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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The family of human epidermal growth factor receptors (EGFR, HER2-4) exerts key functions in normal and malignant epithelial cells. Both EGFR and HER2 are valuable targets for anti-cancer drugs by interfering with ligand binding, receptor dimerization, or tyrosine kinase activity. A similar therapeutic strategy has been advocated for chronic psoriasis since plaque lesions overexpress EGFR and its ligands. Our aim was to characterize EGFR/HER2 protein expression in skin cultures and to evaluate the effects of tyrosine kinase inhibitors on epidermal outgrowth, morphology, and EGFR activation. Human skin explants were established on cell-free dermis and cultured at the air-liquid interface. The impact of small-molecule HER inhibitors on outgrowth was assayed by fluorescence-based image analysis and histometry. Effects of a dual EGFR/HER2 kinase inhibitor, PKI166, on neoepidermis were studied by immunohistochemistry and Western blot. Receptor immunostaining showed in vivo-like distributions with highest EGFR intensity in the proliferative layers whereas HER2 was mainly expressed by suprabasal keratinocytes. Reepithelialization was associated with EGFR autophosphorylation irrespective of exogenous ligand stimulation. PKI166 inhibited neoepidermal EGFR activation, keratinocyte proliferation, and outgrowth from normal and psoriatic skin explants. The rate of epidermalization in presence of other HER inhibitors varied suggesting that drug specificity, potency, and reversibility determine the dynamic outcome. Overall, agents predominantly targeting EGFR kinase were more efficient inhibitors of epidermal regeneration than an HER2-selective drug. The study illustrates the usefulness of a dynamic skin model and emphasizes the potential of HER-directed approaches to control epidermal growth in hyperproliferative skin disorders.
...
PMID:Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase. 1844 55

Endothelial progenitor cells (EPCs) are a population of bone marrow derived cells which have been attributed with the ability to migrate into areas of tissue ischemia and to posses reparative qualities. EPCs have been shown to be decreased in level and function in various inflammatory disorders. Psoriasis and psoriatic arthritis are associated with an increase in cardiovascular morbidity. The aim of the study was to investigate the number of EPCs among patients suffering from psoriasis and psoriatic arthritis. Patients suffering from active psoriasis and psoriatic arthritis were recruited as well as healthy controls. Disease activity was assessed with the DAS-28, BASDAI and PASI scores. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using the CD34/133 and CD34/KDR. No significant difference was found between numbers of EPCs between healthy controls, patients with psoriasis and psoriatic arthritis. A significant correlation was found between levels of VGEF and the BASDAI score. The results of the current study do not support a significant role for EPCs in the pathogenesis of psoriasis and psoriatic arthritis.
...
PMID:Normal levels and function of endothelial progenitor cells in patients with psoriatic arthritis. 1870 28

The use of molecular targeted therapies currently is on the rise in the treatment of severe diseases, particularly for malignant tumors. The targeted agents show a high specificity against one or more molecular target structures, hereby inhibiting or modifying signal transduction pathways connected to these targets, and thus strongly altering proliferation, activation and interaction of the targeted cells. These manipulations of highly specific signaling pathways are associated with again highly specific side effects, which often affect the skin. These cutaneous reactions present a new spectrum of adverse drug events to the dermatologist. We reviews the cutaneous reactions of molecular targeted agents used in the treatment of psoriasis (alefacept, efalizumab, etanercept, infliximab and adalimumab), as well as agents used in cancer therapy (imatinib, sorafenib, sunitinib, EGFR antagonists and CTLA-4-antagonists).
...
PMID:[Cutaneous reactions to molecular targeted therapies]. 1876 22

Cathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. The mechanism of increased cathelicidin in psoriatic keratinocytes is not known, but recent observations have found that psoriasis has abundant Th17 cells that produce IL-17A and IL-22. We found that human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increased expression of cathelicidin when stimulated in the presence of 1,25-dihydroxyvitamin D(3) (1,25D(3)). This increase was signaled through the IL-17RA. In vitro, IL-17A, but not IL-22, enhanced cathelicidin mRNA and peptide expression in keratinocytes dependent on the presence of 1,25D(3). At the same time, coincubation with 1,25D(3) blocked induction of human beta-defensin 2 (HBD2), IL-6, and IL-8, which are other target genes of IL-17A. Act1, an adaptor associated with IL-17RA and essential for IL-17A signaling, mediated cathelicidin induction, as its suppression by small interfering RNA inhibited HBD2 and cathelicidin. Both, 1,25D(3) and IL-17A signaled cathelicidin induction through MEK-ERK. These results suggest that increased IL-17A in psoriatic skin increases cathelicidin through a vitamin D(3)-, Act1-, and MEK-ERK-dependent mechanism. Therapy targeting this cathelicidin-regulating system might be beneficial in patients suffering from psoriasis.
...
PMID:IL-17A enhances vitamin D3-induced expression of cathelicidin antimicrobial peptide in human keratinocytes. 1905 Feb 68

Psoriasis vulgaris is an autoimmune dermatosis with Th17 infiltration. Prolactin (PRL) may participate in the pathogenesis of psoriasis. The chemokine CCL20 recruits Th17 cells, and CCL20 production by epidermal keratinocytes is enhanced in psoriatic lesions. We examined the in vitro effects of PRL on CCL20 production in human keratinocytes. PRL increased basal and IL-17-induced CCL20 secretion, and mRNA expression in keratinocytes. CCL20 production by PRL was suppressed by antisense oligonucleotides against the AP-1 components c-Fos and c-Jun, whereas that by IL-17 was suppressed by antisense NF-kappaB p50 and p65. CCL20 production induced by PRL plus IL-17 was suppressed by antisense c-Fos, c-Jun, p50, and p65. PRL alone increased the transcriptional activity of AP-1, and c-Fos and c-Jun expression; moderately enhanced NF-kappaB activity and IkappaBalpha phosphorylation; and potently increased IL-17-induced NF-kappaB activity. MEK and JNK inhibitors suppressed PRL- or PRL-plus-IL-17-induced CCL20 production and AP-1 activities. MEK inhibitor suppressed PRL-induced c-Fos expression, whereas JNK inhibitor suppressed c-Jun expression. PRL induced ERK and JNK phosphorylation. These results suggest that PRL may enhance basal and IL-17-induced CCL20 production in keratinocytes by AP-1 and NF-kappaB activation, which is partially mediated via MEK/ERK and JNK. PRL may promote Th17 infiltration into psoriatic lesions via CCL20.
...
PMID:Prolactin enhances basal and IL-17-induced CCL20 production by human keratinocytes. 1935 May 75

The effects of exogenous hydrogen sulfide (H2S) on normal skin-derived immortalized human keratinocytes have been investigated in detail. We show in vitro that exogenous hydrogen sulfide reduces clonal growth, cell proliferation and cell adhesion of human keratinocytes. H(2)S, in fact, decreases the frequency of the putative keratinocyte stem cell subpopulation in culture, consequently affecting clonal growth, and impairs cell proliferation and adhesion of mature cells. As a mechanistic explanation of these effects, we show at the molecular level that (i) H2S reduces the Raf/MAPK kinase/ERK signaling pathway; (ii) the reduced adhesion of sulfur-treated cells is associated to the downregulation of the expression of beta4, alpha2 and alpha6 integrins that are necessary to promote cell adhesion as well as anti-apoptotic and proliferative signaling in normal keratinocytes. One specific interest of the effects of sulfurs on keratinocytes derives from the potential applications of the results, as sulfur is able to penetrate the skin and a sulfur-rich balneotherapy has been known for long to be effective in the treatment of psoriasis. Thus, the relevance of our findings to the pathophysiology of psoriasis was tested in vivo by treating psoriatic lesions with sulfurs at a concentration comparable to that most commonly found in sulfurous natural springs. In agreement with the in vitro observations, the immunohistochemical analysis of patient biopsies showed a specific downregulation of ERK activation levels, the key molecular event in the sulfur-induced effects on keratinocytes.
...
PMID:Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling. 1954 51

Psoriasis is a common inflammatory and hyperproliferative skin disease. Recent studies have reported that common genetic factors may underlie both skin and immune-mediated disorders. We hypothesized that such genes may be involved in susceptibility to psoriasis, and undertook an association analysis of 22 candidate genes in a set of French high-risk psoriasis families. One hundred fifty-three single-nucleotide polymorphisms (SNPs) were genotyped and the transmission of alleles in nuclear families was analyzed using the FBAT (family-based association test). To further investigate suggestive associations, LNM (logistic-normal models) and MQLS (modified quasi-likelihood score) methods, which take the whole pedigree structure information of families into consideration, were also applied. Our study supported the involvement of six candidate genes in susceptibility to psoriasis: SCL12A8, which belongs to the solute carrier gene family; FLG and TGM5, which are involved in epidermal differentiation; CARD15 and CYLD, which modulate the transcription factor NF-kB; and IL1RN, which encodes an IL receptor antagonist. Furthermore, we found evidence for interaction between the major risk allele, HLA-Cw6, and CARD15, CYLD, and TGM5 susceptibility alleles. Taken together, our data show that shared genetic factors may contribute to the etiology of both psoriasis and other skin or immune-mediated disorders.
...
PMID:An association study of 22 candidate genes in psoriasis families reveals shared genetic factors with other autoimmune and skin disorders. 1955 25

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.
...
PMID:Vitamin D analogs differentially control antimicrobial peptide/"alarmin" expression in psoriasis. 1962 55

Psoriasis is a chronic disease characterized by keratinocyte hyperproliferation and inflammation. It has been demonstrated that the expression of calcitonin gene-related peptide (CGRP) is elevated in psoriasis lesions and CGRP-containing neuropeptide nerve fibers are denser in the psoriatic epidermis. CGRP has been previously described to influence proliferation of several cell types, such as Schwann cell, tracheal epithelial cells, and human gingival fibroblasts. In the present study, we determined the effect of CGRP on HaCaT keratinocyte proliferation and the role of mitogen-activated protein kinases (MAPKs) in CGRP induced keratinocyte proliferation. Our data indicate CGRP increased [(3)H]-thymidine incorporation and MTT activity of HaCaT in a concentration-dependent manner. CGRP also enhanced serum-induced HaCaT cell proliferation. HaCaT cells cultured with CGRP had a significant increase in phosphorylated ERK1/2, p38 and JNK, and CGRP induced DNA synthesis was inhibited by PD 98059 or SB 203580, selective inhibitors of MAP kinase kinase (MEK, which is upstream from ERK) and p38, respectively. These findings suggest that HaCaT cell proliferate in response to CGRP, which is mediated by phosphorylation of ERK1/2 and p38 MAPK.
...
PMID:Calcitonin gene-related peptide increases proliferation of human HaCaT keratinocytes by activation of MAP kinases. 1965 Dec 23

Recent advances in the knowledge of the EGFR pathway have revealed its contribution to distinct immune/inflammatory functions of the epidermis. The purpose of our study was to evaluate the role of EGFR in the regulation of keratinocyte GM-CSF expression. In cultured human keratinocytes, proinflammatory cytokines synergized with TGF-alpha to induce GM-CSF expression. Accordingly, high epidermal levels of EGFR activation are associated with enhanced expression of GM-CSF in lesional skin of patients with psoriasis or allergic contact dermatitis. In cultured keratinocytes, pharmacological inhibition of EGFR activity reduced GM-CSF promoter transactivation, whereas genetic inhibition of AP-1 reduced expression of GM-CSF. Furthermore, EGFR activation enhanced TNF-alpha-induced c-Jun phosphorylation and DNA binding, whereas c-Jun silencing reduced GM-CSF expression. Using two different mouse models, we showed that the lack of a functional EGFR pathway was associated with reduced cytokine-induced phosphorylation of ERK1/2, JNK1/2, c-Jun and reduced keratinocyte-derived GM-CSF expression both in vitro and in vivo. Finally, the analysis of GM-CSF expression in the skin of cancer patients treated with anti EGFR drugs showed an association between ERK activity, c-Jun phosphorylation, and epidermal GM-CSF expression. These data demonstrate that the EGFR pathway is critical for the upregulation of keratinocyte GM-CSF expression under conditions of cytokine stimulation.
...
PMID:EGFR regulates the expression of keratinocyte-derived granulocyte/macrophage colony-stimulating factor in vitro and in vivo. 1989 Mar 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---