Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genistein, a soybean-derived isoflavone, may contribute to the lower cancer incidence in South Asian countries. In this study, the effects and molecular mechanisms of genistein on growth and differentiation of B16-BL6 mouse melanoma cells were investigated. Genistein suppressed the growth of these melanoma cells. The IC50 value is 15.5 microM. On the other hand, genistein induced the changes of cell shape and cytoskeletal network. The cytoskeletal filaments were induced to form a bundle along the direction of elongation of the cells. Moreover, tyrosine phosphorylation levels of cytoskeleton-associated proteins decreased after the cells were exposed to 20 or 30 microM of genistein for 3 days. All these morphological and molecular changes were accompanied by appearance of the differentiated phenotypes. Genistein induced the increase of cellular melanin content, enhancement of tyrosinase activity, and decrease of colonization potentials in soft agar in a time-dependent and dose-dependent manner. The effective concentration was no more than 10 microM after 3 days' exposure. The tumorigenic potentials of B16-BL6 cells in C57BL/6 mouse also decreased after exposure to 20 or 30 microM of genistein for 3 days. When expressions of tumor-related genes were investigated in the differentiation-induced cells, the content of P53 dramatically increased while that of c-Myc protein decreased. Therefore, due to its ability to induce cellular and molecular changes, genistein suppressed the growth and induced differentiated phenotypes in B16-BL6 melanoma cells.
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PMID:Effects of genistein, a soybean-derived isoflavone, on proliferation and differentiation of B16-BL6 mouse melanoma cells. 1152 49

Tyrosinase, the rate-limiting enzyme for melanin synthesis, is induced after ultraviolet irradiation as part of the tanning response, the major recognized photoprotective response of human skin. Other DNA-damaging agents and DNA fragments such as thymidine dinucleotides also induce tyrosinase gene expression. Moreover, like ultraviolet light they also activate p53. To determine whether p53 activation is required for this increased tyrosinase expression, we employed two experimental systems: (i) a human melanoma line (WM35) known to express wild-type p53 versus WM35 cells engineered to express a transcriptionally inactive dominant-negative p53 (WM35-p53DN) or the empty vector alone (WM35-pCMV7) and (ii) mice with wild-type p53 versus p53 knockout mice. In WM35-p53DN cells, the baseline p53 protein level was higher than in WM35 or WM35-pCMV7 cells, and tyrosinase transcripts were lower. After ultraviolet irradiation, in all cell lines the p53 protein level increased within the first 24 h, as expected; and at 24 h tyrosinase mRNA levels were decreased. Consistent with the literature, these data in combination suggest that increased p53 protein level downregulates tyrosinase mRNA. In WM35 and WM35-pCMV7 cells at 48 and 72 h, however, whereas p53 levels remained elevated, tyrosinase mRNA levels compared to pre-irradiation levels tripled, whereas in WM35-p53DN cells levels remained below baseline. In thymidine-dinucleotide-treated WM35 and WM35-pCMV7 cells there was a comparable upregulation of tyrosinase mRNA within 24 h that persisted through 72 h, but there was no upregulation of tyrosinase mRNA in WM35-p53DN cells any time after ultraviolet irradiation or thymidine dinucleotide treatment. In ear skin of p53 wild-type mice, topical application of thymidine dinucleotide induced a 4-5-fold increase in epidermal melanin content after 3 wk, but in p53 knockout mice thymidine dinucleotide application caused no detectable increase in melanin. Together, these data demonstrate that p53 activation increases tyrosinase mRNA level and subsequently pigmentation. The data further suggest that tanning is part of a p53-mediated adaptive response of mammalian skin to DNA damage from ultraviolet irradiation.
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PMID:Tyrosinase gene expression is regulated by p53. 1185 85

The p53 knockout mouse has been widely used as a model in cancer research and other applications. Because neither homozygous nor heterozygous mutant p53 mice exhibit an overt phenotype, each animal requires laborious molecular genotyping. Here we describe a new p53 mutant mouse that is tagged with a tyrosinase coat color minigene. On an albino background, heterozygous tyrosinase-tagged p53 mutant mice exhibit a light tan coat color, while homozygous mutants display a darker brown coat color. Thus, by 8-10 days of age, mice with two, one, or no mutant p53 alleles are immediately distinguishable by their coat color, eliminating the time, costs, and errors associated with molecular genotyping. Moreover, the homozygous mutant p53-tyrosinase mice display a tumor incidence and spectrum virtually identical to previous p53 null mouse lines. Thus, tagging targeted mutations with such coat color markers provides a generally applicable genotyping method for embryonic stem cell-derived mice.
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PMID:Visual genotyping of a coat color tagged p53 mutant mouse line. 1243 62

Photo-unstable chemicals sometimes behave as phototoxins in skin, inducing untoward clinical side-effects when exposed to sunlight. Some drugs, such as psoralens or fluoroquinolones, can damage genomic DNA, thus increasing the risk of photocarcinogenesis. Here, lomefloxacin, an antibiotic from the fluoroquinolone family known to be involved in skin tumor development in photoexposed mice, was studied using normal human skin cells in culture: fibroblasts, keratinocytes, and Caucasian melanocytes. When treated cells were exposed to simulated solar ultraviolet A (320-400 nm), lomefloxacin induced damage such as strand breaks and pyrimidine dimers in genomic DNA. Lomefloxacin also triggered various stress responses: heme-oxygenase-1 expression in fibroblasts, changes in p53 status as shown by the accumulation of p53 and p21 proteins or the induction of MDM2 and GADD45 genes, and stimulation of melanogenesis by increasing the tyrosinase activity in melanocytes. Lomefloxacin could also lead to apoptosis in keratinocytes exposed to ultraviolet A: caspase-3 was activated and FAS-L gene was induced. Moreover, keratinocytes were shown to be the most sensitive cell type to lomefloxacin phototoxic effects, in spite of the well-established effectiveness of their antioxidant equipment. These data show that the phototoxicity of a given drug can be driven by different mechanisms and that its biologic impact varies according to cell type.
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PMID:Molecular responses to photogenotoxic stress induced by the antibiotic lomefloxacin in human skin cells: from DNA damage to apoptosis. 1292 21

Differentiated melanocytic cells produce melanin, through several redox reactions including tyrosinase-catalyzed DOPA oxidation to DOPA quinone. We now developed a method based on DOPA oxidase in-gel detection and Sypro Ruby fluorometric normalization to investigate induction of specific DOPA oxidase isoforms in response to hydrogen peroxide-mediated stress, and to ask whether this is associated with p53-dependent adaptive responses. This report shows that hydrogen peroxide leads to comparable induction of 60 and 55 kDa DOPA oxidases in poorly pigmented B16 melanoma, in contrast to sole induction of a major 55 kDa DOPA oxidase in their highly pigmented counterparts. In the latter cells, this response also increases p53 concomitant with joint induction of p53-activated proteins like the cell-cycle inhibitor p21WAF1 and pro-apoptotic bax, with no comparable effect on expression of anti-apoptotic bcl-2. Together, these data suggest that response to hydrogen peroxide involves p53-mediated growth-restrictive signaling and unequal induction of specific DOPA oxidases in melanocytic cells with unequal basal pigmentation.
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PMID:Hydrogen peroxide increases a 55-kDa tyrosinase concomitantly with induction of p53-dependent p21 waf1 expression and a greater Bax/Bcl-2 ratio in pigmented melanoma. 1463 45

Melanoma with prominent pigment synthesis or animal-type melanoma (ATM) is a very rare type of melanoma. Its histogenesis has not been elucidated and ultrastructural features have not been described in human beings. We present an additional case of ATM in a 28-year-old woman with positive sentinel node biopsy and provide the results of electron microscopic studies. Histopathologically, the skin lesion was composed of heavily pigmented neoplastic cells mostly arranged as large sheets, focally also in a nodular growth pattern. After bleaching, the neoplastic cells demonstrated round nuclei with 1 or rarely 2 conspicuous nucleoli and a prominent nuclear membrane and abundant, gray, slate-like cytoplasm. Some cells demonstrated round cytoplasmic inclusions. There was no nuclear pleomorphism, and only a few mitotic figures could be found after extensive search. Multiple areas of necrosis en masse of tumor cells were seen. The lymph node biopsy revealed a complete effacement of the lymph node architecture by the extensive proliferation of hyperpigmented cells in the parenchyma. Immunohistochemically, the same pattern of staining was seen on the bleached and unbleached slides both in the skin and in the lymph node. The neoplastic cells stained positively with MiTF (nuclei), NSE, NKI/C3, tyrosinase (weak), p53, and CD68. S-100 protein, HMB45, Melan A, Mac367, and lysozyme reacted negatively. Occasional cells (<1%) reacted with MIB-1. Ultra-structural studies revealed that the neoplastic cells possessed a large, indented nucleus with a prominent nuclear membrane, a single (para) centrally located nucleolus, and peripherally marginated chromatin. The cytoplasm was abundant and contained numerous single melanosomes and rare compound melanosomes. The melanosomes were in stages II to IV of maturation, with a marked predominance of stage II and stage III melanosomes. There was a high number of aberrant melanosomes with a wide variety of configurations. Melanophages were a minor component of the lesion. Our ultrastructural studies provide unequivocal evidence that ATM is a neoplasm of melanosome-producing cells. We also review the literature on ATM.
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PMID:Melanoma with prominent pigment synthesis (animal-type melanoma): a case report with ultrastructural studies. 1524 59

Tyrosinase is expressed in melanoma cells and catalyzes the formation of 3,3',4',5,7-pentahydroxyflavone (quercetin) into reactive quinone species and subsequent glutathionyl adducts. Therefore, we examined the effect of quercetin metabolism on the glutathione (GSH) bioreduction pathway and cell viability in DB-1 melanoma cells that express varying levels of tyrosinase (Tyr+). In a cell-free system, GSH was significantly decreased by quercetin, which coincided with the formation of glutathionyl adducts. In Tyr+ clones, quercetin decreased bioreduction capacity and increased reactive oxygen species (ROS) to a greater degree compared to control cells. The antioxidant/electrophile response element-induced enzymes, glutathione-S-transferase (GST), and nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 were expressed at high levels in Tyr+ cells and contributed to pro-oxidant quercetin metabolism. The basal level of ROS and apoptosis was higher in Tyr+ cells and were selectively increased after exposure to quercetin. The increase in apoptosis following quercetin exposure was p53/Bax mediated and correlated with a decrease in GST-driven bioreduction capacity and an increase in ROS. In conclusion, quercetin can selectively sensitize Tyr+ expressing melanoma cells to apoptosis and may serve as an adjuvant to chemotherapy by enhancing cell death and interfering with GST-mediated drug resistance.
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PMID:Quercetin selectively inhibits bioreduction and enhances apoptosis in melanoma cells that overexpress tyrosinase. 1800 Dec 20

Despite many efforts, regulation of skin and hair pigmentation is still not fully understood. This article focuses mainly on controversial aspects in pigment cell biology which have emerged over the last decade. The central role of tyrosinase as the key enzyme in initiation of melanogenesis has been closely associated with the 6BH4 dependent phenylalanine hydroxylase (PAH) and tyrosine hydroxylase isoform I (THI) providing evidence for an old concept of the three enzyme theory in the initiation of the pigmentation process. In this context, it is noteworthy that intracellular L-phenylalanine uptake and turnover to L-tyrosine via PAH is vital for substrate supply of THI and tyrosinase. While PAH acts in the cytosol of melanocytes, THI and tyrosinase are sitting side by side in the melanosomal membrane. THI at low pH provides L-3,4-hydroxyphenylalanine L-DOPA which in turn is required for activation of met-tyrosinase. After an intramelanosomal pH change, possibly by the p-protein, has taken place, tyrosinase is subject to control by 6/7BH4 and the proopiomelanocortin (POMC) peptides alpha-MSH melanocyte stimulating hormone and beta-MSH in a receptor independent manner. cAMP is required for the activation of microphthalmia-associated transcription factor to induce expression of tyrosinase, for transcription of THI and for activation of PAH. The redundancy of the cAMP signal is discussed. Finally, we propose a novel mechanism involving H2O2 in the regulation of tyrosinase via p53 through transcription of hepatocyte nuclear factor 1alpha which in turn can also affect the POMC response.
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PMID:Regulation of melanogenesis--controversies and new concepts. 1817 48

Dacarbazine (DTIC) has been used for the treatment of melanoma for decades. However, monotherapy with this chemotherapeutic agent results only in moderate response rates. To improve tumor response to DTIC current clinical trials in melanoma focus on combining a novel targeted agent with chemotherapy. Here, we demonstrate that tyrosinase which is commonly overexpressed in melanoma activates the bioflavonoid quercetin (Qct) and promotes an ataxia telangiectasia mutated (ATM)-dependent DNA damage response. This response sensitizes melanoma cells that overexpress tyrosinase to DTIC. In DB-1 melanoma cells that overexpress tyrosinase (Tyr(+) cells), the threshold for phosphorylation of ATM and p53 at serine 15 was observed at a low dose of Qct (25 microM) when compared to the mock transfected pcDNA3 cells, which required a higher dose (75 microM). Both pcDNA3 and Tyr(+) DB-1 cells demonstrated similar increases in phosphorylation of p53 at other serine sites, but in the Tyr(+) cells, DNApk expression was found to be reduced compared to control cells, indicating a shift towards an ATM-mediated response. The DB-1 control cells were resistant to DTIC, but were sensitized to apoptosis with high dose Qct, while Tyr(+) cells were sensitized to DTIC with low or high dose Qct. Qct also sensitized SK Mel 5 (p53 wildtype) and 28 (p53 mutant) cells to DTIC. However, when SK Mel 5 cells were transiently transfected with tyrosinase and treated with Qct plus DTIC, SK Mel 5 cells demonstrated a more than additive induction of apoptosis. Therefore, this study demonstrates that tyrosinase overexpression promotes an ATM-dependent p53 phosphorylation by Qct treatment and sensitizes melanoma cells to dacarbazine. In conclusion, these results suggest that Qct or Qct analogues may significantly improve DTIC response rates in tumors that express tyrosinase.
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PMID:Tyrosinase overexpression promotes ATM-dependent p53 phosphorylation by quercetin and sensitizes melanoma cells to dacarbazine. 1879 Dec 69

Hyperpigmentation of the skin is characterized by increases in melanin synthesis and deposition. Although considered a significant psychosocial distress, little is known about the detailed mechanisms of hyperpigmentation. Recently, the tumor suppressor protein p53 has been demonstrated to promote ultraviolet B-induced skin pigmentation by stimulating the transcription of a melanogenic cytokine, POMC (pro-opiomelanocortin), in keratinocytes. Given that p53 can be activated by various kinds of diverse stresses, including sun exposure, inflammation, and aging, this finding led us to examine the involvement of p53 in cytokine receptor signaling, which might result in skin hyperpigmentation. Immunohistochemical and reverse transcription-PCR analyses revealed the increased expression and phosphorylation of p53 in the epidermis of hyperpigmented spots, accompanied by the higher expression of melanogenic cytokines, including stem cell factor, endothelin-1, and POMC. The involvement of p53 in hyperpigmentation was also indicated by the significantly higher expression of p53 transcriptional targets in the epidermis of hyperpigmented spots. Treatment of human keratinocytes and melanocytes with known p53 activators or inhibitors, including pifithrin-alpha (PFT), demonstrated significant increases or decreases, respectively, in the expression of melanogenic factors, including cytokines and their receptors. Additionally, PFT administration abolished stem cell factor-induced phosphorylation of mitogen-activated protein kinase in human melanocytes. Furthermore, when organ-cultured hyperpigmented spots, in vitro human skin substitutes, and mouse skin were treated with PFT or p53 small interfering RNA, the expression of melanogenic cytokines and their receptors was significantly decreased, as were levels of tyrosinase and melanogenesis. Taken together, these data reveal the essential role of p53 in hyperpigmentation of the skin via the regulation of paracrine-cytokine signaling, both in keratinocytes and in melanocytes.
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PMID:The essential role of p53 in hyperpigmentation of the skin via regulation of paracrine melanogenic cytokine receptor signaling. 1909 8


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