Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human skin is exposed daily to solar ultraviolet (UV) radiation. UV induces the matrix metalloproteinases collagenase, 92-kD gelatinase, and stromelysin, which degrade skin connective tissue and may contribute to premature skin aging (photoaging). Pretreatment of skin with all-trans retinoic acid (tRA) inhibits UV induction of matrix metalloproteinases. We investigated upstream signal transduction pathways and the mechanism of tRA inhibition of UV induction of matrix metalloproteinases in human skin in vivo. Exposure of human skin in vivo to low doses of UV activated EGF receptors, the GTP-binding regulatory protein p21Ras, and stimulated mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38. Both JNK and p38 phosphorylated, and thereby activated transcription factors c-Jun and activating transcription factor 2 (ATF-2), which bound to the c-Jun promoter and upregulated c-Jun gene expression. Elevated c-Jun, in association with constitutively expressed c-Fos, formed increased levels of transcription factor activator protein (AP) 1, which is required for transcription of matrix metalloproteinases. Pretreatment of human skin with tRA inhibited UV induction of c-Jun protein and, consequently, AP-1. c-Jun protein inhibition occurred via a posttranscriptional mechanism, since tRA did not inhibit UV induction of c-Jun mRNA. These data demonstrate, for the first time, activation of MAP kinase pathways in humans in vivo, and reveal a novel posttranscriptional mechanism by which tRA antagonizes UV activation of AP-1 by inhibiting c-Jun protein induction. Inhibition of c-Jun induction likely contributes to the previously reported prevention by tRA of UV induction of AP-1-regulated matrix-degrading metalloproteinases in human skin.
 ...
PMID:Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. 950 86

Jun N-terminal kinases (JNKs) are serine-threonine kinases that play a critical role in the regulation of cell growth and differentiation. We previously observed that JNK activity is suppressed by all-trans-retinoic acid (t-RA), a ligand for retinoic acid nuclear receptors (RARs), in normal human bronchial epithelial cells, which are growth inhibited by t-RA. In this study, we investigated the mechanism by which t-RA inhibits JNK and the possibility that this signaling event is blocked in non-small cell lung cancer (NSCLC) cells. Virtually all NSCLC cell lines are resistant to the growth-inhibitory effects of t-RA, and a subset of them have a transcriptional defect specific to retinoid nuclear receptors. We found that in NSCLC cells expressing functional retinoid receptors, serum-induced JNK phosphorylation and activity were inhibited by t-RA in a bimodal pattern, transiently within 30 min and in a sustained fashion beginning at 12 h. Retinoid receptor transcriptional activation was required for the late, but not the early, suppression of JNK activity. t-RA inhibited serum-induced JNK activity by blocking mitogen-activated protein (MAP) kinase kinase 4-induced signaling events. This effect of t-RA was phosphatase dependent and involved an increase in the expression of the dual-specificity MAP kinase phosphatase 1 (MKP-1). t-RA did not activate MKP-1 expression or inhibit JNK activity in a NSCLC cell line with retinoid receptors that are refractory to ligand-induced transcriptional activation. These findings provide the first evidence that t-RA suppresses JNK activity by inhibiting JNK phosphorylation. Retinoid receptor transcriptional activation was necessary for the sustained inhibition of JNK activity by t-RA, and this signaling event was disrupted in NSCLC cells with retinoid receptors that are refractory to ligand-induced transcriptional activation.
 ...
PMID:All-trans-retinoic acid inhibits Jun N-terminal kinase by increasing dual-specificity phosphatase activity. 1002 84

Established treatments for psoriasis act ei-ther on hyperproliferation, inflammation, aberrant epidermal differentiation or a combination of these aspects of the disease. Potential new drugs for treatment of psoriasis or other disorders with abnormalities in epidermal differentiation can be identified by high-throughput screening of large compound libraries using surrogate markers for the disease. Here we describe a screening model to detect pharmacologically active drugs in two keratinocyte-based, 96-well culture models that use expression of cytokeratin 10 (CK10) and skin-derived antileucoprotease (SKALP)/elafin as markers for normal and psoriatic differentiation, respectively, and allow multiple parameters to be determined from a single well. In this model we tested a number of compounds in a pharmacological range from 10(-7) to 10(-5) M, including known antipsoriatic drugs, and experimental drugs that are potentially useful in the treatment of psoriasis. All-trans-retinoic acid, dithranol and the p38 mitogen-activated protein (MAP) kinase inhibitor SB220025 displayed a strong inhibitory effect on SKALP expression while cyclosporin A, dexamethasone, the vitamin D(3) derivative calcipotriol and the p38 MAP kinase inhibitor SB203580 showed only moderate inhibition. Methotrexate and dimethylfumarate did not affect the expression of SKALP. With respect to CK10 expression, all-trans-retinoic acid, calcipotriol, SB203580 and SB220025 exhibited strong inhibition while dithranol showed only moderate suppression of this normal differentiation marker. Expression levels of CK10 were not significantly affected by dexamethasone, methotrexate, cyclosporin A or dimethylfumarate. This model system parallels most, but not all, findings on the in vitro effect of known antipsoriatic drugs on keratinocytes. In addition, the model identifies p38 MAP kinase inhibitors as potent suppressors of differentiation-associated gene expression. Although further delineation and validation of this model is required, we conclude that the system is amenable to down-scaling and application as a high-throughput screen for differentiation-modifying compounds.
 ...
PMID:A simple technique for high-throughput screening of drugs that modulate normal and psoriasis-like differentiation in cultured human keratinocytes. 1221 87

We have investigated the role of Smad family proteins, known to be important cytoplasmic mediators of signals from the transforming growth factor-beta (TGF-beta) receptor serine/threonine kinases, in TGF-beta-dependent differentiation of hematopoietic cells, using as a model the human promyelocytic leukemia cell line, HL-60. TGF-beta-dependent differentiation of these cells to monocytes, but not retinoic acid-dependent differentiation to granulocytes, was accompanied by rapid phosphorylation and nuclear translocation of Smad2 and Smad3. Vitamin D(3) also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-beta1. Simultaneous treatment of these cells with TGF-beta1 and all-trans-retinoic acid (ATRA), which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho-Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-beta1 alone. TGF-beta1 and ATRA activate P42/44 mitogen-activated protein (MAP) kinase with nearly identical kinetics, ruling out its involvement in these effects on Smad phosphorylation. Addition of the inhibitor-of-protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-beta-induced phospho-Smad2 and shifts the differentiation toward monocytic end points. In HL-60R mutant cells, which harbor a defective retinoic acid receptor-alpha (RAR-alpha), ATRA is unable to reduce levels of TGF-beta-induced phospho-Smad2/3, coincident with its inability to differentiate these cells along granulocytic pathways. Together, these data suggest a new level of cross-talk between ATRA and TGF-beta, whereby a putative RAR-alpha-dependent phosphatase activity limits the levels of phospho-Smad2/3 induced by TGF-beta, ultimately reducing the levels of nuclear Smad complexes mediating the TGF-beta-dependent differentiation of the cells to monocytic end points.
 ...
PMID:Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. 1239 16

The aim of this study was to evaluate the effects of 9-cis retinoid acid (9-cis RA) and all-trans RA (ATRA) on proliferation, migratory ability, synthesis of extracellular matrix, intracellular signal transduction, and differentiation of human aortic smooth muscle cells (haSMCs) in vitro. Changes of cell proliferation following incubation with RAs in different doses (10-6 M, 10-7 M, and 10-8 M) were determined directly by proliferation kinetics and indirectly by bromodeoxyuridine enzyme-linked immuno sorbant assays and colony-formation assays. The migratory ability of haSMCs was examined with the help of migration assays. The production of the extracellular matrix protein tenascin was explored by immunostaining. The amounts of total p44/p42 mitogen-activated protein kinases (MAPKs) and their phosphorylated forms were detected with the help of Western blots. To judge the state of differentiation of haSMCs, cell cycle distribution and the pattern of alpha-actin were analyzed. Both RAs clearly inhibited the proliferation of haSMCs in a dose-dependent manner. 9-cis RA had a tendency to be more effective than ATRA. After treatment with RAs, the migratory ability was especially reduced during stimulation with platelet-derived growth factor (PDGF) and the synthesis of tenascin decreased. Although the total p44/p42 MAPKs were downregulated, the amounts of activated forms increased markedly in the cells incubated with RAs and particularly stimulated with PDGF. The cell-cycle analysis demonstrated an increased G1-phase, complemented by a stronger expression of alpha-actin after treatment. 9-cis RA especially has the potential to inhibit the proliferation, migration, and synthesis of extracellular matrix of haSMCs by inducing differentiation in vitro.
 ...
PMID:All-trans and 9-cis retinoid acids inhibit proliferation, migration, and synthesis of extracellular matrix of human vascular smooth muscle cells by inducing differentiation in vitro. 1265 53

The effects of hormone and growth factor signaling on gene expression contribute significantly to breast tumorigenesis and disease progression; however, the targets of signaling networks associated with deregulated growth are not well understood. We defined the dynamic transcriptional effects elicited in MCF7, T-47D, and MDA-MB-436 breast cancer cell lines by nine regulators of growth and differentiation (17beta-estradiol, antiestrogens fulvestrant and tamoxifen, progestin R5020, antiprogestin RU486, all-trans-retinoic acid, epidermal growth factor, mitogen-activated protein/extracellular signal-regulated kinase 1/2 inhibitor U0126 and phorbol ester 12-O-tetradecanoylphorbol-13-acetate) and compared the patterns of gene regulation to published tumor expression profiles. The complex pattern of response to these agents revealed unexpected relationships between their effects, including a profound overlap in genes regulated by both steroids and epidermal growth factor, and striking overlaps between fulvestrant and all-trans-retinoic acid. Estrogen-responsive genes could be divided into two major clusters, only one of which is associated with cell proliferation. Gene ontology analysis was used to highlight functionally distinct biological responses to different mitogens. Significant correlations were identified between several clusters of drug-responsive genes and genes that discriminate estrogen receptor status or disease outcome in patient samples. The majority of estrogen receptor status discriminators were not responsive in our dataset and are therefore likely to reflect underlying differences in histogenesis and disease progression rather than growth factor signaling. This article highlights the overall impact at the gene expression level of diverse regulators of breast cancer growth and links the behavior of breast cancer cells in culture to important clinical properties of human breast tumors.
 ...
PMID:The gene expression response of breast cancer to growth regulators: patterns and correlation with tumor expression profiles. 1461 9

Acute promyelocytic leukemia is a form of acute myelogenous leukemia, characterized by the t(15;17) chromososmal translocation and the presence of the abnormal PML-RARalpha fusion protein. All-trans-retinoic acid is a potent agent for the treatment of this fatal subtype of AML, and is particularly effective when combined with cytotoxic chemotherapy. The important biological activities of all-trans-retinoic acid in vitro and in vivo have provoked extensive studies over the years, aimed to define the mechanisms by which it induces its antileukemic effects. It is now well established that all-trans-retinoic acid when administered at pharmacological doses can reverse the dominant-negative effects that the PML-RARalpha oncoprotein exhibits on the functions of the wild type PML and RARalpha proteins. All-trans-retinoic acid induces gene transcription via retinoic acid responsive elements (RARE) that are present in the promoters of retinoid-responsive genes that ultimately result in the production of protein products that regulate leukemic cell differentiation and induce cell-cycle arrest. There is now accumulating evidence that additional signalling pathways are activated during all-trans-retinoic acid-treatment of cells, involving Stat-proteins, tyrosine kinases and mitogen-activated protein (Map) kinases. This review summarizes the current knowledge on the signalling cascades activated by all-trans-retinoic acid in APL cells. The clinical implications and potential translational applications from the accumulating knowledge in the field are also discussed.
 ...
PMID:Signalling pathways activated by all-trans-retinoic acid in acute promyelocytic leukemia cells. 1551 5

Despite the use of retinoids in the clinic for many years, their mode of action in the prevention of skin cancer is still unclear. Recent microarray analyses of the chemopreventive effect of all-trans retinoic acid (ATRA), one of the primary naturally occurring biologically active retinoids, in the two-stage mouse skin chemical carcinogenesis model have provided novel insight into their action. Comparison of the gene expression profiles of control skin to skin subjected to the two-stage protocol for 3 wk, with or without ATRA, has shown that approximately half of the genes regulated by 12-o-tetradecanoylphorbol-13-acetate (TPA) are oppositely regulated when ATRA is coadministered with TPA. It was further shown the Raf/Mek/Erk branch of mitogen-activated protein (MAP) kinase pathway contains a disproportionate number of oppositely regulated genes, thereby implicating it as one of the key pathways involved in tumor promotion by TPA, that is blocked by ATRA. This result has pointed the way toward the detailed study of Raf/Mek/Erk pathway signaling in skin cancer development and its potential as a target pathway for chemoprevention by ATRA and other chemopreventive drugs.
 ...
PMID:Retinoids and skin: microarrays shed new light on chemopreventive action of all-trans retinoic acid. 1753 47

The hallmark of acute promyelocytic leukaemia (APL) is the reciprocal translocation t(15;17), which leads to the expression of the promyelocytic leukaemia/retinoic acid receptor alpha (PML/RARalpha) fusion protein and a cell differentiation blockade at the promyelocytic stage. PML/RARalpha is directly targeted by all-trans-retinoic acid (ATRA), which degrades the oncoprotein and induces complete remission of malignancies. The aberrant function of PML/RARalpha, together with the constitutive activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK/ERK) signalling pathway, regulates the ability of haematopoietic cells to proliferate, differentiate, and escape from apoptotic episodes. The role of the MEK/ERK pathway in PML/RARalpha expression, differentiation, proliferation and apoptosis in APL cells was analysed using specific MEK inhibitors. The blockade of MEK/ERK pathway resulted in caspase-dependent degradation of PML/RARalpha, and attenuation of the cell differentiation induction. To our knowledge, this is the first report to show that PML/RARalpha was suppressed by MEK/ERK inhibition, through a mechanism dependent on caspase activation. ATRA co-operated with MEK inhibitor to increase degradation of PML/RARalpha and exhibited a convergence point in caspase activation with MEK inhibitors. Taken together, our data suggest a new role of MEK/ERK pathway in the pathogenesis of APL, thus supporting the use of MEK/ERK inhibitors as an efficient therapeutic strategy for this haematological malignancy.
 ...
PMID:MEK inhibition induces caspases activation, differentiation blockade and PML/RARalpha degradation in acute promyelocytic leukaemia. 1844 86

Clinical use of retinoic acids (RA) is hindered by toxicity possibly related to oxidative stress. Recently, RA at relatively low concentrations was shown to inhibit NRF2 and the expression of its target antioxidative genes. This raises the possibility that RA toxicity may result from cellular inability to cope with resultant oxidative stress. Using in vitro cell and in vivo mouse models, we report that RA, specifically all-trans-RA (atRA) at concentrations implicated in toxicity, can activate NRF2 and induce NRF2 target genes, particularly the subunits of the rate-limiting enzyme of glutathione biosynthesis, glutamate cysteine ligase (GCLM/GCLC). RNA interference-mediated silencing of NRF2, but not of retinoid X receptor-alpha and -beta, reduced basal and atRA-induced GCLM/GCLC gene expression. Moreover, RA increased nuclear accumulation of NRF2, antioxidant response element (ARE) reporter activity, and NRF2 occupancy at AREs. 4-Hydroxynonenal, a lipid peroxidation product, was increased by RA. Inhibition of MEK1/ERK mitogen-activated protein kinases significantly suppressed atRA-induced NRF2 activation and ARE-regulated gene expression, reducing cell resistance against toxic concentrations of RA. NRF2-silenced cells were vulnerable to atRA-induced mitochondrial toxicity and apoptosis. In conclusion, toxic RA activates NRF2, thereby triggering an adaptive response against the resultant oxidative stress. NRF2 enhancement as a therapeutic target of retinoid toxicity awaits further investigation.
 ...
PMID:NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicity. 1884 39


1 2 Next >>