Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effects of various gangliosides on in vitro growth of human metastatic melanoma WM266-4. GD1b, GT1b, and GQ1b inhibited 3H-thymidine uptake and growth rate of WM266-4 whereas the other gangliosides were ineffective. The growth inhibition by GD1b, GT1b, and GQ1b was counteracted by interleukin-8 but not by the other growth factors. The growth inhibition by gangliosides was not detected in the presence of anti-interleukin-8 antibody. GD1b, GT1b, and GQ1b reduced the constitutive interleukin-8 secretion and mRNA levels in WM266-4. Transient transfection showed that GD1b, GT1b, and GQ1b inhibited the constitutive chloramphenicol acetyltransferase expression driven by interleukin-8 promoter in WM266-4. Transfection with a series of 5'-deleted mutants demonstrated that the sequences between -98 and -62 bp on interleukin-8 promoter may be involved in the transcriptional repression by these gangliosides. Cyclic AMP analog dibutyryl cAMP counteracted GD1b, GT1b, and GQ1b-induced inhibition of interleukin-8 production at the levels of protein secretion, mRNA expression, and promoter activity. GD1b, GT1b, and GQ1b reduced cAMP level and protein kinase A activity in WM266-4. These gangliosides suppressed adenylate cyclase activity without altering that of cyclic nucleotide phosphodiesterase in WM266-4. The data indicate that GD1b, GT1b, and GQ1b may suppress the growth of melanoma by inhibiting interleukin-8 production via the inhibition of adenylate cyclase.
J Invest Dermatol 2001 Aug
PMID:Gangliosides GD1b, GT1b, and GQ1b suppress the growth of human melanoma by inhibiting interleukin-8 production: the inhibition of adenylate cyclase. 1151 6

Radiation-recall dermatitis is the occurrence, with subsequent administration of cytotoxic chemotherapy, of an acute inflammatory toxicity in a previously quiescent radiation field. It may occur from days to weeks, and sometimes years, after the radiation therapy. The precise mechanism is unknown. One hypothesis suggests that the initial radiation therapy leads to a depletion of tissue stem cells within the irradiated field and that subsequent cytotoxic chemotherapy exposure causes a 'remembered' reaction among the remaining surviving cells. An alternative proposition suggests that radiation induces heritable mutations within surviving cells, which then produce a subgroup of defective stem cells that are unable to tolerate the second insult of chemotherapy. Recently, ataxia telangiectasia gene mutation and protein kinase deficiency have been associated with patients who have increased susceptibility to severe radiation-induced skin toxicity. Most of the lesions will heal with supportive treatment. Although some reports have noted that radiation-recall dermatitis recurred with subsequent continued administration of the same chemotherapeutic agent, such experience is not universal. At present, a decision as to whether the same chemotherapeutic agent can be continued will usually be determined by the severity of the initial reaction, the chemoresponsiveness of the tumor to this particular agent, the individual patient's wishes, and a clinical judgment that takes into account the availability of alternative therapy.
Am J Clin Dermatol
PMID:Radiation-recall skin disorders associated with the use of antineoplastic drugs. Pathogenesis, prevalence, and management. 1170 10

Human skin is exposed to an environment that varies in humidity from 100 to 0%, leading to seasonal variations in the condition of the skin. Exposure to a low humidity environment creates an osmotic gradient across the stratum corneum, which is known to modulate cutaneous barrier function. Heat shock proteins protect against stress-induced destabilization of proteins. We investigated whether osmotic shock (sorbitol) induced a heat shock protein response in normal human keratinocytes, and used heat shock as a positive control. Both heat shock and osmotic stress (200 and 300 mM sorbitol) clearly induced heat shock proteins 70 and 27 mRNA levels. The induction of heat shock protein 70 mRNA levels by osmotic stress peaked at 16 h and persisted until 24 h, whereas upregulation of heat shock protein 70 mRNA levels by heat peaked at 2 h and returned to baseline levels by 6 h. Sorbitol also increased heat shock protein 70 levels in a concentration-dependent manner. The kinetics of heat shock protein 27 mRNA induction by osmotic stress and heat were similar with peak induction at 6 h. The mitogen activated protein kinase family of proteins plays an important part in the coordination of gene responses to various stress conditions. We have demonstrated that the p38 mitogen activated protein kinase was strongly activated by 200 mM and 300 mM sorbitol. The specific p38 mitogen activated protein kinase inhibitor PD169316 almost completely blocked heat shock protein 70 mRNA induction by 200 mM and 300 mM sorbitol and completely suppressed heat shock protein 27 mRNA induction with 200 mM sorbitol. PD169316 also counteracted upregulation of heat shock protein 70 levels by sorbitol. These data indicate that keratinocytes respond to osmotic stress by p38 mitogen activated protein kinase regulated induction of heat shock proteins. This molecular pathway may be relevant for the mechanisms regulating the response of human skin to variations in environmental humidity.
J Invest Dermatol 2001 Nov
PMID:Human keratinocytes respond to osmotic stress by p38 map kinase regulated induction of HSP70 and HSP27. 1171 Sep 46

We previously reported that histamine induced melanogenesis in cultured human melanocytes and that the stimulatory effect was mediated by protein kinase A activation via H2 receptors. It is well-known that ultraviolet B irradiation causes acute inflammation, known as erythema, and subsequent pigmentation, and there are several reports demonstrating an elevation of the histamine levels in ultraviolet B-irradiated skin. Thus, to evaluate the involvement of histamine in ultraviolet B-induced skin pigmentation, we examined the effect of an H2 antagonist in brownish guinea pig skin. Daily exposure to 200 mJ per cm2 ultraviolet B for 3 d evoked erythema and subsequent pigmentation in the skin samples tested. Moreover, a remarkable increase in dopa-positive melanocytes was observed in the pigmented area, which showed an increase in melanin synthesis. Topical application of famotidine, an H2 antagonist, significantly reduced pigmentation and moderated the increase of dopa-positive melanocytes in the ultraviolet B-irradiated skin. Even when the initiation of famotidine application was delayed to day 2 after irradiation, an inhibitory activity on ultraviolet B-induced pigmentation was observed; however, the ultraviolet B-induced erythema was not suppressed by topically applied famotidine. Thus, we concluded that histamine is involved in ultraviolet B-induced pigmentation and that famotidine suppressed the pigmentation by the prevention of histamine binding to H2 receptors in melanocytes but not by prevention of ultraviolet B permeability and inflammation.
J Invest Dermatol 2002 Feb
PMID:Histamine is involved in ultraviolet B-induced pigmentation of guinea pig skin. 1184 41

In normal human melanocytes various mitogens activate the mitogen-activated protein kinases ERK1/2 and the downstream transcription factor CREB (Ca2+/cAMP response element binding protein). Endothelin-1, basic fibroblast growth factor, and alpha-melanotropin interact synergistically to stimulate human melanocyte proliferation. The former two mitogens phosphorylated ERK1/2, its substrate p90rsk, and CREB. Alpha-melanotropin, forskolin, or dibutyryl cAMP failed to phosphorylate any of those targets, however. The concomitant presence of endothelin-1, basic fibroblast growth factor, and alpha-melanotropin significantly potentiated CREB phosphorylation. The mitogen-induced phosphorylation of p90rsk and CREB was dependent on ERK1/2 activation, and was mediated by intracellular calcium mobilization and by protein kinase C and tyrosine kinase activation, but not by activation of the cAMP-dependent protein kinase A. Exposure of melanocytes to ultraviolet radiation B resulted in the phosphorylation of the stress-induced mitogen- activated protein kinases p38 and JNK/SAPK, but not ERK1/2. Ultraviolet radiation B induced the phosphorylation of CREB via a pathway that was partially dependent on p38, but had no effect on p90rsk or ERK1/2. Therefore, in human melanocytes, CREB is a common downstream target for distinct effectors that are involved in either mitogenic signaling or stress signaling initiated by ultraviolet radiation B.
J Invest Dermatol 2002 Feb
PMID:Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes. 1184 50

The effects of all-trans retinoic acid on the differentiation and proliferation of immature melanocyte precursors were studied. NCC-melb4 cells are an immortal cloned cell line established from mouse neural crest cells using a single-cell cloning method. These cells were positive for tyrosinase-related protein 1, tyrosinase-related protein 2 and KIT, but were negative for tyrosinase and had no dihydroxyphenylalanine reaction. They contained only stage I melanosomes without any melanosomes in more advanced stages. After treatment with all-trans retinoic acid, many of the cells became tyrosinase- and dihydroxyphenylalanine-reaction-positive, changed from polygonal to dendritic in shape, and had stage III to IV melanosomes. These findings indicate that treatment with all-trans retinoic acid induced the differentiation of NCC-melb4 cells. Reverse transcription polymerase chain reaction analysis revealed a marked increase in expression of microphthalmia-associated transcription factor mRNA after all-trans retinoic acid treatment, suggesting that microphthalmia-associated transcription factor may be the key molecule in this event. Enhanced expression of protein kinase Calpha following treatment with all-trans retinoic acid was also demonstrated. The proliferation of NCC-melb4 cells was inhibited by all-trans retinoic acid in a dose-dependent manner. Increased apoptosis after all-trans retinoic acid treatment was observed by electron microscopy, the TUNEL method, DNA fragmentation assay, and flow cytometry. All-trans retinoic acid upregulated caspase-3 and downregulated bcl-2. Electron microscopy showed that apoptotic cells contained melanosomes of advanced stages, suggesting that mature melanocytes may tend to undergo apoptosis after all-trans retinoic acid treatment. This study provides important clues towards understanding the roles and working mechanisms of retinoic acids in melanocyte development and melanogenesis.
J Invest Dermatol 2002 Jan
PMID:All-trans retinoic acid induces differentiation and apoptosis of murine melanocyte precursors with induction of the microphthalmia-associated transcription factor. 1185 73

In some cell systems, the antiproliferative effects of 8-Cl-cAMP, a site-selective cAMP analog specific for the type I cAMP-dependent protein kinase, are mediated by its metabolite, 8-Cl-adenosine. These effects were once thought to be specific to transformed cells. We investigated the ability of 8-Cl-adenosine to regulate growth and differentiation in primary cultures of mouse epidermal keratinocytes. A 24 h exposure of keratinocytes to 8-Cl-adenosine inhibited [3H]thymidine incorporation in a dose-dependent manner with an apparent IC(50) of 7.5 microM, and these effects were completely reversible. To determine the ability of 8-Cl-adenosine to induce differentiation of primary keratinocytes, we measured keratin-1 expression and transglutaminase activity, markers of early and later stages of keratinocyte differentiation, respectively. Interestingly, exposure of keratinocytes to 25 microM 8-Cl-adenosine for 24 h had no effect on keratin-1 expression or transglutaminase activity. The 8-Cl-adenosine-induced growth arrest of keratinocytes required uptake of the compound and was accompanied by an increase in protein expression of the cyclin-dependent protein kinase inhibitor p21(WAF1/Cip1). These results demonstrate that 8-Cl-adenosine inhibits growth in a non-transformed/non-immortalized cell system, possibly through an elevation in p21(WAF1/Cip1) protein levels, without inducing differentiation.
J Invest Dermatol 2001 Dec
PMID:8-Cl-adenosine induces growth arrest without differentiation of primary mouse epidermal keratinocytes. 1188 27

Human keratinocyte motility plays an important role in the re-epithelialization of human skin wounds. The wound bed over which human keratinocytes migrate is rich in extracellular matrices, such as fibrin, fibronectin, and collagen, and serum factors, such as platelet-derived growth factor and transforming growth factor beta 1. Extracellular matrices and the serum factors bind to cell surface receptors and initiate a cascade of intracellular signaling events that regulate cell migration. In this study, we identified an intracellular signaling pathway that mediates collagen- driven motility of human keratinocytes. Pharmaco logic inhibition of the activation of p38-alpha and p38-beta mitogen-activated protein kinase activation potently blocked collagen-driven human keratinocyte migration. Transfection of the same keratinocytes with the kinase-negative mutants of p38-alpha or p38-beta mitogen-activated protein kinase markedly inhibited keratinocyte migration on collagen. Attachment of keratinocytes to collagen activated p38 mitogen- activated protein kinase, as well as p44/p42 ERKs. Interestingly, activation of the p38 mitogen-activated protein kinase cascade by overexpressing the constitutively active MKK3 and MKK6, MKK3b(E) and MKK6b(E), could neither initiate migration in the absence of collagen nor enhance collagen-driven migration. This study provides evidence that the p38-MAPK/SAPK pathway is necessary, but insufficient, for mediating human keratinocyte migration on collagen.
J Invest Dermatol 2001 Dec
PMID:The p38-MAPK/SAPK pathway is required for human keratinocyte migration on dermal collagen. 1188 29

Capacitive calcium influx is associated with the release of calcium from internal stores and participates in intracellular calcium homeostasis. In keratinocytes, its activation is linked to the stimulation of the phospho-inositide (PI) pathway and seems to be altered in psoriasis. An overnight treatment of isolated HaCaT keratinocytes with phorbol 12-myristate 13-acetate (PMA) selectively downregulated the classical, calcium-dependent protein kinase C (PKC) isoenzyme PKC alpha in preconfluent cells. This was parallelled by an increased capacitative calcium influx with no effects on the PI pathway. These observations were strengthened in measurements using cyclopiazonic acid which revealed a 47% increase in PMA pretreated as compared with control cells in the calcium influx rate through store-operated calcium channels (SOC-s) following the emptying of the intracellular calcium stores. In confluent as compared with preconfluent cultures PKC epsilon was markedly increased, while other isoenzymes were not affected. In parallel, the kinetics of capacitative calcium influx were altered, showing clear inactivation. PMA pretreatment in these cells had little effect on PKC alpha but downregulated both PKC beta and PKC epsilon, and did not increase the influx through SOC-s. These observations support the differential regulation of SOC-s by PKC and suggest the involvement of several PKC isoenzymes in human keratinocytes.
Exp Dermatol 2002 Feb
PMID:Effect of protein kinase C on transmembrane calcium fluxes in HaCaT keratinocytes. 1195 25

A cyclic adenosine monophosphate binding abnormality in psoriatic erythrocytes that could be corrected by retinoid treatment has been reported. It was tested whether this binding abnormality is specific for psoriasis and the effects of treatment were compared with etretinate, cyclosporine A, or anthralin on 2-(3)H-8-N(3)-cyclic adenosine monophosphate binding to the regulatory subunit of protein kinase A in erythrocyte membranes. One hundred and fifteen individuals were evaluated, including: (i) 34 healthy persons; (ii) 15 patients with nonatopic inflammatory skin diseases (eczema, erythroderma, tinea, Grover's disease, erysipelas, urticaria); (iii) eight with other dermatoses mediated by immune mechanisms (systemic lupus erythematosus, lichen planus, necrotizing vasculitis, erythema nodosum, systemic sclerosis); (iv) 14 with generalized atopic dermatitis; and (v) 44 with psoriasis vulgaris clinically assessed by Psoriasis Area and Severity Index. In psoriasis, the course of the binding of 2-(3)H-8-N(3)-cyclic adenosine monophosphate to erythrocytes was measured in nine patients during a 10 wk treatment with etretinate, in 21 patients during a 10 wk treatment with cyclosporine A, and one patient under topical treatment with anthralin for 4 wk. We found the following femtomolar binding per mg protein: (i) healthy persons (1064 +/- 124, mean +/- SD); (ii) nonatopic inflammatory skin diseases (995 +/- 103); (iii) immune dermatoses (961 +/- 92); (iv) atopic dermatitis (960 +/- 110); and (v) psoriasis (645 +/- 159; p < 0.0001 compared with nonpsoriatics, Mann-Whitney U test). Treatment of psoriasis with etretinate, cyclosporine A, or anthralin normalized the binding of cyclic adenosine monophosphate, which was inversely correlated to the Psoriasis Area and Severity Index score. It was concluded that the decreased binding of cyclic adenosine monophosphate to protein kinase A in erythrocytes is specific for psoriasis and normalizes after successful treatment.
J Invest Dermatol 2002 Jul
PMID:A highly decreased binding of cyclic adenosine monophosphate to protein kinase A in erythrocyte membranes is specific for active psoriasis. 1216 39


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