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)

On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.
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PMID:A cascade of genes related to Waardenburg syndrome. 1053 86

Compelling evidence has been gathered indicating that pro-opiomelanocortin peptides, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH), through the cyclic AMP pathway, play a pivotal role in melanocyte differentiation and in the regulation of melanogenesis. Recently, the molecular events linking cAMP to melanogenesis up-regulation have been elucidated. This cascade involves the activation of protein kinase A and CREB transcription factor, leading to the up-regulation of the expression of Microphthalmia associated transcription factor (MITF). MITF has been found mutated in patients with Waardenburg syndrome 2A, and plays a crucial role in melanocyte development. MITF binds and activates melanogenic gene promoters, thereby increasing their expression which results in an increased melanin synthesis. Beyond this simplified scheme, It appears that melanogenic gene expression is controlled by a complex network of regulation involving other transcription factors such as Brn2, TBX2, PAX3 and SOX10. Further studies are required to better understand the respective roles of these factors in the regulation of melanin synthesis. In addition, other intracellular signaling pathways, like the phosphatidyl inositol 3-kinase pathway, as well as the molecular cascade of events governed by the small GTP-binding protein Rho, seem to be involved in the regulation of melanogenesis and melanocyte dendricity. Finally, it should be mentioned that cAMP activates a melanocyte-specific pathway leading to MAP kinase activation. MAP kinase, ERK2, phosphorylates MITF, thereby targeting the transcription factor to proteasomes for degradation. Thus, in addition to the complex transcriptional regulation, melanogenesis is also subjected to a post-translational regulation that controls MITF or tyrosinase function. Taken together, these complex molecular processes would finally allow a fine tuning of melanocyte differentiation leading to melanin synthesis.
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PMID:Cyclic AMP a key messenger in the regulation of skin pigmentation. 1084 Oct 26

The authors describe a patient who experienced recurrence of metastatic melanoma after an initial dramatic response to immunotherapy using peptides derived from gp100, MART-1, and tyrosinase emulsified in incomplete Freund's adjuvant, and present data to support the hypothesis that the progression of disease in this patient was due to in vivo immunoselection for immunoresistant tumor variants. The authors previously demonstrated the existence of T-cell clones in this patient's peripheral blood and tumor-infiltrating lymphocytes (TILs) reactive against multiple antigens, including gp100, the tyrosinase-related protein (TRP)-2, a novel TRP-2 isoform-TRP-2-6b, SOX10, and the melanoma antigen NY-ESO-1. In addition to the multiple HLA-A2 restricted T-cell clones, the authors have now identified additional HLA-B/C-restricted as well as class II (HLA-DP)-restricted anti-melanoma antigen T-cell clones from this patient's TIL. One recurrent tumor showed loss of expression of multiple tumor antigens but retention of HLA class I expression. The other recurrent lesion showed total loss of HLA class I expression even though the tumor cells still expressed many melanoma antigens. This paper thus provides evidence for both the effectiveness of the immune destruction of cancer as well as problems associated with antigen-loss tumor escape mechanisms.
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PMID:Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. 1507 35

There is increasing indication that interspecific phenotypic differences result from variations in gene-regulatory interactions. Here we provide evidence that mice differ from zebrafish in the way they use homologous key components to regulate pigment cell differentiation. In both zebrafish and mice, one transcription factor, SOX10, controls the expression of another, MITF (microphthalmia-associated transcription factor), which in turn regulates a set of genes critical for pigment cell development and pigmentation. Mutations in either Sox10 or Mitf impair pigment cell development. In Sox10-mutant zebrafish, experimentally induced expression of Mitf fully rescues pigmentation. Using lineage-directed gene transfer, we show that, in the mouse, Mitf can rescue Sox10-mutant precursor cells only partially. In fact, retrovirally mediated, Sox10-independent Mitf expression in mouse melanoblasts leads to cell survival and expression of a number of pigment biosynthetic genes but does not lead to expression of tyrosinase, the rate-limiting pigment gene which critically depends on both Sox10 and Mitf. Hence, compared with fish, mice have evolved a regulation of tyrosinase expression that includes feed-forward loops between Sox10 and tyrosinase regulatory regions. The results may help to explain how some embryos, such as zebrafish, can achieve rapid pigmentation after fertilization, whereas others, such as mice, become pigmented only several days after birth.
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PMID:Interspecies difference in the regulation of melanocyte development by SOX10 and MITF. 1675 62

SOX (SRY type HMG box) proteins are transcription factors that are predominantly known for their roles during development. During melanocyte development from the neural crest, SOX10 regulates microphthalmia-associated transcription factor, which controls a set of genes critical for pigment cell development and pigmentation, including dopachrome tautomerase and tyrosinase. We report here that another SOX factor, SOX9, is expressed by melanocytes in neonatal and adult human skin and is up-regulated by UVB exposure. We demonstrate that this regulation is mediated by cAMP and protein kinase. We also show that agouti signal protein, a secreted factor known to decrease pigmentation, down-regulates SOX9 expression. In adult and neonatal melanocytes, SOX9 regulates microphthalmia-associated transcription factor, dopachrome tautomerase, and tyrosinase promoters, leading to an increase in the expression of these key melanogenic proteins and finally to a stimulation of pigmentation. SOX9 completes the complex and tightly regulated process leading to the production of melanin by acting at a very upstream level. This role of SOX9 in pigmentation emphasizes the poorly understood impact of SOX proteins in adult tissues.
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PMID:SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation. 1770 66

There are currently no effective therapies for metastatic melanoma and targeted immunotherapy results in the remission of only a very small percentage of tumors. In this study, we show that the noncanonical Wnt ligand, Wnt5A, can increase melanoma metastasis in vivo while down-regulating the expression of tumor-associated antigens important in eliciting CTL responses (e.g., MART-1, GP100, and tyrosinase). Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. Downstream targets such as PAX3, MITF, and MART-1 were also affected by Wnt5A treatment or knockdown. Staining of a melanoma tissue array also highlighted the inverse relationship between MART-1 and Wnt5A expression. PKC activation by phorbol ester mimicked Wnt5A effects, and Wnt5A treatment in the presence of STAT3 or PKC inhibitors did not lower MART-1 levels. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma.
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PMID:Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation. 1907 88

The hypo-pigmentation of human skin on the palms and the soles compared with other areas of the body has recently been reported to be due to mesenchymal-epithelial interactions via a fibroblast-derived factor, dickkopf 1, an inhibitor of the canonical Wnt signaling pathway. Recently, it has been reported that keratinocytes play a significant role in skin color determination by producing cytokines involved in melanogenesis. Thus, we hypothesized that the downregulated expression of keratinocyte- or fibroblast-derived melanogenic cytokines may also be responsible for the decreased function of palmoplantar (PP) melanocytes in addition to the suppressive effects of dickkopf 1 on melanogenic function in epidermal melanocytes. Immunohistochemistry revealed that the number of tyrosinase, S100alpha, c-KIT, endothelin B receptor (ETBR), SOX10, and microphthalmia-associated transcription factor (MITF) immuno-positive melanocytes is significantly reduced in PP epidermis. In contrast, dopa-histochemistry demonstrated no substantial reduction in melanocyte populations in PP epidermis. Real-time RT-PCR revealed that the expression of stem cell factor (SCF) and endothelin (ET)-1 mRNAs in PP skin was significantly downregulated. In parallel, immunohistochemistry revealed that SCF and ET-1 immuno-staining was markedly attenuated in PP skin. Western blotting revealed that the expression of SCF, c-KIT, and MITF-M proteins was significantly decreased in PP skin. These findings suggest the possibility that downregulation of ET-1/SCF/receptor linkages is also associated with the decreased function of melanocytes in PP skin.
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PMID:Downregulated melanogenic paracrine cytokine linkages in hypopigmented palmoplantar skin. 1908 31

The Dark brown (DB) mutation in chickens reduces expression of black eumelanin and enhances expression of red pheomelanin, but only in certain parts of the plumage. Here, we present genetic evidence that an 8.3-kb deletion upstream of the SOX10 transcription start site is the causal mutation underlying the DB phenotype. The SOX10 transcription factor has a well-established role in melanocyte biology and is essential for melanocyte migration and survival. Previous studies have demonstrated that the mouse homolog of a highly conserved element within the deleted region is a SOX10 enhancer. The mechanism of action of this mutation remains to be established, but one possible scenario is that the deletion leads to reduced SOX10 expression which in turn down-regulates expression of key enzymes in pigment synthesis such as tyrosinase. Lower tyrosinase activity leads to a shift toward a more pheomelanistic (reddish) plumage color, which is the characteristic feature of the DB phenotype.
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PMID:The Dark brown plumage color in chickens is caused by an 8.3-kb deletion upstream of SOX10. 2121 Sep 60

Cutaneous angiosarcoma can be challenging to diagnose particularly when poorly vasoformative and studied on biopsies. We report a case of a cutaneous angiosarcoma with strong positivity for tyrosinase, the first to our knowledge, initially misdiagnosed as melanoma. We subsequently evaluated the reactivity of panmelanocytic cocktail (tyrosinase, HMB-45 and Melan-A), SOX10, tyrosinase and MITF in a large tissue microarray (TMA) of angiosarcoma. The TMA included 142 cases of angiosarcomas (29 cutaneous, 22 primary breast, 41 post-radiation breast, 15 visceral, 26 deep soft tissue and bone, 5 chronic lymphedema-associated and 4 angiosarcomas arising in other sarcomas). Immunohistochemical studies were performed with anti-panmelanocytic cocktail, anti-SOX10, anti-MITF and anti-tyrosinase antibodies. TMA staining results were scored on intensity and percentage of tumoral labeling. Aside from the index case, no cases (0 of 133) showed positivity for tyrosinase including 28 cutaneous angiosarcomas. One breast angiosarcoma (1 of 131) was positive for MITF. All cases were negative for SOX10 and panmelanocytic cocktail (0 of 132). Angiosarcomas can rarely be positive for tyrosinase and MITF. Pathologists should be cognizant of these rare exceptions to prevent confusion with melanoma. Additional immunohistochemical markers for vascular and melanocytic differentiation, thorough histological examination for vasoformative and in situ areas as well as clinical impression are helpful in these exceptionally problematic cases.
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PMID:Index report of cutaneous angiosarcomas with strong positivity for tyrosinase mimicking melanoma with further evaluation of melanocytic markers in a large angiosarcoma series. 2855 23

Friend leukemia integration site 1 (FLI-1) nuclear transcription factor has been proposed as a suitable tool in the differential diagnosis of small round cell sarcomas. It has also been described as a nuclear marker of endothelial differentiation. Expression of FLI-1 has been demonstrated in Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) and vascular neoplasms. In the present study, we describe 2 cases of metastatic melanoma with small round blue cell morphology that showed strong nuclear expression of FLI-1. Because of the small round blue cell morphology and negative immunohistochemical staining for pan-melanocytic cocktail (HMB45, anti MART1 and anti-tyrosinase) and SOX10 in both cases, FLI-1 immunostaining was requested as part of the tumors workup. Ultimately, both cases were established as being metastatic melanoma. Dermatopathologists should be aware that melanoma can be strongly positive for FLI-1 and not misinterpret these cases for ES/PNET or vascular lesions, especially when melanomas show unusual morphology.
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PMID:Aberrant expression of FLI-1 in melanoma. 2860 42


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