Summary
Melanocyte cultures from the normally pigmented skin of patients with neurofibromatosis 1 (NF 1) have a higher melanin content than those from the skin of healthy donors. An additional increase in the amount of melanin per cell was found in 5 out of 6 lines of melanocytes derived from café au lait macules of NF 1 patients. Omission of the tumor promoter phorbol-12-myristate-13-acetate from the culture medium brings about a comparable increase in the melanin content in all three kinds of melanocyte cultures. Cultures of NF 1 melanocytes show a higher tyrosine hydroxylase activity than those of control melanocytes, and incorporate larger amounts of dihydroxyphenylalanine than the latter. We conclude that melanogenesis in epidermis melanocytes is affected by defective alleles of the NF 1 gene. Our findings do not contradict the hypothesis that the defect underlying NF 1 impairs the inhibition of a wild-type RAS oncogene by interfering with the GTPase-activating function of the NF 1 gene product.
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References
Auböck J, Köfler D, Sifter M, Fritsch P (1983) Application of the tyrosinase assay to normal melanocytes in culture. Br J Dermatol 109:413–419
Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63:851–859
Bar-Sagi D, Feramisco JR (1985) Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation. Cell 42:841–848
Buchberg AM, Cleveland LS, Jenkins NA, Copeland NG (1990) Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway. Nature 347:291–294
Cawthon RM, Weiss R, Xu G, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, White R (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62:193–201
Eisinger M, Marko O (1982) Selective proliferation of normal human melanocytes in vitro in the presence of phorbol ester and cholera toxin. Proc Natl Acad Sci USA 79:2018–2022
Frenk E, Marazzi A (1984) Neurofibromatosis of von Recklinghausen: a quantitative study of the epidermal keratinocyte and melanocyte populations. J Invest Dermatol 83:23–25
Friedmann PS, Gilchrest BA (1987) Ultraviolet radiation induces pigment production by cultured human melanocytes. J Cell Physiol 133:88–94
Gordon PR, Gilchrest BA (1989) Human melanogenesis is stimulated by diacylglycerol. J Invest Dermatol 93:700–702
Gordon PR, Mansur CP, Gilchrest BA (1989) Regulation of human melanocyte growth, dendricity, and melanization by keratinocyte derived factors. J Invest Dermatol 92:565–572
Guerrero I, Wong H, Pellicer A, Burstein DE (1986) Activated N-ras gene induces neuronal differentiation of PC12 rat pheochromocytoma cells. J Cell Physiol 129:71–76
Halaban R, Alfano FD (1984) Selective elimination of fibroblasts from cultures of normal human melanocytes. In Vitro 20:447–450
Halaban R, Ghosh S, Duray P, Kirkwood JM, Lerner AB (1986) Human melanocytes cultured from nevi and melanomas. J Invest Dermatol 87:95–101
Husain Z, Wick MM (1990) Transcriptional activation of c-fos gene negatively regulates proliferation of human melanocytes as a response to phorbol ester application. J Invest Dermatol 94:536
Ishida O (1987) A computed image analyzing system for quantitation of melanocyte morphology in café-au-lait macules of neurofibromatosis. J Invest Dermatol 88:287–291
Jimbow K, Horikowski T (1982) The nature and significance of macromelanosomes in pigmented skin lesions. Am J Dermatopathol 4:413–420
Kaufmann D, Krone W, Hochsattel R, Martin R (1989) A cell culture study on melanocytes from patients with neurofibromatosis 1. Arch Dermatol Res 281:510–513
Kaufmann D, Wiandt S, Krone W (1990) Increased melanin content in cultured melanocytes from patients with neurofibromatosis 1 (M. Recklinghausen, NF 1). Eur J Cell Biol 51 [Suppl 30]:77
Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, Conroy L, Clark R, O'Connell P, Cawthon RM, Innis MA, McCormick F (1990) The GAP related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63:843–849
Martuza RL, Philippe I, Fitzpatrick TB, Zwaan J, Seki Y, Lederman J (1985) Melanin macroglobules as a cellular marker of neurofibromatosis: a quantitative study. J Invest Dermatol 85:347–350
Nachlas M, Crawford D, Seligman A (1957) Histochemical demonstration of leucine aminopeptidase. J Histochem Cytochem 5:264
Nakagawa H, Hori Y, Sato S, Fitzpatrick TB, Martuza RL (1984) The nature and origin of the melanin macroglobule. J Invest Dermatol 83:134–139
Noda M, Ko M, Ogura A, Liu DG, Amano T, Takano T, Ikawa Y (1985) Sarcoma viruses carrying ras oncogenes induce differentiation-associated properties in a neuronal cell line. Nature 318:73–75
O'Connell P, Leach R, Cawthon RM, Culver M, Stevens J, Viskochil D, Fournier REK, Rich DC, Ledbetter DH, White R (1989) Two NF1 translocations map within a 600-kilobase segment of 17q11. 2. Science 244:1087–1088
Riccardi VM, Eichner JE (1986) Neurofibromatosis: phenotype, natural history, and pathogenesis. Johns Hopkins University Press, Baltimore
Ridley AJ, Paterson HF, Noble M, Land H (1988) Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J 7:1635–1645
Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O'Connell P (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62:187–192
Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, Brownstein BH, Collins FS (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–186
Xu G, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R, Weiss R (1990a) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608
Xu G, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R, Tamanoi F (1990b) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cervisiae. Cell 63:835–841
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Kaufmann, D., Wiandt, S., Veser, J. et al. Increased melanogenesis in cultured epidermal melanocytes from patients with neurofibromatosis 1 (NF1). Hum Genet 87, 144–150 (1991). https://doi.org/10.1007/BF00204170
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DOI: https://doi.org/10.1007/BF00204170