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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variant of B-16 F1 mouse melanoma was selected for its ability to survive and replicate in the presence of melanocyte-stimulating hormone (MSH). Although the variant (MR-4) was completely resistant to growth inhibition of MSH, cyclic AMP was still able to block cell replication. Tyrosinase activity in MR-4 cells was considerably lower than in B-16 F1 cells. MSH induced a two fold to three-fold increase in tyrosinase activity in both cell types, but the absolute activity in MR-4 remained significantly less than in the parental cells. MR-4 cells were also found to have a markedly depressed cyclic AMP-dependent protein kinase activity relative to B-16 F1 cells. The protein kinase from both cell types was stimulated by cyclic AMP, but the level of MR-4 kinase activity at maximal cyclic AMP concentrations remained considerably lower than B-16 F1 kinase activity under the same conditions. In both cell types adenylate cyclase activity was markedly stimulated by MSH. When equal numbers of viable F1 and MR-4 cells were injected subcutaneously into C57/B1 mice, the MR-4 cells formed tumors earlier and killed the host sooner than the parental F1 cells. We conclude that the biochemical alteration which allows MR-4 cells to replicate in the presence of MSH is a low level of tyrosinase activity, which in turn may be the result of low cyclic AMP-dependent protein kinase activity.
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PMID:Isolation and characterization of a variant of B16-mouse melanoma resistant to MSH growth inhibition. 23 92

Staurosporine, a protein kinase (PK) inhibitor, phorbol-12-myristate-13-acetate (PMA), a PKC activator and A23187 calcium ionophore were added to human melanocyte cultures with or without dibutyryl cyclic AMP (dbcAMP). After 2 days' incubation, changes in various melanogenic factors were examined such as tyrosinase activity and the amount of tyrosinase-related protein (TRP) as well as the morphology of the melanocytes. dbcAMP stimulated all the melanogenic factors. Staurosporine increased tyrosinase activity and amount of TRP and caused morphological changes with the formation of numerous dendrites, regardless of the presence of dbcAMP. In contrast, PMA did not significantly affect tyrosinase activity, TRP content or dendrite formation, with or without dbcAMP. The effects of staurosporine on tyrosinase activity and TRP content were completely inhibited by PMA, but PMA did not significantly affect the staurosporine-induced morphological changes. A23187 inhibited both tyrosinase activity and TRP content, regardless of the presence of dbcAMP, but did not affect the morphology of melanocytes. These findings suggest that tyrosinase activity and TRP content are regulated by adenylate cyclase and Ca2+ and partly by PKC, while the morphological features of melanocytes are affected by intracellular cAMP accumulation and by the inhibition of PKC.
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PMID:Effects of staurosporine, PMA and A23187 on human melanocyte cultures with dibutyryl cyclic AMP. 131 Nov 91

Expression of tyrosinase in Streptomyces requires functional MelC1 protein, which is postulated to transfer copper to apotyrosinase. We have previously isolated a mutant of Streptomyces lividans, HT32, that phenotypically suppressed mutations in cloned melC1 (H.-C. Tseng and C. W. Chen, in preparation). Plasmid pLUS132, containing an ATG to ATA transition at the initiation codon of melC1, was used for cloning the suppressor gene from HT32. A 1687 bp suppressor DNA was isolated that contained two characteristic Streptomyces coding sequences: a 217-amino-acid open reading frame (cutR) and a truncated open reading frame (cutS) downstream. Subcloning analysis attributed the phenotypic suppression activity to the putative cutR gene from HT32. The putative CutR exhibited similarity to the response regulator OmpR of the osmoregulatory signal-transduction system in Escherichia coli. The truncated CutS resembled, to a lesser degree, the N-terminus of EnvZ, the histidine protein kinase counterpart of OmpR. DNA hybridizing to the cloned cutR-cutS sequence was detected in 16 other Streptomyces species. We postulate that the putative cutR-cutS operon regulates copper metabolism in Streptomyces.
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PMID:A cloned ompR-like gene of Streptomyces lividans 66 suppresses defective melC1, a putative copper-transfer gene. 195 95

Tyrosinase activity increased in Cloudman S-91 mouse melanoma cell homogenates incubated at 37 degrees C for a minimum of 8 h. Enzyme activity continued to increase for 48 h at which time the maximal level of activation was observed. Activation did not occur at 4 degrees C and did not occur in the cytosol fraction of the cell, suggesting that the response was localized to melanosomes. The activated enzyme was resistant to solubilization with the nonionic detergent, Triton X-100, and preparation of homogenates in this detergent did not inhibit the temperature-dependent activation of the melanosomal fraction of the cell. The activation process increased the Vmax of tyrosinase 10-fold and lowered the Km by a factor of 2 as determined by the tyrosine hydroxylase assay. The increase in tyrosinase activity was detectable by three assay methods: tyrosine hydroxylation, melanin synthesis, and by tyrosine decarboxylation. The formation of melanin, however, was found to be 1/20 that of either tyrosine hydroxylation or decarboxylation, a finding which suggests that the melanin pathway may be blocked at 5,6-dihydroxyindole. The "self-activation" response could not be mimicked by incubating cell homogenates with cyclic AMP-dependent protein kinase. Activated tyrosinase could be inhibited by the addition of fresh cell extracts, a finding which suggests that tyrosinase inhibitors may be present in these cells.
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PMID:Activation of tyrosinase in mouse melanoma cell cultures. 288 48

Melanin is specifically produced in melanocytes. The pathway for melanin biosynthesis is regulated by a number of melanocyte-specific proteins, including tyrosinase and tyrosinase-related protein-1 (TRP-1, b locus protein). To understand the regulation of melanogenesis, we examined tyrosinase activities, mRNA levels of tyrosinase and TRP-1, and eumelanin and pheomelanin contents in mouse B16-F1 melanoma cells after they had been treated with some melanotropic reagents. Cholera toxin, alpha-melanocyte-stimulating hormone, and dibutyryl cyclic AMP increased tyrosinase activity and stimulated eumelanin biosynthesis. These reagents elevated intracellular cAMP levels. In contrast, 12-O-tetradecanoylphorbol 13-acetate reduced tyrosinase activity and eumelanin synthesis. In all cases, the mRNA levels of tyrosinase and TRP-1 changed in parallel with tyrosinase activity and eumelanin content. TRP-1 was induced simultaneously with tyrosinase, although its inducibility was lower than that of tyrosinase. These results suggest that the expressions of tyrosinase and TRP-1 genes are coordinately regulated by melanotropic reagents through cAMP-dependent protein kinase and protein kinase C in mouse B16-F1 cells, and that their coordinate expression causes eumelanin biosynthesis.
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PMID:Eumelanin biosynthesis is regulated by coordinate expression of tyrosinase and tyrosinase-related protein-1 genes. 768 98

A 64-kDa protein was purified from an octyl glucoside/cholate extract of spinach thylakoids. N-Terminal analysis yielded 23 residues of sequence, of which the first 15 were identical to a sequence reported [Gal, A., Herrmann, R. G., Lottspeich, F., & Ohad, I. (1992) FEBS Lett. 298, 33-35] for a protein kinase with specificity toward the photosystem II light-harvesting complex (LHC-II). We report the complete sequence of this 64-kDa protein, deduced from cDNA clones. The transit peptide has a chloroplast import signal at the N-terminus and a C-terminal hydrophobic span bounded by basic amino acids that predicts localization of the protein to the thylakoid lumen. The mature protein sequence is about 50% identical to several polyphenol oxidases (PPOs). Canonical protein kinase motifs are absent, as are sequences characteristic of ATP-binding sites. The mature protein resembles arthropodan hemocyanin (Hc), possessing three major domains. The N-terminal domain is rich in cysteine residues and predicted alpha-helices. The central domain has a conserved motif, N-terminal to a presumptive Cu-A site, that is not found in tyrosinases or Hc and is proposed as the provider of a third imidazole ligand to Cu-A. An unusual 13-residue, glutamine-rich link begins a C-terminal domain containing 7 predicted beta-strands which, by analogy with Hc, may form an antiparallel beta-barrel. We conclude that this 64-kDa polypeptide is a lumenal PPO and the precursor of a 42.5-kDa PPO form described previously [Golbeck, J. H., & Cammarata, K. V. (1981) Plant Physiol. 67, 977-984].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Spinach thylakoid polyphenol oxidase: cloning, characterization, and relation to a putative protein kinase. 779 29

Melanogenesis in melanoma cells can be enhanced by psoralens in the absence of UV light. Melanin biosynthesis is regulated by a number of melanocyte-specific proteins, including tyrosinase, DOPAchrome tautomerase (DCT), and tyrosinase-related protein-1 (TRP-1, gp75). To get more insight on the molecular mechanisms involved in psoralens-induced melanogenesis, we determined tyrosinase and DCT activities as well as mRNA and protein levels of tyrosinase, DCT, and TRP-1 in S91 mouse melanoma cells treated by 5-MOP. High concentration of 5-MOP (5 x 10(-5) M) induced a time-dependent increase of tyrosinase activity and melanin content, which was correlated to an increase of both mRNA and protein levels of tyrosinase. These results demonstrate that the 5-MOP stimulation of melanogenesis is related to increased tyrosinase synthesis. In addition, 5-MOP stimulated TRP-1 synthesis and induced a dose-dependent decrease of DCT activity without any modification in the expression of the protein. We explored then the signalling pathways involved in 5-MOP-induced melanogenesis and, particularly, the role of cyclic AMP and protein kinase C (PKC). A small stimulation of cyclic AMP production was observed in presence of 5-MOP. Furthermore, 1-oleoyl-2-acetylglycerol (OAG), a PKC activator, potentiated the 5-MOP stimulation of tyrosinase activity, while calphostin, a specific PKC inhibitor, inhibited the 5-MOP induction of tyrosinase activity. Phorbol-myristate acetate (PMA), described as a strong activator of PKC, inhibited also the effect of 5-MOP when used at long term. Taken together, these results demonstrate that in murine melanoma cells 5-MOP stimulates melanogenesis by increasing activity and synthesis of tyrosinase. Tyrosinase and TRP-1 expression are coordinately regulated by 5-MOP. Furthermore, a negative correlation between melanogenesis and DCT activity was observed under 5-MOP stimulation. At least, PKA and PKC systems appear to play an important role in the melanogenic effect of 5-MOP.
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PMID:Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in murine melanoma cells. 785 73

The melanocyte-stimulating hormone (alpha-MSH) used at 10(-6)-5 x 10(-8) M concentrations inhibited the growth of amelanotic cells of human malignant melanoma BRO and influenced cell morphology without any effect on melanization or tyrosinase activity. Inhibition of tumour cell growth was accompanied by marked elevation of intracellular cAMP levels but not that of cGMP. Dibutyryl-cAMP and the cAMP-dependent protein kinase A inhibitor also inhibited the cell growth. alpha-MSH increased mono-, di- and 1.4.5-myoinositol triphosphate concentrations and influenced the activities of phosphatidylinositol kinase and phosphatidylinositol-4-phosphate kinase determining phosphatidylinositol-4-phosphate kinase and phosphatidylinositol-4.5-diphosphate levels. Myoinositol phosphate concentrations changed on a second scale and levelled off by the 3rd-5th min, whereas that of cAMP increased drastically by the 30th min.
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PMID:[Melanocyte-stimulating hormone induces growth of human malignant melanoma amelanotic cells with a change in cAMP, phosphatidylinositols, and inositol phosphate concentration]. 838 47

In melanocytes and in melanoma cells, cyclic AMP (cAMP)-elevating agents stimulate melanogenesis and increase the transcription of tyrosinase, the rate-limiting enzyme in melanin synthesis. However, two other enzymes, tyrosinase-related protein 1 (TRP1) and TRP2, are required for a normal melanization process leading to eumelanin synthesis. In B16 melanoma cells, we demonstrated that stimulation of melanogenesis by cAMP-elevating agents results in an increase in tyrosinase, TRP1, and TRP2 expression. cAMP, through a cAMP-dependent protein kinase pathway, stimulates TRP1 and TRP2 promoter activities in both B16 mouse melanoma cells and normal human melanocytes. Regulation of the TRP1 and TRP2 promoters by cAMP involves a M box and an E box. Further, a classical cAMP response element-like motif participates in the cAMP responsiveness of the TRP2 promoter, demonstrating that the TRP2 gene is subjected to different regulatory processes, which could account for its different expression patterns during embryonic development or under specific physiological and pathological conditions. We also found that microphthalmia, a basic helix-loop-helix transcription factor, strongly stimulates the transcriptional activities of the TRP1 and TRP2 promoters, mainly through binding to the M boxes. Additionally, we demonstrated that cAMP increases microphthalmia expression and thereby its binding to TRP1 and TRP2 M boxes. These convergent and compelling results disclose at least a part of the molecular mechanism involved in the regulation of melanogenic gene expression by cAMP and emphasize the pivotal role of microphthalmia in this process.
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PMID:Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia. 944 65

The polyether toxin, bistratene A, induced morphological and functional differentiation of a human melanoma cell line (MM96E). The cells became blocked at the G2/M transition and elaborated a number of processes. Tyrosinase activity and melanin content were substantially increased. Northern blot analysis showed up-regulation of mRNA for several genes known to be involved in melanin biosynthesis (pmel17, pmel34, and tyrosinase related proteins, TRP-1 and TRP-2). Bistratene A induced the phosphorylation of several proteins as assessed by 2D gel electrophoresis and one of these was identified as stathmin (oncoprotein 18), a cell-cycle regulated phosphoprotein. Bistratene A specifically induced the translocation of protein kinase Cdelta (PKCdelta) from a soluble to a particulate fraction without affecting other isoforms. These results implicate a role for protein kinase Cdelta in the induction of differentiation of this human melanoma cell line.
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PMID:Stimulation of melanogenesis in a human melanoma cell line by bistratene A. 963 6


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