ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00064.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Non‐premelanosomal melanogenic compartments and their melanogenesis‐controlling functions have been further elucidated. In addition to enzymatic and nonenzymatic controlling factors, we have also been exploring the role of melanogenesis‐related genes. Naturally occurring intrinsic melanogenic inhibitors, MW30,000(γ), having different modes of action, have been identified within melanoma cells. One of the α‐type melanogenic inhibitors of isolated tyrosinase(Ty) nonsuppressive types, later identified as lactic acid, induces depigmentation of cultured B‐16 cells by the reduction in Ty activity level due to the inhibition of its mRNA expression.The transfection of Ty cDNA, rather than nuclear DNA‐binding master regulatory gene, can induce, within both Ty‐deficient amelanotic melanoma cells and also within fibroblasts, melanin polymer formation. This multisequential step occurs not only by the induction of Ty synthesis but also by the induction of other regulatory proteins and factors such as dopachrome tautomerase, DHICA‐oxidase, catalase, Ty‐glycosylation in GERL, and Ty‐transfer by coated vesicles to newly assigned melanogenic vacuoles in which not only eumelanin but also rather pronounced concomitant pheomelanin formation is seen.Investigation of melanin‐producing vacuoles in transfected fibroblasts and reexamination of premelanosomes in pigment cells has revealed the following: 1) Melanosomes possess phagocytic ability; 2) melanosomes receive tyrosinase and hydrolases via coated vesicles from GERL; 3) melanosomes possess lysosome‐associated membrane protein 1 (LAMP‐1); 4) amelanotic melanoma contains lysosome‐like vacuoles with myelin figures that acquire typical premelanosome structure after Ty‐cDNA transfection. Thus it is proposed that melanosomes are specialized lysosomes in pigment cells.Coated vesicles synthesize melanin monomers such as DHICA and some DHI, and have a monomer‐stabilizing system. Thus they can transport them in intact form with Ty to premelanosomes, which subsequently polymerize these monomers by the action of DHICA‐oxidase and T3‐Ty.Selective eradication and diagnosis of malignant melanoma using our10B‐dopa analogue has been successfully performed in human melanoma patients using combined thermal neutron irradiation for the for

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00065.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Recently, DNA sequence data have been published on tyrosinase and tyrosinase‐related proteins (TRPs) in a wide variety of vertebrates ranging fromRanatoHomo.These proteins are in turn members of a larger family of binuclear copper‐binding proteins, which all contain two highly conserved copper‐binding domains. This gene family also includes tyrosinases from fungi and bacteria as well as arthropodan and molluscan hemocyanins. Parsimony‐based alignment and tree construction algorithms (Malign, vl.85 and PAUP, 3.1.1) were used to analyze the diversification of both the evolutionarily conserved copper‐binding domains i6n copper‐binding proteins in general as well as the diversification of the vertebrate tyrosinase gene family more specifically. These analyses show that the diversification of the vertebrate tyrosinase gene family minimally predates the diversification of vertebrates. Vertebrate tyrosinases proper first diverged from an ancestral tyrosinase‐related protein (TRP) that then subsequently diverged to form tyrosinase‐related protein‐Is (TRP‐1s) and tyrosinase‐relate

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00066.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Pmel 17 cDNA clones, isolated from wild‐type andsi/simurine melanocytes, were sequenced and compared. A single nucleotide (A) insertion was found in the putative cytoplasmic tail of thesi/siPmel 17 cDNA clone. This insertion is predicted to alter the last 24 amino acids at theC‐terminus and to extend the Pmel 17 protein by 12 residues. The mutation was confirmed by the sequence of the PCR‐amplified genomic region including the mutation site.SilverPmel 17 was not recognized by antibodies directed toward theC‐terminal amino acids of wild‐type Pmel 17, indicating a defect in this region. These results indicate thatsilverPmel 17 protein has a major defect at the carboxyl

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00067.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Mutations at the mouse pink‐eyed dilution locus,p, cause hypopigmentation. We have cloned the mousepgene cDNA and the cDNA of its human counterpart, P. The region of mouse chromosome 7 containing theplocus is syntenic with human chromosome 15q11‐q13, a region associated with Prader‐Willi syndrome (PWS) and Angelman syndrome (AS), both of which involve profound imprinting effects. PWS patients lack sequences of paternal origin from 15q, whereas AS patients lack a maternal copy of an essential region from 15q. However, the critical regions for these syndromes are much smaller than the chromosomal region commonly deleted that often includes the P gene. Hypopigmentation in PWS and AS patients is correlated with deletions of one copy of the human P gene that is highly homologous with its mouse counterpart. A subset of PWS and AS patients also have OCA2. These patients lack one copy of the P gene in the context of a PWS or AS deletion, with a mutation in the remaining chromosomal homologue of the P gene. Mutations in both homologues of the P gene of OCA2 patients who do not have PWS or AS have also been det

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00068.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

O‐Methylation of L‐dopa was investigated as a possible regulatory mechanism in melanin metabolism. The methylation product of L‐dopa, 3‐O‐methoxytvrosine was detected in extracts of cultured human melanocytes. The enzyme catechol‐O‐methyltransferase is responsible for this O‐methylation and that of the dihydroxyindolic intermediates of melanogenesis. The enzyme is present in melanocytes in its soluble and membrane‐bound isoforms. Immuno‐electron microscopy suggests the presence of the membrane‐bound enzyme in the endoplasmic reticulum. This localization may indicate a role of catechol‐O‐methyltransferase in protecting the melanocyte against reactive dihydroxyphenolic intermediates of melanogenesis leaking from the melanogenic compartments. On the other hand, the O‐methylation of L‐dopa may serve as a regulatory point in melanogenesis during early stage of tyrosinase processing

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00069.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Feather melanocytes in the Barred Plymouth Rock (BPR) and White Leghorn (WL) chickens die prematurely in vivo when compared to the wild type Jungle Fowl (JF) chicken. Since these mutant melanocytes live in vitro, an environmental factor in the feather must precipitate their death. Results show that the addition of selected antioxidants, glutathione (GSH) and superoxide dismutase (SOD), can rescue these mutant melanocytes in vitro that have been placed under stress conditions that cause their premature cell death. Measurements of in vivo levels of GSH, catalase, and SOD show no significant difference in catalase activity between the JF, BPR, and WL feathers but do show a significant reduction in GSH activity in both the BPR and WL feathers to approximately 66% of the GSH concentration found in JF feathers. SOD activity in the BPR tissue is reduced significantly to approximately 50% of the JF activity and the WL SOD activity is reduced significantly to approximately 50% of the BPR SOD activity. Preliminary results of measurements of glutathione peroxidase activity indicate there is no difference in the levels of this enzyme in JF, BPR and WL feathers. A working hypothesis, based on current results, is proposed for premature cell death in BPR and WL feather melanocytes. The BPR melanocytes are genetically sensitive due to a defect in their SOD and GSH levels caused by the barring gene (B) and their death, due to reactive species of oxygen radicals, is precipitated in the poorly vascularized feather by the accumulation of oxygen radicals due to the low turnover of tissue fluids. The WL chicken carries the dominant white gene (I) in addition to theBgene. This gene directs the further reduction of the level of SOD and, when combined with the cell death mechanism already present in the BPR chicken, causes the WL feather melanocytes to die much earlier than the BPR feather melanocytes which in turn die much earlier than the wild type JF melanocytes. This same mechanistic hypothesis could apply asacause of premature melanocyte cell death in human vitiligo wherein the vitiliginous melanocytes may have a genetic defect in their oxygen radical protection system.

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00070.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Information on the composition of melanins is obtained by analysis both of 4‐amino‐3‐hydroxyphenylalanine (AHP) after hydriodic acid degradation and of pyrrole‐2,3,5‐tricarboxylic acid (PTCA) after potassium permanganate oxidation. Analysis of thiazole‐4,5‐dicarboxylic acid (TDCA) and pyrrole‐2,3‐dicarboxylic acid (PDCA) after permanganate oxidation, provides additional information on the composition, TDCA on pheomelanin residues, and PDCA on indolic residues without carboxy groups. Using model melanins formed from dopa and cysteinyldopa in different proportions, we found the TDCA/(PTCA+PDCA) ratio to yield a reliable estimate of the relative proportions of pheomelanin and eumelanin. The PDCA/PTCA ratio reflects the relationship between indole residues with and without carboxy groups. We have analyzed degradation products from cultures of IGR 1, an extensively studied melanoma cell line. Cell cultures were harvested after 2, 4, and 7 days. Culture media were changed after 2 days in all series, and also after 4 days in one series harvested at 7 days. Cells without medium change had seven times the amount of melanin found in cultures with medium change. The PDCA/PTCA ratio decreased with increasing amounts of melanin. With increased melanization, eumelanin is increased relatively more than pheomelanin. The cell content of 5‐S‐cysteinyldopa (5‐S‐CD) was similar in all cultures, while 6‐hydroxy‐5‐methoxyindole‐2‐carboxylic acid (6H5MICA), a eumelanin precursor metabolite, was found in increased amounts of

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00071.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Melanoma formation in platyfish/swordtail hybrids of genus Xiphophorus is due to overexpression of the receptor tyrosine kinase oncogeneXmrk.This gene is the molecular equivalent to theTu‐locus of platyfish, formerly identified by Mendelian genetics. The supposed evolutionary origin of the Xmrk oncogene is a nonhomologous recombination event in the 5’region of the correspondingXmrkprotooncogene with an anonymous sequence,D.This event led to a gene duplication ofXmrk, whereby the new copy obtained a novel promoter derived fromD.Inactivity of this promoter in parental fish warrants lack of tumorigenicity of theXmrkoncogene in wild playfish. In hybrids, however, the promoter is active. This leads to the pigment cell transforming overexpression ofX

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00072.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The worldwide accelerating increase of neoplasia in humans is difficult to explain. We use theXiphophorustumor model to approach this problem by melanoma provocation with X‐rays. Melanoma develops following inappropriate expression ofx‐erbB‐conducted developmental genes and their controllers. These oncodeterminants are inherited according to Mendelian rules. We detected a new type of oncodeterminants that, following a single treatment of embryos with X‐rays, generates a self‐generating non‐Mendelian melanoma transmission and accelerating increase of its incidence in succeeding generations (e.g., 0→18→33→52%). To localize these oncodeterminants, we crossed nonirradiated fish having half of their chromosomes irradiated with nonirradiated fish having none of, half of, or all of their chromosomes irradiated. Because tumor rate and expression in the following generations correspond to the rates of treated chromosomes, we conclude that the new oncodeterminants are distributed over the chromosomes of the fish, where they may increase in the changing generations. By means of xiphophorine‐specific retroviral DNA, we isolated two retrotransposons that behave hereditarily like the new transgenerational oncodeterminants. Sequence analysis revealed three ORFs flanked by LTRs containing motives of regulatory sequences typical for known retroviral and retrotransposal LTRs.Pol‐andenv‐resembling sequences are lacking. Southern and in situ hybridization showed their multiple and repetitive nature distributed throughout the chromosomes and indications for their capability to increase in number without further treatment. Their transcripts are expressed in concert with those of most of the other known xiphophorine tumor determinants. Their expression is extremely high in cell cultures from tumorous embryos derived from ancestors treated

ISSN:0893-5785    

DOI:10.1111/j.1600-0749.1994.tb00073.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY