Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pineal hormone, melatonin (5-methoxy N-acetyltryptamine) induces a rapid aggregation of melanin-containing pigment granules in isolated melanophores of Xenopus laevis. Treatment of melanophores with activators of protein kinase C (PKC), including phorbol esters, mezerein and a synthetic diacylglycerol, did not affect pigment granule distribution but did prevent and reverse melatonin-induced pigment aggregation. This effect was blocked by an inhibitor of PKC, Ro 31-8220. The inhibitory effect was not a direct effect on melatonin receptors, per se, as the slow aggregation induced by a high concentration of an inhibitor of cyclic AMP-dependent protein kinase (PKA), adenosine 3',5'-cyclic monophosphothioate, Rp-diastereomer (Rp-cAMPS), was also reversed by PKC activation. Presumably activation of PKC, like PKA activation, stimulates the intracellular machinery involved in the centrifugal translocation of pigment granules along microtubules. alpha-Melanocyte stimulating hormone (alpha-MSH), like PKC activators, overcame melatonin-induced aggregation but this response was not blocked by the PKC inhibitor, Ro 31-8220. This data indicates that centrifugal translocation (dispersion) of pigment granules in Xenopus melanophores can be triggered by activation of either PKA, as occurs after alpha-MSH treatment, or PKC. The very slow aggregation in response to inhibition of PKA with high concentrations of Rp-cAMPS, suggests that the rapid aggregation in response to melatonin may involve multiple intracellular signals in addition to the documented Gi-mediated inhibition of adenylate cyclase.
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PMID:Protein kinase C activation antagonizes melatonin-induced pigment aggregation in Xenopus laevis melanophores. 133 61

The involvement of the calcium messenger system in the control of steroidogenesis in the rat and bovine adrenal cortex has been studied extensively. However the role of these second messengers in the control of human adrenocortical function is not established. This was therefore studied by incubating collagenase-dispersed human adrenocortical cells with the calcium ionophore A23187 and the protein kinase C activator phorbol 12-myristate 13-acetate (TPA). The effects of the calcium channel blocker verapamil on basal and stimulated steroidogenesis were also studied. Both TPA (1 pmol/l-10 mumol/l) and A23187 (1 nmol/l-10 mumol/l) caused a dose-dependent increase in cortisol, aldosterone and corticosterone production. Verapamil (10 mumol/l) inhibited the increase in aldosterone, corticosterone and cortisol produced in response to ACTH(1-24), potassium, and desacetyl-alpha MSH. Unlike previous results in the rat, these effects were not specific for aldosterone secretion. The results suggest that, as in other species, calcium mobilization and protein kinase C activation have a role in the control of steroidogenesis in the human adrenal cortex. However, in contrast to the rat, these mechanisms appear to be involved in the control of steroidogenesis in both the zona glomerulosa and inner zone cells.
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PMID:Control of steroidogenesis by the calcium messenger system in human adrenocortical cells. 201 56

We show that Cloudman melanoma cells undergo rapid arborization in response to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone, a potent analogue of alpha-melanocyte stimulating hormone (alpha-MSH). The arbors were established by extension of processes and resembled dendrites. We used this system to study the regulation of cell shape. alpha-MSH is known to induce increases in cAMP levels, and agents such as forskolin and isobutylmethylxanthine that led to increased cAMP also caused arborization. However, equally dramatic arbors were formed after incubation with the protein kinase C inhibitor H-7 [1-(5-isoquinolinesulfonyl)-alpha-methyl-piperazine]. Phorbol diesters that activate protein kinase C led to cell rounding and antagonized alpha-MSH. The actions of protein kinase C cannot be rationalized in terms of indirect effects on cAMP: neither H-7 nor phorbol diesters alone altered cAMP levels, nor did they affect the increase in cAMP induced by MSH. We show also that MSH produced longer-term effects that cannot be mimicked by cAMP. Specifically, even in the continued presence of alpha-MSH, arborization was followed by morphological reversal to the unstimulated flattened configuration within 2 hr. (This did not occur with other agents that increase cAMP or with H-7.) Most importantly, whereas MSH-induced arborization occurred in the presence of cycloheximide, actinomycin D, or in enucleated cells, the reversal of arborization did not. Thus, MSH induced a program of rapid shape change that was dependent on new protein synthesis and gene transcription.
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PMID:Regulation of cell shape in the Cloudman melanoma cell line. 303 40

Human melanocytes, maintained on bovine corneal endothelium-derived extracellular matrix for at least 4 days in the absence of phorbol 12-myristate 13-acetate (PMA) and cholera toxin (CT), displayed increased tyrosinase activity when exposed to several pro-opiomelanocortin-derived (POMC) peptides. Melanocytes from 9 of 14 donors showed significantly increased tyrosinase activity after treatment with adrenocorticotropic hormone (ACTH; mean increase 320 +/- 107 (S.E.M.)% of control, P < 0.005), while melanocytes from 8 of 13 donors increased tyrosinase in the presence of diacetyl-melanocyte stimulating hormone (di-MSH; mean increase 223 +/- 31 (S.E.M.)% of control, P < 0.005). Maximal increases in tyrosinase were seen after treatment with 10(-10) M ACTH and with 10(-6) M di-MSH. In two cell cultures which showed tyrosinase stimulation, melanin synthesis was similarly increased in the presence of added POMC peptides. PMA but not CT increased tyrosinase activity in melanocytes cultured under these conditions. In the presence of staurosporine, an inhibitor of protein kinase C (PKC), the magnitude of the increase in tyrosinase due to PMA, ACTH and di-MSH was significantly reduced. These results indicate that tyrosinase activity in melanocytes from most human donors, under appropriate conditions, is susceptible to the stimulatory effects of POMC peptides, that ACTH is considerably more potent than di-MSH in this test system and that in human cells the PKC pathway may be important in modulating melanogenesis.
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PMID:Stimulation of tyrosinase in human melanocytes by pro-opiomelanocortin-derived peptides. 759 39

A mouse genomic clone named HGMP01B has been isolated by homology screening with a probe representing part of the human melanocortin 3 receptor gene. HGMP01B was found to encode a 325 amino acid protein with all the landmarks of G-protein-coupled receptors and belonging to the growing melanocortin receptor family. This receptor displays four potential sites for N-linked glycosylation and five potential sites of phosphorylation by protein kinase C. The HGMP01B gene was found to be expressed in many tissues, including skin, adrenal gland, skeletal muscle, bone marrow, spleen, thymus, gonads, uterus, and brain. A stable Chinese hamster ovary (CHO) cell line expressing approximately 10,000 receptors per cell was established. This cell line displayed a saturable binding capacity for the radioiodinated alpha-melanocyte-stimulating hormone (alpha-MSH) analog [Nle4,D-Phe7]-alpha-MSH (NDP-MSH) with an apparent Kd of 1.47 +/- 0.15 nM. Binding of the labeled ligand was competed for by all melanocortin peptides, except beta-endorphin or corticotropin-like intermediate lobe peptide (CLIP). NDP-MSH was the most powerful competitor, followed by alpha-MSH, adrenocorticotropic hormone (ACTH), beta-MSH, the gamma-MSHs, and ACTH 4-10. Functional assays confirmed that HGMP01B, like other melanocortin receptors, stimulated adenylyl cyclase. The potency order obtained in these cyclic adenosine monophosphate (cAMP) accumulation assays was consistent with that of the binding studies. HGMP01B therefore appears as a fifth melanocortin receptor (MC5), responding mainly to alpha-MSH (EC50 = 1.07 +/- 0.13 nM) and endowed with a pharmacological profile similar to that of the melanocyte MSH (MC1) receptor, but characterized by a broad tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. 816 9

The combined action of cholera toxin (CT)-dependent activation of the adenylate cyclase signaling pathway, stimulation of protein kinase C, and activation of the tyrosine kinase activity of cell surface receptors and proto-oncogene products, have been shown to stimulate melanocyte proliferation. However, natural factors responsible for the optimal stimulation of normal human melanocyte growth, either isolated or co-cultured with keratinocytes, remain largely unknown. alpha MSH (alpha melanocyte stimulating hormone) has previously been shown to bind to murine and human melanoma cells and to stimulate their adenylate cyclase and tyrosinase activity. In contrast, very little is known about the presence and function of alpha MSH receptors in normal human melanocytes. We now report that alpha MSH: (i) binds to normal human melanocytes through a single class of high-affinity receptors; (ii) does not induce per se melanocytes to enter the S-phase of the cell cycle; (iii) does indeed stimulate melanocyte proliferation in a dose-dependent fashion; but its stimulatory effect requires bFGF and/or the activation of protein kinase C.
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PMID:Alpha melanocyte stimulating hormone (alpha MSH) stimulates normal human melanocyte growth by binding to high-affinity receptors. 822 96

We have explored the role of protein kinase C (PKC) in pigmentation induced by alpha-melanocyte stimulating hormone (alpha-MSH). Using the well-studied S91 Cloudman mouse melanoma model system in which 10(-7) M alpha-MSH is known to produce a time-dependent increase in pigmentation, we found an increase in the activity of tyrosinase, the key enzyme in pigmentation, between Days 2 and 6 accompanied by an increase in mRNA and protein levels of tyrosinase, as well as an increase in the level of specifically the beta isoform of PKC. When S91 cells were treated with phorbol dibutyrate, 95% of PKC activity was lost within 48 h and the alpha-MSH-induced melanogenesis was completely blocked, as was the induction of tyrosinase mRNA and protein. Serially passaged S91 cells no longer capable of responding to alpha-MSH had an undetectable level of PKC-beta, although the tyrosinase protein level was identical to that of alpha-MSH-responsive cells. Furthermore, in these S91 cells alpha-MSH also did not increase the level of tyrosinase mRNA. Thus, induction of murine melanogenesis by alpha-MSH involves up-regulation of tyrosinase mRNA and protein mediated in part by the PKC-dependent pathway, associated with an up-regulation of the beta isoform previously demonstrated to specifically activate tyrosinase in human melanocytes.
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PMID:Alpha-melanocyte stimulating hormone-induced pigmentation is blocked by depletion of protein kinase C. 880 53

In the amphibian Xenopus laevis, adaptation of the skin color to background light intensity is regulated by alpha-melanophore-stimulating hormone (alpha-MSH), a proopiomelanocortin (POMC)-derived peptide. In animals adapted to a white background, the level of POMC biosynthesis in the intermediate pituitary is much lower than in animals adapted to a black background. Release of alpha-MSH from neurointermediate lobes of white-adapted animals is stimulated in vitro by the regulatory peptides sauvagine and thyrotropin-releasing hormone (TRH), which are produced in the magnocellular nucleus of the hypothalamus. To study the role of sauvagine, cAMP, TRH and phorbol 12-myristate 13-acetate (PMA) in the regulation of POMC biosynthesis, the degree of incorporation of radioactive amino acids into the POMC protein was determined after treatment of the neurointermediate lobes with these secretagogues. When lobes of white-adapted animals are incubated in vitro, biosynthetic activity spontaneously increases because hypothalamic inhibitory control is removed by dissection. In addition to this control situation, the effects of secretagogues were tested on lobes with an inhibited level of biosynthesis, which is achieved by addition of neuropeptide Y (NPY) to the incubation medium. After 24 h of treatment, TRH stimulated POMC biosynthesis in NPY-inhibited lobes of white-adapted animals from 40.2 to 95.3% of control level. This stimulation could not be reduced by adding PMA, which indicates that protein kinase C is not involved in the stimulation of POMC biosynthesis by TRH. Sauvagine partially restored POMC biosynthesis from 27.2 to 62.5% of control level, whereas 8-Br-cAMP completely counteracted NPY inhibition from 27.8 to 97.5% of control level. After 3 days of treatment, stimulation by sauvagine and 8-Br-cAMP was maintained (sauvagine increased POMC biosynthesis in NPY-inhibited lobes from 7.4 to 36.2% of control level and 8-Br-cAMP stimulated from 6.5 to 82.5% of control level). TRH had no effect on POMC biosynthesis after 3 days of treatment, although its receptor was still functional as was shown in superfusion experiments where TRH stimulated alpha-MSH secretion. The observations indicate that the neuropeptides sauvagine and TRH differently control POMC biosynthesis in the Xenopus intermediate pituitary. This differential regulation is not only apparent with regard to time aspects (sauvagine has a sustained regulatory function, whereas TRH is only effective in the initial phase of POMC biosynthesis stimulation), but also an uncoupling of biosynthetic and release processes could be shown for TRH, which did not occur with sauvagine.
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PMID:Sauvagine and TRH differentially stimulate proopiomelanocortin biosynthesis in the Xenopus laevis intermediate pituitary. 926 7

Administration of gamma-2-melanocyte stimulating hormone (gamma-2-MSH) to rats increases blood pressure, heart rate and natriuresis by acting through the nervous system and this response is more pronounced in spontaneous hypertensive rat (SHR). The molecular mechanisms underlying these effects are unknown, however, protein kinase C (PKC) activity is higher in SHR tissues and melanocortins are known to activate the phosphoinositide (PI) signaling pathway. In this study, we tested the hypothesis that gamma-2-MSH potentiation of PKC activation is increased in nerve terminals from SHR brain. Synaptosomes were isolated from SHR and age-matched control Wistar Kyoto (WKY) rats and incubated with gamma-2-MSH. Total particulate-fraction associated PKC activity was determined and the expression of individual isozymes analyzed by immunoblotting. Treatment with gamma-2-MSH resulted in an increase in particulate-associated PKC activity in hindbrain synaptosomes that was more prominent in SHR. The levels of membrane-associated PKC-alpha and beta-isozymes were considerably less than for PKC-gamma in these tissues as determined by immunoblotting. The novel PKC isozymes delta and epsilon were detected in total synaptosomes but not in membrane fractions. These data suggest that PKC-gamma is the major presynaptic PKC isozyme and that PKC may be an important mediator for gamma-2-MSH in neural tissues.
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PMID:Effects of gamma-2-melanocyte-stimulating hormone on protein kinase C activity and expression in spontaneous hypertensive rats (SHR). 1178 59

The aim of this study is to investigate the regulation of the human melanocortin 1 receptor (MC1R) expression in cultured normal human melanocytes (NHM) by specific paracrine and endocrine factors, and by ultraviolet radiation (UVR). Treatment of NHM with alpha-melanotropin [alpha-melanocyte stimulating hormone (alpha-MSH)] increased MC1R mRNA level; the response was often more pronounced in NHM with a low (NHM-c) than in NHM with a high melanin content (NHM-b). Endothelin-1 increased MC1R mRNA level in NHM regardless of their melanin content. Basic fibroblast growth factor consistently up regulated MC1R mRNA level in NHM-b but not in NHM-c. Activation of protein kinase C by 12-0-tetradecanoylphorbol-13-acetate slightly increased, while stimulation of adenylate cyclase by forskolin markedly up-regulated the MC1R mRNA level. beta-Estradiol increased, and combined treatment with beta-estradiol and alpha-MSH further elevated, MC1R mRNA level in NHM-c and NHM-b. Testosterone reduced, while progesterone had no effect on, MC1R mRNA level. Agouti signaling protein reduced, and UVR down regulated dose-dependently MC1R mRNA level in NHM-b and NHM-c. This effect was reversed 24 h after irradiation with the lower doses of 7 or 14 mJ/cm2, but not after exposure to a higher, more cytotoxic dose of UVR. We conclude that the MC1R is regulated by paracrine factors, including its own ligands, by specific endocrine sex hormones, and by UVR. Differences in the responses of NHM to some of these factors suggest differential regulation of MC1R gene expression, which may contribute to the variation in constitutive and UV-induced cutaneous pigmentation in humans.
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PMID:Regulation of the human melanocortin 1 receptor expression in epidermal melanocytes by paracrine and endocrine factors and by ultraviolet radiation. 1245 85


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