Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sulfur mustard (SM) is a strong vesicant that has been used as a chemical warfare agent. To understand the molecular mechanisms that underlie the inflammatory skin reaction in response to SM, we analyzed the activation pattern of the NF-kappaB and mitogen-activated protein kinase (MAPK) pathways. Keratinocytes responded with an induction of the canonical NF-kappaB pathway, including activation of IkappaB kinase 2, followed by phosphorylation and degradation of IkappaBalpha and of the transactivating subunit RelA at Ser536. The biphasic NF-kappaB response was strictly dependent on the transactivating subunit RelA, as demonstrated by keratinocytes lacking RelA. Parallel to NF-kappaB activation, we observed an induction of the Raf-1/MEK1/2/ERK1/2/MSK1 and MKK3/6/p38/MSK1 pathways. Although mitogen and stress-activated kinase 1 has been described as a RelA kinase with Ser276 as its target, this site remained unphosphorylated in response to SM. A further MAPK pathway induced by SM was the MKK4/7/JNK1/2 pathway, which resulted in phosphorylation of the transcription factor activating transcription factor-2, but not c-Jun. Our results indicate that SM induces a complex cellular response in keratinocytes, with the activation of three MAPK pathways and the NF-kappaB pathway.
J Invest Dermatol 2008 Jul
PMID:Role of NF-kappaB/RelA and MAPK pathways in keratinocytes in response to sulfur mustard. 1820 59

The RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways are activated through multiple mechanisms and appear to play a major role in melanoma progression. Herein, we examined whether targeting the RAS-RAF-MEK-ERK pathway with the RAF inhibitor sorafenib and/or the PI3K-AKT-mTOR pathway with the mTOR inhibitor rapamycin has therapeutic effects against melanoma. A combination of sorafenib (4 microM) with rapamycin (10 nM) potentiated growth inhibition in all six metastatic melanoma cell lines tested. The absolute enhancement of growth inhibition rates ranged from 13.0-27.8% in different cell lines (P<0.05, combination treatment vs monotreatment). Similar results were obtained with combinations of the MEK inhibitors U0126 (30 microM) or PD98059 (50 microM) with rapamycin (10 nM). The combined treatment of melanoma cells with sorafenib and rapamycin led to an approximately twofold increase of cell death compared with sorafenib monotreatment (P<0.05) as assessed by propidium iodide staining and cell death detection ELISA. Moreover, sorafenib in combination with rapamycin completely suppressed invasive melanoma growth in organotypic culture mimicking the physiological context. These effects were associated with complete downregulation of the antiapoptotic proteins Bcl-2 and Mcl-1. Sorafenib combined with rapamycin appears to be a promising strategy for the effective treatment of melanoma and merits clinical investigation.
J Invest Dermatol 2008 Aug
PMID:Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. 1832 81

Keloids are benign skin tumors characterized by collagen accumulation and hyperproliferation of fibroblasts. To find an effective therapy for keloids, we explored the pharmacological potential of (-)-epigallocatechin-3-gallate (EGCG), a widely investigated tumor-preventive agent. When applied to normal and keloid fibroblasts (KFs) in vitro, proliferation and migration of KFs were more strongly suppressed by EGCG than normal fibroblast proliferation and migration (IC(50): 54.4 microM (keloid fibroblast (KF)) versus 63.0 microM (NF)). The level of Smad2/3, signal transducer and activator of transcription-3 (STAT3), and p38 phosphorylation is more enhanced in KFs, and EGCG inhibited phosphorylation of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated protein kinase 1/2 (ERK1/2), and STAT3 (Tyr705 and Ser727). To evaluate the contribution of these pathways to keloid pathology, we treated KFs with specific inhibitors for PI3K, ERK1/2, or STAT3. Although a PI3K inhibitor significantly suppressed proliferation, PI3K and MEK/ERK inhibitors had a minor effect on migration and collagen production. However, a JAK2/STAT3 inhibitor and a STAT3 siRNA strongly suppressed proliferation, migration, and collagen production by KFs. We also found that treatment with EGCG suppressed growth and collagen production in the in vivo keloid model. This study demonstrates that EGCG suppresses the pathological characteristics of keloids through inhibition of the STAT3-signaling pathway. We propose that EGCG has potential in the treatment and prevention of keloids.
J Invest Dermatol 2008 Oct
PMID:Green tea polyphenol epigallocatechin-3-gallate suppresses collagen production and proliferation in keloid fibroblasts via inhibition of the STAT3-signaling pathway. 1846 84

Due to elaborate control mechanisms, in benign tumors the activation of oncogenes primarily induces senescence, associated with cessation of cellular proliferation; for example, melanocytic nevi expressing mutant B-Raf. These mechanisms include the RB and/or the p53 pathway. The current model of melanomagenesis postulates that progression to immortal melanoma cells requires inactivating aberrations in signaling cascades controlling senescence. Thus, melanoma cells carrying mutant B-Raf should be resistant to mitogen-activated protein kinase (MAPK) pathway-induced senescence. Here, we demonstrate that hyperactivation of the MAPK pathway following activation of an inducible form of oncogenic C-Raf induces a senescence-like proliferation arrest in B-Raf mutant melanoma cells. This Raf-induced senescence is initially strictly dependent on MEK signaling, but seems to be independent of MAPK signaling after prolonged continuance. It is associated with reduced levels of RB phosphorylation and an increase in p21 expression, but is independent of p16(Ink4a) and p53. These data argue against the existence of fundamental changes in melanoma cells completely precluding senescence.
J Invest Dermatol 2009 Feb
PMID:Proliferation arrest in B-Raf mutant melanoma cell lines upon MAPK pathway activation. 1865 Aug 48

Tumor expression of inducible nitric oxide synthase (iNOS) predicts poor outcomes for melanoma patients. We have reported the regulation of melanoma iNOS by the mitogen-activated protein kinase (MAPK) pathway. In this study, we test the hypothesis that NF-kappaB mediates this regulation. Western blotting of melanoma cell lysates confirmed the constitutive expression of iNOS. Western blot detected baseline levels of activated nuclear extracellular signal-regulated kinase and NF-kappaB. Indirect immunofluorescence confirmed the presence of NF-kappaB p50 and p65 in melanoma cell nuclei, with p50 being more prevalent. Electrophoretic mobility shift assay demonstrated baseline NF-kappaB activity, the findings confirmed by supershift analysis. Treatment of melanoma cells with the MEK inhibitor U0126 decreased NF-kappaB binding to its DNA recognition sequence, implicating the MAPK pathway in NF-kappaB activation. Two specific NF-kappaB inhibitors suppressed iNOS expression, demonstrating regulation of iNOS by NF-kappaB. Several experiments indicated the presence of p50 homodimers, which lack a transactivation domain and rely on the transcriptional coactivator Bcl-3 to carry out this function. Bcl-3 was detected in melanoma cells and co-immunoprecipitated with p50. These data suggest that the constitutively activated melanoma MAPK pathway stimulates activation of NF-kappaB hetero- and homodimers, which, in turn, drive iNOS expression and support melanoma tumorigenesis.
J Invest Dermatol 2009 Jan
PMID:NF-kappaB mediates mitogen-activated protein kinase pathway-dependent iNOS expression in human melanoma. 1866 40

Cimicifuga rhizoma has long been used in traditional Korean medicine. In particular, a Cimicifuga heracleifolia extract (CHE) was reported to inhibit the formation of glutamate and the glutamate dehydrogenase activity in cultured rat islet. Glutamate activates melanogenesis by activating tyrosinase. Accordingly, it was hypothesized that a CHE might inhibit the melanogenesis-related signal pathways including the inhibition of microphthalmia-associated transcription factor (MITF)-tyrosinase signaling and/or the activation of extracellular signal-regulated kinase (ERK)-Akt signaling. The results showed that CHE inhibits the cellular melanin contents, tyrosinase activity and expression of melanogenesis-related proteins including MITF, tyrosinase and tyrosinase-related protein (TRP)s in alpha-melanocyte-stimulating hormone-stimulated B16 cells. Moreover, CHE phosphorylates MEK, ERK1/2 and Akt, which are melanogenesis inhibitory proteins. The data suggest that CHE inhibits melanogenesis signaling by both inhibiting the tyrosinase directly and activating the MEK-ERK or Akt signal pathways-mediated suppression of MITF and its downstream signal pathway, including tyrosinase and TRPs. Therefore, C. heracleifolia would be a useful therapeutic agent for treating hyperpigmentation and an effective component in whitening and/or lightening cosmetics.
Exp Dermatol 2009 Mar
PMID:Dichloromethane fraction of Cimicifuga heracleifolia decreases the level of melanin synthesis by activating the ERK or AKT signaling pathway in B16F10 cells. 1880 55

IL-17F is known to be involved in many inflammatory diseases, but its role in skin diseases has not been fully examined. Because IL-8 is involved in many skin diseases such as psoriasis, we investigated the production of IL-8 in normal human epidermal keratinocytes (NHEKs) stimulated by IL-17F, tumor necrosis factor-alpha (TNF-alpha), IL-17A, and control using real-time PCR and ELISA. The results showed that IL-17F induced production of IL-8 in NHEKs in a time-dependent manner. Interestingly, the amounts of IL-8 stimulated by IL-17F were much higher than those stimulated by TNF-alpha or IL-17A. Next, we confirmed that selective mitogen-activated protein kinase kinase inhibitors significantly inhibited IL-17F-induced IL-8 production. Moreover, mouse skin intradermally injected with IL-17F expressed high level of IL-8 mRNA and induced ERK1/2 phosphorylation. Histological examination of mouse skin that was injected with IL-17F revealed marked neutrophilia in dermis and the infiltration was significantly inhibited by anti-IL-8 antibody. Finally, IL-17F expression in skin biopsy samples from psoriasis patients were examined by western blotting and ELISA. IL-17F was upregulated in lesional psoriatic skin compared with nonlesional skin. These results indicate that IL-17F may be involved in psoriasis via, in part, the activation of ERK1/2 and the induction of IL-8 in keratinocytes.
J Invest Dermatol 2009 Mar
PMID:Functional characterization of IL-17F as a selective neutrophil attractant in psoriasis. 1883 Feb 71

In melanoma, the PI3K-AKT-mTOR (AKT) and RAF-MEK-ERK (MAPK) signaling pathways are constitutively activated and appear to play a role in chemoresistance. Herein, we investigated the effects of pharmacological AKT and MAPK pathway inhibitors on chemosensitivity of melanoma cells to cisplatin and temozolomide. Chemosensitivity was tested by examining effects on growth, cell cycle, survival, expression of antiapoptotic proteins, and invasive tumor growth of melanoma cells in monolayer and organotypic culture, respectively. MAPK pathway inhibitors did not significantly increase chemosensitivity. AKT pathway inhibitors consistently enhanced chemosensitivity yielding an absolute increase of cell growth inhibition up to 60% (P<0.05, combination therapy vs monotherapy with inhibitors or chemotherapeutics). Cotreatment of melanoma cells with AKT pathway inhibitors and chemotherapeutics led to a 2- to 3-fold increase of apoptosis (P<0.05, combination therapy vs monotherapy) and completely suppressed invasive tumor growth in organotypic culture. These effects were associated with suppression of the antiapoptotic Bcl-2 family protein Mcl-1. These data suggest that inhibition of the PI3K-AKT-mTOR pathway potently increases sensitivity of melanoma cells to chemotherapy.
J Invest Dermatol 2009 Jun
PMID:Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide. 1907 92

Collagen XVII (COL17) participates in keratinocyte adhesion and possibly migration, as COL17 defects disrupt keratinocyte-basal lamina adhesion and underlie the disease non-Herlitz junctional epidermolysis bullosa. Using small interference RNA (siRNA) to knock down COL17 expression in HaCaT cells, we assessed cell characteristics, including adhesion, migration, and signaling. Control and siRNA-transfected keratinocytes showed no difference in adhesion on plastic dishes after incubation for 8 hours in serum-free keratinocyte-growth medium; however, when grown on collagen IV alone or BD matrigel (containing collagen IV and laminin isoforms), COL17-deficient cells showed significantly reduced adhesion compared with controls (P<0.01), and mitogen-activated protein kinase (MAPK)/ERK kinase (MEK)1/2 and MAPK showed reduced phosphorylation. Furthermore, COL17-deficient HaCaT cells plated on plastic exhibited reduced motility that was p38MAPK-dependent (after addition of the p38MAPK inhibitor SB203580). Together, these results suggest that COL17 has significantly wider signaling roles than were previously thought, including the involvement of COL17 in keratinocyte adhesion to collagen IV, in p38MAPK-dependent cell migration, and multiple cell signaling events pertaining to MEK1/2 phosphorylation.
J Invest Dermatol 2009 Sep
PMID:Collagen XVII participates in keratinocyte adhesion to collagen IV, and in p38MAPK-dependent migration and cell signaling. 1924 20

KIT is an essential receptor that modulates melanocyte function and whose function is disrupted in several pigmentary disorders. However, little is known about the effects of a single UVB exposure on the expression of KIT and two important regulatory transcription factors, MITF and AP-2 alpha, in human melanocytes. We found that a single UVB exposure of human melanocytes induces an early decrease and a subsequent increase in functional KIT expression in concert with up-regulated MITF expression. The increased MITF expression was accompanied by a markedly stimulated and prolonged phosphorylation of p38/CREB. The UVB-stimulated expression of KIT could be completely abolished by a p38 inhibitor, concomitant with a reduced phosphorylation of CREB and a down-regulation of MITF expression. Interestingly, in non-UVB exposed human melanocytes, a MEK inhibitor stimulated the phosphorylation of p38/CREB which was associated with an increased production of MITF and KIT in a pattern similar to that induced by UVB. These findings indicate that UVB stimulates functional KIT expression in human melanocytes via the up-regulation of MITF which is, in turn, due to the activation of p38 and CREB.
Arch Dermatol Res 2010 May
PMID:A single UVB exposure increases the expression of functional KIT in human melanocytes by up-regulating MITF expression through the phosphorylation of p38/CREB. 1993 54


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