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

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In response to oxidant stress, the cardiovascular system is known to express a number of genes, which could occur owing to the participation of mitogen-activated protein kinases such as MAPKs, ERK and JNK (SAPK) followed by stimulation of at least two well-defined transcription factors NF-KB and AP-1 (c-Fos and c-Jun). Oxidants activate cytosolic and membrane-bound PLA2 activities with the subsequent production of AA metabolites such as HETEs, which subsequently stimulate ERK and JNK (SAPK) activities leading to the activation of transcriptional factors and the ultimate stimulation of the transcription of several mitogen-stress-responsive genes. LacCer, a ceramide analogue present in atherosclerotic plaques, has been found to induce proliferation of aortic smooth muscle cells. LacCer is involved in Ras-GTP loading, activation of kinase cascades (MEK, Raf, p44 MAPK) and c-fos expression. TNF-alpha, on the other hand, induces c-fos, c-myc and c-jun expression. Recent investigations link ceramide and its analogues to the extracellular signal-regulated kinase (ERK) cascade, stress-activated protein kinase-c-Jun kinase (SAPK/JNK) cascade and apoptotic responses. These critical steps in the signalling pathways are sensitive to intracellular thiol-redox and protease(s)-antiprotease(s) status, both of which can be modified by oxidants. Because mobilisation of intracellular Ca2+ caused by a variety of signals also plays a role in the activation of the signalling pathways, an important aspect of future work will be to ascertain the roles of oxidants and Ca2+ individually and in combination in the activation of the signalling pathways. The following two important questions also deserve future attention: (1) How does NF-kB shield cells from apoptotic death? and (2) By what mechanisms does the activated NF-kB cause cellular transformation? Furthermore, the role of AP-1 acting as transcriptional activator seems clear, but the target genes remain to be defined.
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PMID:Oxidant-mediated activation of mitogen-activated protein kinases and nuclear transcription factors in the cardiovascular system: a brief overview. 988 18

Mouse selenocysteine transfer RNA (tRNA) gene transcription-activating factor (mStaf) is a transcriptional activator that enhances RNA polymerase III-dependent mouse selenocysteine tRNA (tRNA(Sec)) gene transcription. The DNA-binding activity of mStaf in mouse mammary gland undergoes developmental changes, reaching a maximal level during the period of lactation. In this study, we employed an organ culture system to examine the hormonal regulation of mStaf binding and its role in the tRNA(Sec) transcription in the mammary gland. The results showed that mStaf binding in mammary explants was stimulated by treatment with the lactogenic hormones, PRL, insulin, and hydrocortisone and that a specific MEK inhibitor, PD98059, inhibited the hormonal stimulation of mStaf binding. Other kinase inhibitors, such as a Janus kinase inhibitor and a calmodulin kinase inhibitor, had no apparent effect. Northern and Western blot analyses revealed that the level of both mStaf messenger RNA and protein was enhanced by the lactogenic hormones and was reduced by the concomitant treatment with PD98059. The mitogen-activated protein kinase activity in cultured explants was rapidly induced and maintained at high levels by the lactogenic hormones. We also found that the lactogenic hormones increased the amount of tRNA(Sec) in a time-dependent manner, which followed the increase in mStaf binding in cultured mammary explants. These results support the view that mStaf plays a key role in the hormonal stimulation of tRNA(Sec) transcription in the mammary gland.
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PMID:Hormonal induction of mouse selenocysteine transfer ribonucleic acid (tRNA) gene transcription-activating factor and its functional importance in the selenocysteine tRNA gene transcription in mouse mammary gland. 992 85

Because both the brain natriuretic peptide (BNP) gene and the cytokine interleukin-1beta (IL-1beta) are induced in the infarcted myocardium, localized production of IL-1beta may regulate the BNP gene. We tested whether (1) IL-1beta regulates the human BNP promoter, (2) cis elements in the proximal promoter respond to IL-1beta, and (3) mitogen-activated protein kinase (MAPK) signaling pathways [p42/44, c-jun (JNK) and p38 kinase] are involved. We transferred the hBNP promoter coupled to a luciferase reporter gene or constructs with mutations in the proximal promoter GATA and M-CAT elements into neonatal rat ventricular myocytes and treated the cells with IL-1beta for 24 hours. IL-1beta-stimulated hBNP luciferase activity was eliminated by pretreatment with the transcription inhibitor actinomycin D. Both the p38 kinase inhibitor SB205380 (SB) and cotransfection of a dominant-negative mutant of p38 kinase reduced IL-1beta stimulation of the hBNP promoter. Dominant-negative mutants of Ras and Rac inhibited IL-1beta-stimulated hBNP luciferase activity by 64% and 90%, respectively. Constitutively active forms of Rac and MKK6, the immediate upstream activator of p38, were stimulatory; however, only the effect of MKK6 was inhibited by SB. Neither the p42/44 nor the JNK pathway was involved in the action of IL-1beta. Both IL-1beta and MKK6 activation of the hBNP promoter were partially reduced when the promoter contained a mutated M-CAT element. In summary, (1) IL-1beta is a transcriptional activator of the hBNP promoter; (2) IL-1beta acts through a Ras-dependent pathway not coupled to activation of p42/44 MAPK or JNK; (3) IL-1beta acts through a Rac-dependent pathway, but the downstream effector is not known; and (4) IL-1beta activation of p38 kinase is partially involved in regulation of the hBNP promoter, targeting the proximal M-CAT element.
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PMID:Interleukin-1beta regulation of the human brain natriuretic peptide promoter involves Ras-, Rac-, and p38 kinase-dependent pathways in cardiac myocytes. 993 Nov 18

Pituitary tumor-transforming gene (PTTG) is a recently characterized oncogene that can act as a transcriptional activator. In this study, we have characterized the transactivation domain of PTTG. Transient transfection of fusion constructs containing GAL4 DNA-binding domain and different parts of PTTG indicated the transactivation domain of PTTG is located between amino acids 119 and 164. Mitogen-activated protein (MAP) kinase cascade is important in the regulation of cell growth, apoptosis, and differentiation. Therefore, we have explored the possibility that this kinase cascade plays a role in regulating PTTG transactivation function. Activation of the MAP kinase cascade by epidermal growth factor or an expression vector for a constitutively active form of the MAP kinase kinase (MEK1) led to stimulation of PTTG transactivation activity. We showed that PTTG is phosphorylated in vitro on Ser(162) by MAP kinase and that this phosphorylation site plays an essential role in PTTG transactivation function. We demonstrated that PTTG interacts directly with MEK1 through a putative SH3 domain-binding site located between amino acids 51 and 54 and that this interaction is crucial for PTTG transactivation function. In addition, we showed that activation of MAP kinase phosphorylation cascade resulted in nuclear translocation of PTTG. Together, our data establish that a growth factor-stimulated MAP kinase plays an important role in modulating PTTG function.
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PMID:Activation of mitogen-activated protein kinase cascade regulates pituitary tumor-transforming gene transactivation function. 1090 23

Human T-cell leukemia virus type I (HTLV-I) is the etiological agent for adult T-cell leukemia (ATL), as well as for tropical spastic paraparesis (TSP) and HTLV-I associate myelopathy (HAM). A biological understanding of the involvement of HTLV-I and in ATL has focused significantly on the workings of the virally-encoded 40 kDa phospho-oncoprotein, Tax. Tax is a transcriptional activator. Its ability to modulate the expression and function of many cellular genes has been reasoned to be a major contributory mechanism explaining HTLV-I-mediated transformation of cells. In activating cellular gene expression, Tax impinges upon several cellular signal-transduction pathways, including those for CREB/ATF and NF-kappa B. In this paper, we review aspects of Tax's transcriptional potential with particular focus on recent evidence linking Tax to IKK (I kappa B-kinase)-complex and MAP3Ks (mitogen-activated protein kinase kinase kinases).
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PMID:Functional activities of the human T-cell leukemia virus type I Tax oncoprotein: cellular signaling through NF-kappa B. 1132 3

The zinc finger protein early growth response 1 (Egr-1) is a transcriptional activator involved in the regulation of growth and differentiation. We show here that a constitutive active mutant of mitogen-activated kinase kinase-1 (MAPKK-1) strongly stimulates the activity of the Egr-1 promoter, thus explaining the effects of mitogens upon Egr-1 mRNA and protein levels. Moreover, we show that a constitutive active MAPKK-1 leads to an increase in the biological activity of Egr-1 to activate transcription. We conclude that the signaling pathway involving mitogen-activated protein kinase/extracellular signal-regulated protein kinase has a dual impact on the biology of Egr-1 by controlling the transcription of the Egr-1 gene and the transcriptional activity of the Egr-1 protein.
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PMID:The extracellular signal-regulated protein kinases Erk1/Erk2 stimulate expression and biological activity of the transcriptional regulator Egr-1. 1153 Sep 39

The phosphorylation state of transcription factors is a critical determinant of their function. C/EBPbeta occurs in cells as the transcriptional activator liver-enriched activating protein (LAP) and in the truncated form liver-enriched inhibitory protein (LIP) that inhibits transcription. Analysis of C/EBPbeta phosphorylation by isoelectric focusing (IEF) shows that LAP is present in multiple forms, each with a different degree of phosphorylation in 3T3-F442A fibroblasts. Growth hormone (GH) treatment induces a new band near the negative pole, consistent with GH-promoted dephosphorylation of LAP. In addition, bands near the positive pole are rapidly and transiently induced, suggesting that GH also stimulates phosphorylation at some site(s) on LAP. C/EBPbeta contains a highly conserved MAPK consensus site that corresponds to Thr(188) in murine (m) LAP and Thr(37) in mLIP. Immunoblotting with antiphosphopeptide antibodies specific for Thr(188/37) of C/EBPbeta (anti-P-C/EBPbeta) shows that GH rapidly and transiently promotes phosphorylation of mLAP and mLIP on the MAPK site. MEK inhibitors prevent this GH-promoted phosphorylation of LAP and LIP, suggesting that such phosphorylation depends on GH-activated MAPK signaling. Mutation of Thr(235) to Ala in the homologous MAPK site of human (h) LAP (hLAPT235A) inhibits transcription mediated by the c-fos promoter in response to GH, indicating that phosphorylation at the MAPK site is required for LAP to be transcriptionally active in the context of GH-stimulated activation of the c-fos promoter. Complexes bound to the c-fos C/EBP site transiently contain C/EBPbeta phosphorylated at the MAPK site. As phosphorylation subsides, the binding of less transcriptionally active forms of LAP increases, consistent with the transient nature of c-fos stimulation by GH and other growth factors. Thus, both phosphorylation and dephosphorylation of C/EBPbeta, in response to a single physiological stimulus such as GH, coordinately modulate the ability of C/EBPbeta to activate transcription by modulating its DNA binding activity and its transactivation capacity.
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PMID:Dual regulation of phosphorylation and dephosphorylation of C/EBPbeta modulate its transcriptional activation and DNA binding in response to growth hormone. 1221 25

Transcriptional regulation of downstream gene expression by thyroid hormone (T(3)) is mediated by the thyroid hormone receptor (TR). T(3) binding induces a complicated transition, where TR converts from a transcriptional repressor into a transcriptional activator and instigates downstream gene transcription. Binding of T(3) to TR also induces the degradation of TR, resulting in desensitization of the cells to further T(3) treatment. It has been shown that phosphorylation of TR plays a critical role in its activity and stability after T(3) binding. However, the kinases in control of phosphorylating TR in the nucleus have not been identified. In this study we demonstrate that MAPKs are possible candidates responsible for the nuclear phosphorylation of TR. Suppression of MAPKs with specific inhibitors repressed TR transcriptional activity and antagonized okadeic acid-induced TR transcriptional activity potentiation. Overexpression of the MAPK activator, MKK6, and its constitutively active mutant, MKK6EE, significantly increased TR activity and protected TR from degradation. Involvement of the 26S ubiquitin proteasome in hormone binding-induced TR degradation was also examined. We found that MAPKs enhanced the DNA binding affinity of TR. Our results suggest that MAPKs are the major kinases responsible for the nuclear phosphorylation of TR and are critical factors modulating the transcriptional activity and protein stability of TR subsequent to ligand binding.
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PMID:Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein. 1263 24

Mitogen-activated protein kinase (MAPK) signaling cascades are multifunctional signaling networks that influence cell growth, differentiation, apoptosis, and cellular responses to stress. Since the activation/propagation of MAPK signaling requires the sequential phosphorylation of many downstream proteins, the phosphatases that dephosphorylate MAPKs represent critical elements in the control of MAPK-signaling networks. Here we show that hypoxia induces a transient increase in the activity of apoptosis signal-regulating kinase 1 (ASK-1), a MAPKKK that responds to oxidative stress by triggering cascades leading to the phosphorylation/activation of c-Jun N-terminal kinases (JNK) and p38-MAPK. Hypoxia-induced ASK-1/MKK-4/JNK signaling is suppressed by serine/threonine protein phosphatase type 5 (PP5), which acts to turn off ASK-1/MKK-4/JNK signaling via two mechanisms. First, in a rapid response hypoxia facilitates the association of endogenous PP5 with ASK-1. PP5 binds to the C-terminal domain of ASK-1, and studies with siRNA targeting PP5 indicate that PP5 acts to suppress the phosphorylation of MKK4 (Thr-261), JNK (Thr-183/Tyr-185), and c-Jun (Ser-63) without affecting the activating phosphorylation of p38 MAPK (Thr-180/Tyr-182), p44/p42-MAPK/ERK1/2 (Thr-202/Tyr-204), or c-Jun protein levels. If hypoxia is prolonged, the expression of PP5 is increased due to the activation of a transcriptional activator, which was identified as hypoxia-inducible factor-1. Together, these studies indicate that PP5 plays an important role in the survival of cells in a low oxygen environment by suppressing a hypoxia-induced ASK-1/MKK4/JNK signaling cascade that promotes an apoptotic response.
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PMID:Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. 1532 43

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor regulating an array of diverse functions in a variety of cell types including regulation of genes associated with growth and differentiation. Its most notable function is to regulate development of adipose tissue, which involves coordinating expression of many hundreds of genes responsible for establishment of the mature adipocyte phenotype. Our recent studies have demonstrated a role for MEK/ERK signaling and CCAAT/enhancer binding proteins (C/EBP)beta in regulating expression of PPARgamma during adipogenesis. Furthermore, we have shown that cAMP-dependent signaling along with C/EBPbeta leads to the stimulation of PPARgamma activity by mechanisms that probably involve production of PPARgamma ligands. Additionally, we have recently demonstrated that phosphorylation of C/EBPbeta at a consensus ERK/GSK3 site is required for the PPARgamma-associated expression of adiponectin during the terminal stages of adipogenesis. GSK3beta also influences PPARgamma activity by regulating the turnover and subcellular localization of beta-catenin, a potent transcriptional activator of Wnt signaling. In fact, we have recently shown a crosstalk between PPARgamma and beta-catenin signaling. Specifically, activation of PPARgamma induces the degradation of beta-catenin during preadipocyte differentiation by mechanisms that require GSK3beta and the proteasome. In contrast, expression of a GSK3beta-phosphorylation-defective beta-catenin renders beta-catenin resistant to the degradatory action of PPARgamma. Interestingly, expression of the mutant beta-catenin blocks expression of adiponectin and C/EBPalpha in response to the activation of PPARgamma.
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PMID:Regulation of PPARgamma activity during adipogenesis. 1571 76


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