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)

The tyrosinase gene is specifically expressed in melanocytes. Understanding the molecular basis of tissue-specific expression of the tyrosinase gene will greatly explain the mechanisms controlling pigmentation. We report a nucleotide sequence, TGATGTATTC, located -236 base pairs upstream of the transcription start site, that enhances tyrosinase gene expression in mouse melanoma cells. The sequence is referred to as the tyrosinase element-1 (TE-1). TE-1 was protected from DNase I cleavage by pigment cell nuclear extracts but was not protected by non-pigment cell nuclear extract. Partial purification of TE-1 binding protein (TEBP-1) was performed from the B16 mouse melanoma cell nuclear extract using biotin-cellulose affinity chromatography. The affinity-purified fraction exhibited binding to the DNA fragment containing TE-1, and to a synthetic oligomer representing TE-1. UV-cross-linking indicated that the size of TEBP-1 is approximately 49 kD. TE-1 also directed enhanced CAT activity in the B16 melanoma cells but not in non-pigment cells. These data indicate that TE-1 may be an enhancer element that is responsible for pigment cell specific expression of the tyrosinase gene.
 ...
PMID:A cis-acting element involved in mouse tyrosinase gene expression and partial purification of its binding protein. 149 37

We have assessed the importance of a melanocyte-specific DNase I hypersensitive site and matrix attachment region situated 15 kb upstream of the mouse tyrosinase gene by analysis in transgenic mice. Transgenes containing all, part, or none of this region linked to the tyrosinase promoter and human tyrosinase cDNA were introduced into genetically albino mice, and pigmentation and transgene message levels were analyzed in the resulting transgenic lines. The effect of the upstream region was to enhance significantly gene expression in melanocytes, and to provide position-independent expression of the transgene. Two exceptions to complete position independence were seen; these lines displayed a mosaic expression pattern in which the transgene was expressed fully in some melanocyte clones but less so in others, resulting in transverse stripes of colours ranging from near white to dark grey. Unexpectedly, pigmentation in the eye of all transgenic lines containing the upstream region was nonuniform, in that the neural-crest-derived melanocytes of the choroid and anterior iris contained significantly more pigment than those derived from the optic cup (retinal pigment epithelium and posterior iris). Transgenes containing a small part or none of the upstream region were expressed poorly and in a position-dependent manner; of those lines that were visibly pigmented, expression was equal in the neural crest and optic-cup-derived cells of the eye.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:A distal tyrosinase upstream element stimulates gene expression in neural-crest-derived melanocytes of transgenic mice: position-independent and mosaic expression. 792 14

The tyrosinase gene is expressed specifically in melanocytes and the cells of the retinal pigment epithelium, which together are responsible for skin, hair, and eye color. By using a combination of DNase I footprinting and band shift assays coupled with mutagenesis of specific DNA elements, we examined the requirements for melanocyte-specific expression of the human tyrosinase promoter. We found that as little as 115 bp of the upstream sequence was sufficient to direct tissue-specific expression. This 115-bp stretch contains three positive elements: the M box, a conserved element found in other melanocyte-specific promoters; an Sp1 site; and a highly evolutionarily conserved element located between -14 and +1 comprising an E-box motif and an overlapping octamer element. In addition, two further elements, one positive and one negative, are located between positions -185 and -150 and positions -150 and -115, respectively. We also found that the basic helix-loop-helix factor encoded by the microphthalmia gene, which is essential for melanocyte differentiation, can transactivate the tyrosinase promoter via the M box and the conserved E box located close to the initiator. Since in vitro assays failed to identify any melanocyte-specific DNA-binding activity, the possibility that the specific arrangement of elements within the basal tyrosinase promoter determines melanocyte-specific expression is discussed.
 ...
PMID:Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator. 796 39

The tyrosinase gene encodes the key enzyme of melanin production and is tightly regulated during development. A yeast artificial chromosome covering the mouse tyrosinase gene has been shown to rescue completely the albino phenotype of recipient mouse strains, conferring copy number-dependent, position-independent expression. To investigate the presence of cis-acting regulatory elements responsible for the appropriate expression of the tyrosinase gene, DNase I hypersensitive site mapping was performed. A melanoma cell-specific DNase I hypersensitive site was identified at -12 kb upstream of the tyrosinase gene. Functional analysis of the corresponding cis-acting element in transgenic mice and transient transfection assays revealed properties of a strong cell-specific enhancer. RNA expression levels of the transgene correlate with copy number, which is reflected in coat colour and eye pigmentation of transgenic mice. Full enhancer activity in transient transfections is obtained with a minimal sequence of 200 bp. Protein binding analysis reveals the presence of a melanoma cell-specific complex which might contribute to the faithful expression of the tyrosinase gene.
 ...
PMID:A cell-specific enhancer far upstream of the mouse tyrosinase gene confers high level and copy number-related expression in transgenic mice. 803 2

We have shown previously that the tyrosinase gene encompassed in a 250 kb yeast artificial chromosome (YAC) is expressed faithfully in transgenic mice. To define the sequences important for this qualitatively and quantitatively correct expression pattern, we have generated transgenic mice with YACs carrying several deletions in the mouse tyrosinase locus. In particular, we wanted to address the in vivo relevance of a regulatory element indicated by a cell-specific DNase I hypersensitive site (HS) located -12 kb upstream of the gene. Wild-type level expression was observed only when the YACs transferred contained this HS. Constructs in which the HS was deleted gave rise to much weaker expression and variable patterns of expression. In conclusion, this HS region appears to harbour the essential regulatory element for the correct expression of the tyrosinase gene. Moreover, it behaves as a locus control region in that it commands the functional status of this expression domain, protecting it from position effects.
 ...
PMID:A locus control region at -12 kb of the tyrosinase gene. 894 25

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.
 ...
PMID:Chromatin configuration during meiosis I prophase of spermatogenesis. 940 97

Locus control regions (LCRs) are complex high-order chromatin structures harbouring several regulatory elements, including enhancers and boundaries. We have analysed the mouse tyrosinase LCR functions, in vitro, in cell lines and, in vivo, in transgenic mice and flies. The LCR-core (2.1 kb), located at -15 kb and carrying a previously described tissue-specific DNase I hypersensitive site, operates as a transcriptional enhancer that efficiently transactivates heterologous promoters in a cell-specific orientation-independent manner. Furthermore, we have investigated the boundary activity of these sequences in transgenic animals and cells. In mice, the LCR fragment (3.7 kb) rescued a weakly expressed reference construct that displays position effects. In Drosophila, the LCR fragment and its core insulated the expression of a white minigene reporter construct from chromosomal position effects. In cells, sequences located 5' from the LCR-core displayed putative boundary activities. We have obtained genomic sequences surrounding the LCR fragment and found a LINE1 repeated element at 5'. In B16 melanoma and L929 fibroblast mouse cells, this element was found heavily methylated, supporting the existence of putative boundary elements that could prevent the spreading of condensed chromatin from the LINE1 sequences into the LCR fragment, experimentally shown to be in an open chromatin structure.
 ...
PMID:Functional dissection of the mouse tyrosinase locus control region identifies a new putative boundary activity. 1457 18

Mutations of the tyrosinase gene produce oculocutaneous albinism type 1 (OCA1). Most affected individuals are compound heterozygotes with different maternal and paternal mutations, but a substantial number of presumed tyrosinase alleles in these individuals have no identifiable mutation in the coding or proximal promoter region of the gene. This suggests that mutations in other regions of the gene, such as regulatory regions that are removed from the direct proximity of the coding sequence, may account for these currently unidentifiable mutations. The mouse tyrosinase gene has a distal enhancer or locus control region (LCR) that provides position-independent stimulation of gene expression, and a homologous regulatory region (HR) of the human gene could be the site of some of these mutations. We report a region 9 kb upstream of the human tyrosinase transcriptional start site that may be involved in regulation of this gene. Analysis of this region shows DNase I hypersensitivity in a cell lineage-specific pattern, a pattern indicative of regulatory regions of a gene. This region also has significant enhancer function when reporter vectors containing it are transfected into either human or mouse melanocyte cell lines, and elimination of specific sequences with homology to the mouse core enhancer in this region extinguishes the enhancer function. We believe that this region of homology contains sequences critical in the regulation of the human tyrosinase gene and is a candidate for the location of OCA1 mutations.
 ...
PMID:Identification and characterization of a DNase hypersensitive region of the human tyrosinase gene. 1462 26