Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are several known examples of mutations which influence copper homeostasis in humans and animals. Pleiotropic effects are observed when the mutant gene disturbs copper flux. In some cases, the mutation alters the level of a specific copper ligand (enzyme) and the clinical consequences are unique. The two most widely studied genetic maladies in humans are Menkes' and Wilson's diseases. Menkes' disease is an X-linked fatal disorder in which copper accumulates in some organs (intestine and kidney) and is low in others (liver and brain). Wilson's disease is an autosomal recessive disorder in which copper accumulates, if untreated, in liver and subsequently in brain and kidney. Pathophysiological consequences of copper deficiency and toxicity characterize these two disorders. Specific mutations of human cuproenzymes include overproduction of copper-zinc superoxide dismutase in Down's syndrome, absence of tyrosinase in albinism, hereditary mitochondrial myopathy due to reduction in cytochrome c oxidase, and altered lysyl oxidase in X-linked forms of cutis laxa and Ehlers-Danlos syndrome. Mutations altering copper metabolism are also known in animals. Several murine mutants have been studied. The most extensively investigated mutants are the mottled mice, in particular brindled mice, which have a mutation analogous to that of Menkes' disease. Another recently described murine mutation is toxic milk (tx) an autosomal recessive disorder that is characterized by copper accumulation in liver. Two other mutants, crinkled and quaking, were once thought to exhibit abnormal copper metabolism. Recent data has not confirmed this. A mutation in Bedlington terriers has been described which is very similar to Wilson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic diseases of copper metabolism. 351 56

Although the administration of melanocyte-stimulating hormone (MSH) peptides results in skin darkening in man, cultured human melanocytes have been reported to be unresponsive to these peptides. This may be a consequence of the conditions under which the cells were maintained in vitro, particularly the use of phorbol esters and cholera toxin as melanocyte mitogens. By culturing the cells in the absence of these additives, we demonstrate that alpha-MSH and its synthetic analogue Nle4DPhe7 alpha-MSH (NDP-MSH) induce dose-related increases in melanin content and tyrosinase activity and affect cell morphology in the majority of human melanocyte cultures. In addition, NDP-MSH induces increases in tyrosinase mRNA and tyrosinase-related protein-1 (TRP-1) mRNA. The dose-response curves for the MSH peptides are sigmoidal and the two peptides are equipotent in their effects on human melanocytes. Adrenocorticotropic hormone (ACTH) also affects morphology and stimulates melanogenesis and tyrosinase activity in human melanocytes. However, the dose-response curves for ACTH are biphasic, and the melanocytes respond to lower concentrations of ACTH than MSH peptides, similar to those normally present in human plasma. These findings may be important in understanding the role of these pro-opiomelanocortin peptides in human skin pigmentation.
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PMID:Cultured human melanocytes respond to MSH peptides and ACTH. 785 66

Genetic transmission in manic depressive illness (MDI) has been explored in twins, adoption, association, and linkage studies. The X-linked transmission hypothesis has been tested by using several markers on chromosome X: Xg blood group, colour blindness, glucose-6-phosphate dehydrogenase (G6PD), factor IX (haemophilia B), and DNA probes such as DXS15, DXS52, F8C, ST14. The hypothesis of autosomal transmission has been tested by association studies with the O blood group located on chromosome 9, as well as linkage studies on chromosome 6 with the Human Leucocyte Antigens (HLA) haplotypes and on Chromosome 11 with DNA markers for the following genes: D2 dopamine receptor, tyrosinase, C-Harvey-Ras-A (HRAS) oncogene, insuline (ins), and tyrosine hydroxylase (TH). Although linkage studies support the hypothesis of a major locus for the transmission of MDI in the Xq27-28 region, several factors are limiting the results, and are discussed in the present review.
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PMID:Minireview: Molecular genetics in affective illness. 842 7

During the pachytene stage of meiotic prophase in male mammals, the X and Y chromosomes become transcriptionally inactive and establish a chromatin domain, the sex body, that is visually distinct from the transcriptionally active autosomes. We used objective criteria to assess these chromatin differences by DNase I sensitivity (DS) of sex chromosome and autosomal sequences at both the cytological and molecular levels. For cytological studies, in situ nick translation techniques were used on air-dried preparations of testicular cells. For molecular studies, nuclei from pachytene spermatocytes were subjected to nuclease sensitivity assays. Both sex-linked and autosomal sequences were assessed, including some gene sequences that are expressed and some that are not expressed in pachytene spermatocytes. There was a wide range of DS in different genomic sequences; however, the sex-linked sequences generally were less nuclease sensitive than were autosomal sequences. Interestingly, a hot spot of recombination (within the Eb gene) showed a high level of nuclease sensitivity, while a cold spot of recombination (centromeric satellite region) exhibited lower sensitivity, more similar to that of sex-linked sequences. We also examined the nuclease sensitivity of a tyrosinase transgene insert, TyBS. In one line of mice, the transgene insert is X-linked, whereas in another, it is autosomal. The transgene was less nuclease sensitive when X-linked than as an autosomal insert. These results support the hypothesis that in pachytene spermatocytes the XY chromosome pair is more condensed and inaccessible to enzymatic digest, whereas the autosomal chromatin is in a more open configuration. In addition, we examined the nuclease sensitivity of some of the same genes in the earlier leptotene/zygotene prophase stage, when the sex chromatin is not maximally condensed. We found that while autosomal gene nuclease sensitivity was equivalent to that at the pachytene stage, X-linked sequences were more nuclease sensitive. Overall, these differences in chromatin nuclease sensitivity correlate with differences in meiotic recombination activity and may be mechanistically related.
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PMID:Chromatin configuration during meiosis I prophase of spermatogenesis. 940 97

Menkes protein (ATP7A) is a P-type ATPase involved in copper uptake and homeostasis. Disturbed copper homeostasis occurs in patients with Menkes disease, an X-linked disorder characterized by mental retardation, neurodegeneration, connective tissue disorders, and early childhood death. Mutations in ATP7A result in malfunction of copper-requiring enzymes, such as tyrosinase and copper/zinc superoxide dismutase. The first step of the two-step amidation reaction carried out by peptidylglycine alpha-amidating monooxygenase (PAM) also requires copper. We used tissue from wild-type rats and mice and an ATP7A-specific antibody to determine that ATP7A is expressed at high levels in tissues expressing high levels of PAM. ATP7A is largely localized to the trans Golgi network in pituitary endocrine cells. The Atp7a mouse, bearing a mutation in the Atp7a gene, is an excellent model system for examining the consequences of ATP7A malfunction. Despite normal levels of PAM protein, levels of several amidated peptides were reduced in pituitary and brain extracts of Atp7a mice, demonstrating that PAM function is compromised when ATP7A is inactive. Based on these results, we conclude that a reduction in the ability of PAM to produce bioactive end-products involved in neuronal growth and development could contribute to many of the biological effects associated with Menkes disease.
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PMID:Menkes protein contributes to the function of peptidylglycine alpha-amidating monooxygenase. 1248 45

We have previously shown that Kupffer cells (KCs) of Rana esculenta L. possess melanogenic ability. The melanogenic enzyme activities in these cells are different from those described in skin melanocytes, and very little is known about their regulation by extracellular signalling molecules. In order to study this regulation, we analysed the effects of NDP-MSH on the levels of expression of the tyrosinase gene and on dopa-oxidase activity, using primary cultures of KCs. Incubation of the cells with NDP-MSH increases tyrosinase gene transcription, within the first 24 h of stimulation. To gain insight into the signalling mechanism involved in the cell response to the hormone, KCs in culture were incubated with IBMX or forskolin. These agents mimic the effects of alpha-MSH on melanocytes by increasing the intracellular level of cAMP. The experimental results showed that while the hormonal treatment always activated the KC tyrosinase system, treatment with IBMX or forskolin never did. Therefore, in KCs the tyrosinase-stimulating action of NDP-MSH was not mimicked by cAMP elevating agents. Assays of cAMP levels in cells stimulated with NDP-MSH demonstrated that the hormone does not produce significant increases in intracellular cAMP. On the contrary, forskolin produced significant increases in cAMP starting from 30 min of incubation. These results suggest that tyrosinase induction by melanocortins in KCs is not mediated by the cAMP pathway, and highlight the existence of substantial differences in the hormone signal transduction mechanisms between amphibian KCs and melanocytes or melanoma cells.
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PMID:Melanogenic response of the Kupffer cells of Rana esculenta L to melanocyte stimulating hormone. 1501 1

The CRISPR/Cas system is an efficient genome-editing tool to modify genes in mouse zygotes. However, only the Streptococcus pyogenes Cas9 (SpCas9) has been systematically tested for generating gene-modified mice. The protospacer adjacent motif (PAM, 5'-NGG-3') recognized by SpCas9 limits the number of potential target sites for this system. Staphylococcus aureus Cas9 (SaCas9), with its smaller size and unique PAM (5'-NNGRRT-3') preferences, presents an alternative for genome editing in zygotes. Here, we showed that SaCas9 could efficiently and specifically edit the X-linked gene Slx2 and the autosomal gene Zp1 in mouse zygotes. SaCas9-mediated disruption of the tyrosinase (Tyr) gene led to C57BL/6J mice with mosaic coat color. Furthermore, multiplex targeting proved efficient multiple genes disruption when we co-injected gRNAs targeting Slx2, Zp1, and Tyr together with SaCas9 mRNA. We were also able to insert a Flag tag at the C-terminus of histone H1c, when a Flag-encoding single-stranded DNA oligo was co-introduced into mouse zygotes with SaCas9 mRNA and the gRNA. These results indicate that SaCas9 can specifically cleave the target gene locus, leading to successful gene knock-out and precise knock-in in mouse zygotes, and highlight the potential of using SaCas9 for genome editing in preimplantation embryos and producing gene-modified animal models.
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PMID:Efficient Production of Gene-Modified Mice using Staphylococcus aureus Cas9. 2758 92

One of the first lines of cutaneous defense against photoaging is a) the synthesis of melanin and b) the initiation of an oxidative stress response to protect skin against the harmful effects of solar radiation. Safe and selective means to stimulate epidermal pigmentation associated with oxidative stress defense are; however, scarce. Activation of the melanocortin-1 receptor (MC1R) on epidermal melanocytes represents a key step in cutaneous pigmentation initiation and, additionally, it regulates cellular defense mechanisms like oxidative stress and DNA-repair. Thus, making the activation of MC1R an attractive strategy for modulating skin pigmentation and oxidative stress. In this context, we designed and synthesized pentapeptides that act as MC1R agonists. These peptides bound, with high potency, to MC1R and activated cAMP synthesis in CHO cells expressing human MC1R. Using one lead pentapeptide, we could show that this activation of MC1R was specific as testing the activation of other G-protein coupled receptors, including the MC-receptor family, was negative. In vitro efficacy on mouse melanoma cells showed similar potency as for the synthetic MC1R agonist alpha-melanocyte stimulating hormone (NDP-alpha-MSH). Moreover, we could reproduce this activity in human skin tissue culture. The lead pentapeptide was able to induce ex-vivo protein expression of key melanogenesis markers melanocyte inducing transcription factor (MITF), tyrosinase (TYR), and tyrosinase-related protein 1 (TYRP-1). Concerning oxidative stress response, we found that the pentapeptide enhanced the activation of Nrf2 after UVA-irradiation. Our results make this pentapeptide an ideal candidate as a skin pigmentation enhancer that mimics alpha-MSH and may also have anti-photoaging effects on the skin.
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PMID:Discovery of a Highly Selective MC1R Agonists Pentapeptide to Be Used as a Skin Pigmentation Enhancer and with Potential Anti-Aging Properties. 3181 32