRC, Bota Raton, FL, 1993, pp. 211–238.

    Google Scholar 

  31. Dunlop D. Eighty-six cases of Addison’s disease. Br Med J 1963;5362:887–891.

    Article  Google Scholar 

  32. Nerup J. Addison’s disease—clinical studies. A report of 108 cases. Acta Endocrinol (Copenh) 1974;76:127–41.

    CAS  Google Scholar 

  33. Smith AG, Shuster S, Thody AJ, Peberky M. Chloasma, oral contraceptives, and plasma immunoreactive β-melanocyte-stimulating hormone. J Invest Dermatol 1977;68:169–170.

    Article  PubMed  CAS  Google Scholar 

  34. Stulberg DL, Clark N, Tovey D. Common hyperpigmentation disorders in adults: Part II. Melanoma, seborrheic keratoses, acanthosis nigricans, melasma, diabetic dermopathy, tinea versicolor, and postinflammatory hyperpigmentation. Am Fam Physician 2003;68:1963–1968.

    PubMed  Google Scholar 

  35. Snell RS. The pigmentary changes occurring in the breast skin during pregnancy and following estrogen treatment. J Invest Dermatol 1964;43:181–186.

    Article  PubMed  CAS  Google Scholar 

  36. Wilson MJ, Spaziani E. The melanogenic response to testosterone in scrotal epidermis; the effects on tyrosinase activity and protein synthesis. Acta Endocrin 1976;81:435–448.

    CAS  Google Scholar 

  37. Friedmann PS, Wren F, Buffey J, MacNeil S. α-MSH causes a small rise in cAMP but has no effect on basal or ultraviolet-stimulated melanogenesis in human melanocytes. Br J Dermatol 1990;123:145–151.

    Article  PubMed  CAS  Google Scholar 

  38. Halaban R, Tyrrell L, Longley J, Yarden Y, Rubin J. Pigmentation and proliferation of human melanocytes and the effects of melanocyte-stimulating hormone and ultraviolet B light. Ann N Y Acad Sci 1993;680:290–301.

    Article  PubMed  CAS  Google Scholar 

  39. Fuller BB, Rungta D, Iozumi K, et al. Hormonal regulation of melanogenesis in mouse melanoma and in human melanocytes. Ann N Y Acad Sci 1993;680:302–319.

    Article  PubMed  CAS  Google Scholar 

  40. Tomita Y, Maeda K, Tagami H. Mechanisms for hyperpigmentation in postinflammatory pigmentation, urticaria pigmentosa and sunburn. Dermatologica 1989;179(suppl 1):49–53.

    Article  PubMed  Google Scholar 

  41. Thestrup-Pedersen K, Larsen CS, Kristensen M, Zachariae C. Interleukin-1 release from peripheral blood monocytes and soluble interleukin-2 and cd8 receptors in serum from patients with atopic dermatitis. Acta Derm Venereol 1990;70:395–399.

    PubMed  CAS  Google Scholar 

  42. Ferreri NR, Millet I, Paliwal V, et al. Induction of macrophage TNF alpha, IL-1, IL-6, and PGE2 production by DTH-initiating factors. Cell Immunol 1991;137:389–405.

    Article  PubMed  CAS  Google Scholar 

  43. Ford-Hutchinson AW, Rackman A. Leukotrienes as mediators of skin inflammation. Br J Dermatol 1983;109(suppl 25):26–29.

    PubMed  CAS  Google Scholar 

  44. Fogh K, Herlin T, Kragballe K. Eicosanoids in skin of patients with atopic dermatitis: prostaglandin E2 and leukotriene B4 are present in biologically active concentrations. J Allergy Clin Immunol 1989;83:450–455.

    Article  PubMed  CAS  Google Scholar 

  45. Tomita Y, Maeda K, Tagami H. Histamine stimulates normal human melanocytes in vitro: one of the possible inducers of hyperpigmentation in urticaria pigmentosa. J Dermatol Sci 1993;6:146–154.

    Article  PubMed  CAS  Google Scholar 

  46. Yoshida M, Takahashi Y, Inoue S. Histamine induces melanogenesis and morphologic changes by protein kinase A activation via H2 receptors in human normal melanocytes. J Invest Dermatol 2000;114:334–342.

    Article  PubMed  CAS  Google Scholar 

  47. Gordon PR, Mansur CP, Gilchrest BA. Regulation of human melanocyte growth, dendricity, and melanization by keratinocyte derived factors. J Invest Dermatol 1989;92:565–572.

    Article  PubMed  CAS  Google Scholar 

  48. Toyoda M, Luo Y, Makino T, Matsui C, Morohashi M. Calcitonin gene-related peptide upregulates melanogenesis and enhances melanocyte dendricity via induction of keratinocyte-derived melanotrophic factors. J Investig Dermatol Symp Proc 1999;4:116–125.

    Article  PubMed  CAS  Google Scholar 

  49. Imokawa G, Yada Y, Morisaki N, Kimura M. Biological characterization of human fibroblastderived mitogenic factors for human melanocytes. Biochem J 1998;330:1235–1239.

    PubMed  CAS  Google Scholar 

  50. Matsui Y, Zsebo KM, Hogan BL. Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit. Nature 1990;347:667–669.

    Article  PubMed  CAS  Google Scholar 

  51. Longley BJ Jr, Morganroth GS, Tyrrell L, et al. Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med 1993;328:1302–1307.

    Article  PubMed  Google Scholar 

  52. Matsumoto K, Tajima H, Nakamura T. Hepatocyte growth factor is a potent stimulator of human melanocyte DNA synthesis and growth. Biochem Biophys Res Commun 1991;176:45–51.

    Article  PubMed  CAS  Google Scholar 

  53. Yaar M, Grossman K, Eller M, Gilchrest BA. Evidence for nerve growth factor-mediated paracrine effects in human epidermis. J Cell Biol 1991;115:821–828.

    Article  PubMed  CAS  Google Scholar 

  54. Di-Marco E, Marchisio PC, Bondanza S, Franzi AT, Cancedda R, De Luca M. Growth regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes. J Biol Chem 1991;266:21,718–21,722.

    PubMed  CAS  Google Scholar 

  55. Tron VA, Coughlin MD, Jang DE, Stanisz J, Sauder DN. Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). J Clin Invest 1990;85:1085–1089.

    PubMed  CAS  Google Scholar 

  56. Zhai S, Yaar M, Gilchrest BA. Nerve growth factor rescues pigment cells from ultraviolet induced apoptosis by upregulating BCL-2 levels. Exp Cell Res 1996;224:335–343.

    Article  PubMed  CAS  Google Scholar 

  57. Yaar M, Eller MS, DiBenedetto P, et al. The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes. J Clin Invest 1994;94:1550–1562.

    PubMed  CAS  Google Scholar 

  58. Yamaguchi Y, Itami S, Watabe H, et al. Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation. J Cell Biol 2004;165:275–285.

    Article  PubMed  CAS  Google Scholar 

  59. Swope VB, Abdel-Malek ZA, Kassem L, Nordlund JJ. Interleukins 1α and 6 and tumor necrosis factor-α are paracrine inhibitors of human melanocyte proliferation and melanogenesis. J Invest Dermatol 1991;96:180–185.

    Article  PubMed  CAS  Google Scholar 

  60. Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor β in human disease. N Engl J Med 2000;342:1350–1358.

    Article  PubMed  CAS  Google Scholar 

  61. Krasagakis K, Garbe C, Schrier PI, Orfanos CE. Paracrine and autocrine regulation of human melanocyte and melanoma cell growth by transforming growth factor beta in vitro. Anticancer Res 1994;14:2565–2571.

    PubMed  CAS  Google Scholar 

  62. Swope VB, Sauder DN, McKenzie RC, et al. Synthesis of interleukin-1α and β by normal human melanocytes. J Invest Dermatol 1994;102:749–753.

    Article  PubMed  CAS  Google Scholar 

  63. Swope VB, Medrano EE, Smalara D, Abdel-Malek Z. Long-term proliferation of human melanocytes is supported by the physiologic mitogens α-melanotropin, endothelin-1, and basic fibroblast growth factor. Exp Cell Res 1995;217:453–459.

    Article  PubMed  CAS  Google Scholar 

  64. Suzuki I, Cone R, Im S, Nordlund J, Abdel-Malek Z. Binding capacity and activation of the MC1 receptors by melanotropic hormones correlate directly with their mitogenic and melanogenic effects on human melanocytes. Endocrinology 1996;137:1627–1633.

    Article  PubMed  CAS  Google Scholar 

  65. Tada A, Suzuki I, Im S, et al. Endothelin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and participates in their responses to ultraviolet radiation. Cell Growth Differ 1998;9:575–584.

    PubMed  CAS  Google Scholar 

  66. Bach MK. Mediators of anaphylaxis and inflammation. Ann Rev in Microbiol 1982;36:371–413.

    Article  CAS  Google Scholar 

  67. Bregman MD, Peters E, Sander D, Meyskens FL Jr. Dexamethasone, prostaglandin A, and retinoic acid modulation of murine and human melanoma cells grown in soft agar. J Natl Cancer Inst 1983;71:927–932.

    PubMed  CAS  Google Scholar 

  68. Bregman MD, Funk C, Fukushima M. Inhibition of human melanoma growth by prostaglandin A, D and J analogues. Cancer Res 1986;46:2740–2744.

    PubMed  CAS  Google Scholar 

  69. Abdel-Malek Z, Swope VB, Amornsiripanitch N, Nordlund JJ. In vitro modulation of proliferation and melanization of S91 melanoma cells by prostaglandins. Cancer Res 1987;47:3141–3146.

    PubMed  CAS  Google Scholar 

  70. Morelli JG, Yohn JJ, Lyons MB, Murphy RC, Norris DA. Leukotrienes C4 and D4 as potent mitogens for cultured human melanocytes. J Invest Dermatol 1989;93:719–722.

    Article  PubMed  CAS  Google Scholar 

  71. Tomita Y, Maeda K, Tagami H. Melanocyte-stimulating properties of arachidonic acid metabolites: possible role in postinflammatory pigmentation. Pigment Cell Res 1992;5:357–361.

    Article  PubMed  CAS  Google Scholar 

  72. Krey G, Braissant O, L’Horset F, et al. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 1997;11:779–791.

    Article  PubMed  CAS  Google Scholar 

  73. Scott G, Leopardi S, Printup S, Malhi N, Seiberg M, Lapoint R. Proteinase-activated receptor-2 stimulates prostaglandin production in keratinocytes: analysis of prostaglandin receptors on human melanocytes and effects of PGE2 and PGF2a on melanocyte dendricity. J Invest Dermatol 2004;122:1214–1224.

    Article  PubMed  CAS  Google Scholar 

  74. Leikauf GD, Abdel-Malek ZA, Swope VB, Doupnik CA, Nordlund JJ. Constitutive biosynthesis of 12-hydroxy-5,8,10,14-eicosatetraenoic acid and 6-keto prostaglandin F1a by human melanocytes and Cloudman S91 melanoma cells. In: Hammerstrom S, Marnett LW, eds. Prostaglandins, Leukotrienes and Cancer. Boston, MA: Kluwer Academic Press; 1994.

    Google Scholar 

  75. Pittelkow MR, Shipley GD. Serum-free culture of normal human melanocytes: growth kinetics and growth factor requirements. J Cell Physiol 1989;140:565–576.

    Article  PubMed  CAS  Google Scholar 

  76. Gospodarowicz D, Cohen DC, Fujii DK. Regulation of cell growth by the basal lamina and plasma factors: relevance to embryonic control of cell proliferation. In: Sato G, Pardee A, Sirbasku D, eds. Cold Spring Harbor Conferences on Cell Proliferation 9: Growth of Cells in Hormonally Deficient Media. Vol. 9. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1982, pp. 95–124.

    Google Scholar 

  77. Cooper CS, Park M, Blair DG, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 1984;311:29–33.

    Article  PubMed  CAS  Google Scholar 

  78. Park M, Dean M, Cooper CS, et al. Mechanism of met oncogene activation. Cell 1986;45:895–904.

    Article  PubMed  CAS  Google Scholar 

  79. Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 1995;376:768–771.

    Article  PubMed  CAS  Google Scholar 

  80. Halaban R, Rubin JS, Funasaka Y, et al. Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells. Oncogene 1992;7:2195–2206.

    PubMed  CAS  Google Scholar 

  81. Zsebo KM, Williams DA, Geissler EN, et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit receptor. Cell 1990;63:213–214.

    Article  PubMed  CAS  Google Scholar 

  82. Grabbe J, Welker P, Dippel E, Czarnetzki BM. Stem cell factor, a novel cutaneous growth factor for mast cells and melanocytes [Review]. Arch Dermatol Res 1994;287:78–84.

    Article  PubMed  CAS  Google Scholar 

  83. Manova K, Bacharova RF. Expression of c-kit encoded at the W locus of mice in developing embryonic germ cells and presumptive melanoblasts. Dev Biol 1991;146:312–324.

    Article  PubMed  CAS  Google Scholar 

  84. Keshet E, Lyman SD, Williams DE, et al. Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development. EMBO J 1991;10:2425–2435.

    PubMed  CAS  Google Scholar 

  85. Besmer P, Manova K, Duttlinger R, et al. The {Ikit} ligand (steel factor) and its receptor {Ic-kit/W}: pleiotropic roles in gametogenesis and melanogenesis. Development 1993;(suppl):125–137.

    Google Scholar 

  86. Giebel LB, Spritz RA. Mutation of the KIT (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. Proc Natl Acad Sci U S A 1991;88:8696–8699.

    Article  PubMed  CAS  Google Scholar 

  87. Funasaka Y, Boulton T, Cobb M, et al. c-Kit-Kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogenactivated protein kinase but is down-regulated in melanomas. Mol Biol Cell 1992;3:197–209.

    PubMed  CAS  Google Scholar 

  88. Grichnik JM, Burch JA, Burchette J, Shea CR. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol 1998;111:233–238.

    Article  PubMed  CAS  Google Scholar 

  89. Scott G, Ewing J, Ryan D, Abboud C. Stem cell factor regulates human melanocyte-matrix interaction. Pigment Cell Res 1994;7:44–51.

    Article  PubMed  CAS  Google Scholar 

  90. Scott G, Liang H, Luthra D. Stem cell factor regulates the melanocyte cytoskeleton. Pigment Cell Res 1996;9:134–141.

    Article  PubMed  CAS  Google Scholar 

  91. Pincelli C, Yaar M. Nerve growth factor: its significance in cutaneous biology. J Investig Dermatol Symp Proc 1997;2:31–36.

    PubMed  CAS  Google Scholar 

  92. Yohn JJ, Morelli JG, Walchak SJ, Rundell KB, Norris DA, Zamora MR. Cultured human keratinocytes synthesize and secrete endothelin-1. J Invest Dermatol 1993;100:23–26.

    Article  PubMed  CAS  Google Scholar 

  93. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 1994;46:325–415.

    PubMed  CAS  Google Scholar 

  94. Baynash AG, Hosoda K, Giaid A, et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 1994;79:1277–1285.

    Article  PubMed  CAS  Google Scholar 

  95. Imokawa G, Yada Y, Kimura M. Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes. Biochem J 1996;314:305–312.

    PubMed  CAS  Google Scholar 

  96. McCallion AS, Chakravarti A. EDNRB/EDN3 and Hirschsprung disease type II. Pigment Cell Res 2001;14:161–169.

    Article  PubMed  CAS  Google Scholar 

  97. Tada A, Pereira E, Beitner Johnson D, Kavanagh R, Abdel-Malek ZA. Mitogen and ultraviolet-B-induced signaling pathways in normal human melanocytes. J Invest Dermatol 2002;118:316–322.

    Article  PubMed  CAS  Google Scholar 

  98. Lee HO, Levorse JM, Shin MK. The endothelin receptor-B is required for the migration of neural crest-derived melanocyte and enteric neuron precursors. Dev Biol 2003;259:162–175.

    Article  PubMed  CAS  Google Scholar 

  99. Inoue A, Yanagisawa M, Kimura S, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 1989;86:2863–2867.

    Article  PubMed  CAS  Google Scholar 

  100. Puffenberger EG, Hosoda K, Washington SS, et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 1994;79:1257–1266.

    Article  PubMed  CAS  Google Scholar 

  101. Murase K, Murakami Y, Takayanagi K, Furukawa Y, Hayashi K. Human fibroblast cells synthesize and secrete nerve growth factor in culture. Biochem Biophys Res Commun 1992;184:373–379.

    Article  PubMed  CAS  Google Scholar 

  102. Stefanato CM, Yaar M, Bhawan J, et al. Modulations of nerve growth factor and Bcl-2 in ultravioletirradiated human epidermis. J Cutan Pathol 2003;30:351–357.

    Article  PubMed  Google Scholar 

  103. Burbach GJ, Kim KH, Zivony AS, et al. The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor. J Invest Dermatol 2001;117:1075–1082.

    Article  PubMed  CAS  Google Scholar 

  104. Kauser S, Schallreuter KU, Thody AJ, Gummer C, Tobin DJ. Regulation of human epidermal melanocyte biology by beta-endorphin. J Invest Dermatol 2003;120:1073–1080.

    Article  PubMed  CAS  Google Scholar 

  105. Suzuki I, Kato T, Motokawa T, Tomita Y, Nakamura E, Katagiri T. Increase of pro-opiomelanocortin mRNA prior to tyrosinase, tyrosinase-related protein 1, dopachrome tautomerase, Pmel-17/gp100, and P-protein mRNA in human skin after ultraviolet B irradiation. J Invest Dermatol 2002;118:73–78.

    Article  PubMed  CAS  Google Scholar 

  106. Slominski A, Ermak G, Mazurkiewicz JE, Baker J, Wortsman J. Characterization of corticotropinreleasing hormone (CRH) in human skin. J Clin Endocrinol Metab 1998;83:1020–1024.

    Article  PubMed  CAS  Google Scholar 

  107. Eberle AN. Proopiomelanocortin and the melanocortin peptides. In: Cone RD, ed. The Melanocortin Receptors. Humana, Totowa, NJ, 2000, pp. 3–67.

    Chapter  Google Scholar 

  108. Seidah NG, Day R, Marcinkiewicz M, Chretien M. Mammalian paired basic amino acid convertases of prohormones and proproteins. Ann N Y Acad Sci 1993;680:135–146.

    Article  PubMed  CAS  Google Scholar 

  109. Abdel-Malek ZA. Melanocortin receptors: their functions and regulation by physiological agonists and antagonists. Cell Mol Life Sci 2001;58:434–441.

    Article  PubMed  CAS  Google Scholar 

  110. Sawyer TK, Hruby VJ, Hadley ME, Engel MH. α-Melanocyte stimulating hormone: chemical nature and mechanism of action. Am Zool 1983;23:529–540.

    CAS  Google Scholar 

  111. Castrucci AM, Hadley ME, Hruby VJ. Melanotropin bioassays: in vitro and in vivo comparisons. Gen Comp Endocrinol 1984;55:104–111.

    Article  PubMed  CAS  Google Scholar 

  112. Castrucci AML, Hadley ME, Sawyer TK, et al. α-Melanotropin: the minimal active sequence in the lizard skin bioassay. Gen Comp Endocrinol 1989;73:157–163.

    Article  PubMed  CAS  Google Scholar 

  113. Visconti MA, Ramanzini GC, Camargo CR, Castrucci AM. Elasmobranch color change: a short review and novel data on hormone regulation. J Exp Zool 1999;284:485–491.

    Article  PubMed  CAS  Google Scholar 

  114. Geschwind II, Huseby RA, Nishioka R. The effect of melanocyte-stimulating hormone on coat color in the mouse. Rec Prog Hormone Res 1972;28:91–130.

    CAS  Google Scholar 

  115. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science 1992;257:1248–1251.

    Article  PubMed  CAS  Google Scholar 

  116. Chhajlani V, Wikberg JES. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett 1992;309:417–420.

    Article  PubMed  CAS  Google Scholar 

  117. Hunt G, Kyne S, Wakamatsu K, Ito S, Thody AJ. Nle4DPhe7 α-melanocyte-stimulating hormone increases the eumelanin:phaeomelanin ratio in cultured human melanocytes. J Invest Dermatol 1995;104:83–85.

    Article  PubMed  CAS  Google Scholar 

  118. Hunt G, Donatien PD, Lunec J, Todd C, Kyne S, Thody AJ. Cultured human melanocytes respond to MSH peptides and ACTH. Pigment Cell Res 1994;7:217–221.

    Article  PubMed  CAS  Google Scholar 

  119. Scott MC, Suzuki I, Abdel-Malek ZA. Regulation of the human melanocortin 1 receptor expression in epidermal melanocytes by paracrine and endocrine factors, and by UV radiation. Pigment Cell Res 2002;15:433–439.

    Article  PubMed  CAS  Google Scholar 

  120. Tamate HB, Takeuchi T. Action of the e locus of mice in the response of phaeomelanic hair follicles to α-melanocyte-stimulating hormone in vitro. Science 1984;224:1241–1242.

    Article  PubMed  CAS  Google Scholar 

  121. Robbins LS, Nadeau JH, Johnson KR, et al. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 1993;72:827–834.

    Article  PubMed  CAS  Google Scholar 

  122. Abdel-Malek ZA, Scott MC, Furumura M, et al. The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling protein on mammalian melanocytes. J Cell Sci 2001;114:1019–1024.

    PubMed  CAS  Google Scholar 

  123. Siracusa LD. The agouti gene: turned on to yellow. Trends Genet 1994;10:423–428.

    Article  PubMed  CAS  Google Scholar 

  124. Kwon HY, Bultman SJ, Loffler C, et al. Molecular structure and chromosomal mapping of the human homolog of the agouti gene. Proc Natl Acad Sci U S A 1994;91:9760–9764.

    Article  PubMed  CAS  Google Scholar 

  125. Wilson BD, Ollmann MM, Kang L, Stoffel M, Bell GI, Barsh GS. Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet 1995;4:223–230.

    Article  PubMed  CAS  Google Scholar 

  126. Suzuki I, Tada A, Ollmann MM, et al. Agouti signaling protein inhibits melanogenesis and the response of human melanocytes to α-melanotropin. J Invest Dermatol 1997;108:838–842.

    Article  PubMed  CAS  Google Scholar 

  127. Voisey J, Box NF, van Daal A. A polymorphism study of the human Agouti gene and its association with MC1R. Pigment Cell Res 2001;14:264–267.

    Article  PubMed  CAS  Google Scholar 

  128. Kanetsky PA, Swoyer J, Panossian S, Holmes R, Guerry D, Rebbeck TR. A polymorphism in the agouti signaling protein gene is associated with human pigmentation. Am J Hum Genet 2002;70:770–775.

    Article  PubMed  CAS  Google Scholar 

  129. Harding RM, Healy E, Ray AJ, et al. Evidence for variable selective pressures at MC1R. Am J Hum Genet 2000;66:1351–1361.

    Article  PubMed  CAS  Google Scholar 

  130. Box NF, Wyeth JR, O’Gorman LE, Martin NG, Sturm RA. Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet 1997;6:1891–1897.

    Article  PubMed  CAS  Google Scholar 

  131. Smith R, Healy E, Siddiqui S, et al. Melanocortin 1 receptor variants in Irish population. J Invest Dermatol 1998;111:119–122.

    Article  PubMed  CAS  Google Scholar 

  132. Palmer JS, Duffy DL, Box NF, et al. Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 2000;66:176–186.

    Article  PubMed  CAS  Google Scholar 

  133. Bastiaens MT, ter Huurne JAC, Kielich C, et al. Melanocortin-1 receptor gene variants determine the risk of non-melanoma skin cancer independent of fair skin type and red hair. Am J Hum Genet 2001;68:884–894.

    Article  PubMed  CAS  Google Scholar 

  134. Scott MC, Wakamatsu K, Ito S, et al. Human melanocortin 1 receptor variants, receptor function and melanocyte response to ultraviolet radiation. J Cell Sci 2002;115:2349–2355.

    PubMed  CAS  Google Scholar 

  135. Duffy DL, Box NF, Chen W, et al. Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Hum Mol Genet 2004;13:447–461.

    Article  PubMed  CAS  Google Scholar 

  136. Kauser S, Thody AJ, Schallreuter KU, Gummer CL, Tobin DJ. beta-Endorphin as a regulator of human hair follicle melanocyte biology. J Invest Dermatol 2004;123:184–195.

    Article  PubMed  CAS  Google Scholar 

  137. Babiarz-Magee L, Chen N, Seiberg M, Lin CB. The expression and activation of protease-activated receptor-2 correlate with skin color. Pigment Cell Res 2004;17:241–251.

    Article  PubMed  CAS  Google Scholar 

  138. Epstein JH. Photocarcinogenesis, skin cancer and aging. J Am Acad Dermatol 1983;9:487–502.

    PubMed  CAS  Google Scholar 

  139. Rees JL. Genetics of hair and skin color. Annu Rev Genet 2003;37:67–90.

    Article  PubMed  CAS  Google Scholar 

  140. Tadokoro T, Kobayashi N, Zmudzka BZ, et al. UV-induced DNA damage and melanin content in human skin differing in racial/ethnic origin. FASEB J 2003 [online]. April 8, 2003;express article 10.1096/fj.02-0865fje.

    Google Scholar 

  141. Barker D, Dixon K, Medrano EE, et al. Comparison of the responses of human melanocytes with different melanin contents to ultraviolet B irradiation. Cancer Res 1995;55:4041–4046.

    PubMed  CAS  Google Scholar 

  142. Brash DE, Rudolph JA, Simon JA, et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A 1991;88:10,124–10,128.

    Article  PubMed  CAS  Google Scholar 

  143. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin cancer. Nature 1994;372:773–776.

    Article  PubMed  CAS  Google Scholar 

  144. Pollock PM, Yu F, Qiu L, Parsons PG, Hayward NK. Evidence for u.v. induction of CDKN2 mutations in melanoma cell lines. Oncogene 1995;11:663–668.

    PubMed  CAS  Google Scholar 

  145. Flores JF, Walker GJ, Glendening JM, et al. Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma. Cancer Res 1996;56:5023–5032.

    PubMed  CAS  Google Scholar 

  146. Chedekel MR, Smith SK, Post PW, Pokora A, Vessell DL. Photodestruction of pheomelanin: role of oxygen. Proc Natl Acad Sci U S A 1978;75:5395–5399.

    Article  PubMed  CAS  Google Scholar 

  147. Smit NPM, Vink AA, Kolb RM, et al. Melanin offers protection against induction of cyclobutane pyrimidine dimers and 6-4 photoproducts by UVB in cultured human melanocytes. Photochem Photobiol 2001;74:424–430.

    Article  PubMed  CAS  Google Scholar 

  148. Hachiya A, Kobayashi A, Ohuchi A, Takema Y, Imokawa G. The paracrine role of stem cell factor/c-kit signaling in the activation of human melanocytes in ultraviolet-B-induced pigmentation. J Invest Dermatol 2001;116:578–586.

    Article  PubMed  CAS  Google Scholar 

  149. Imokawa G. Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. Pigment Cell Res 2004;17:96–110.

    Article  PubMed  CAS  Google Scholar 

  150. Black AK, Greaves MW, Hensby CN, Plummer NA. Increased prostaglandins E2 and F2a in human skin at 6 and 24 h after ultraviolet B irradiation (290–320 nm). Br J Clin Pharmacol 1978;5:431–436.

    PubMed  CAS  Google Scholar 

  151. Kupper TS, Chua AO, Flood P, McGuire J, Gubler U. Interleukin 1 gene expression in cultured human keratinocytes is augmented by ultraviolet irradiation. J Clin Invest 1987;80:430–436.

    Article  PubMed  CAS  Google Scholar 

  152. Imokawa G, Miyagishi M, Yada Y. Endothelin-1 as a new melanogen: coordinated expression of its gene and the tyrosinase gene in UVB-exposed human epidermis. J Invest Dermatol 1995;105:32–37.

    Article  PubMed  CAS  Google Scholar 

  153. Im S, Moro O, Peng F, et al. Activation of the cAMP pathway by α-melanotropin mediates the response of human melanocytes to UVB light. Cancer Res 1998;58:47–54.

    PubMed  CAS  Google Scholar 

  154. Westbroek W, Lambert J, Naeyaert JM. The dilute locus and Griscelli syndrome: gateways towards a better understanding of melanosome transport. Pigment Cell Res 2001;14:320–327.

    Article  PubMed  CAS  Google Scholar 

  155. Seiberg M, Paine C, Sharlow E, et al. The protease-activated receptor-2 regulates pigmentation via keratinocyte-melanocyte interactions. Exp Cell Res 2000;254:25–32.

    Article  PubMed  CAS  Google Scholar 

  156. Seiberg M, Paine C, Sharlow E, et al. Inhibition of melanosome transfer results in skin lightening. J Invest Dermatol 2000;115:162–167.

    Article  PubMed  CAS  Google Scholar 

  157. Scott G, Deng A, Rodriguez-Burford C, et al. Protease-activated receptor 2, a receptor involved in melanosome transfer, is upregulated in human skin by ultraviolet irradiation. J Invest Dermatol 2001;117:1412–1420.

    Article  PubMed  CAS  Google Scholar 

  158. Scott G. Rac and rho: the story behind melanocyte dendrite formation. Pigment Cell Res 2002;15:322–330.

    Article  PubMed  CAS  Google Scholar 

  159. Klein-Parker HA, Warshawski L, Tron VA. Melanocytes in human skin express bcl-2 protein. J Cutan Pathol 1994;21:297–301.

    Article  PubMed  CAS  Google Scholar 

  160. Plettenberg A, Ballaun C, Pammer J, et al. Human melanocytes and melanoma cells constitutively express the bcl-2 proto-oncogene in situ and in cell culture. Am J Pathol 1995;146:651–659.

    PubMed  CAS  Google Scholar 

  161. Kadekaro AL, Kanto H, Kavanagh RJ, Schwemberger S, Babcock G, Abdel-Malek ZA. A novel role for the paracrine factors endothelin-1 and alpha-melanocortin as survival factors for human melanocytes. Pigment Cell Res 2003;16:416 (Abstract).

    Article  Google Scholar 

  162. Larribere L, Khaled M, Tartare-Deckert S, et al. PI3K mediates protection against TRAIL-induced apoptosis in primary human melanocytes. Cell Death Differ 2004.

    Google Scholar 

  163. Kadekaro AL, Kavanagh R, Kanto H, et al. α-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res 2005;65:4292–4299.

    Article  PubMed  CAS  Google Scholar 

  164. Rouzaud F, Kadekaro AL, Abdel-Malek ZA, Hearing VJ. MC1R and the response of melanocytes to ultraviolet radiation. Mutat Res 2005;571:133–152.

    PubMed  CAS  Google Scholar 

  165. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cellintrinsic death machinery. Cell 1997;91:231–241.

    Article  PubMed  CAS  Google Scholar 

  166. Pugazhenthi S, Nesterova A, Sable C, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000;275:10,761–10,766.

    Article  PubMed  CAS  Google Scholar 

  167. Price ER, Horstmann MA, Wells AG, et al. α-Melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome. J Biol Chem 1998;273:33,042–33,047.

    Article  PubMed  CAS  Google Scholar 

  168. McGill GG, Horstmann M, Widlund HR, et al. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 2002;109:707–718.

    Article  PubMed  CAS  Google Scholar 

  169. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 2004;22:735–742.

    Article  PubMed  CAS  Google Scholar 

  170. Wong AK, Pero R, Ormonde PA, Tavtigian SV, Bartel PL. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J Biol Chem 1997;272:31,941–31,944.

    Article  PubMed  CAS  Google Scholar 

  171. Chen PL, Chen CF, Chen Y, Xiao J, Sharp ZD, Lee WH. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci USA 1998;95:5287–5292.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH

    Zalfa A. Abdel-Malek & Ana Luisa Kadekaro

Authors
  1. Zalfa A. Abdel-Malek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Luisa Kadekaro
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Laboratory of Cell Biology National Cancer Institute, National Institutes of Health, Bethesda, MD

    Vincent J. Hearing PhD

  2. Department of Surgery, University of California, San Francisco

    Stanley P. L. Leong MD

  3. School of Medicine, San Francisco, CA

    Stanley P. L. Leong MD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, N.J.

About this chapter

Cite this chapter

Abdel-Malek, Z.A., Kadekaro, A.L. (2006). Human Cutaneous Pigmentation. In: Hearing, V.J., Leong, S.P.L. (eds) From Melanocytes to Melanoma. Humana Press. https://doi.org/10.1007/978-1-59259-994-3_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-994-3_5

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-459-3

  • Online ISBN: 978-1-59259-994-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation