Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The androgen receptor (AR) is a nuclear hormone receptor superfamily member that conveys both trans repression and ligand-dependent trans-activation function. Activation of the AR by dihydrotestosterone (DHT) regulates diverse physiological functions including secondary sexual differentiation in the male and the induction of apoptosis by the JNK kinase, MEKK1. The AR is posttranslationally modified on lysine residues by acetylation and sumoylation. The histone acetylases p300 and P/CAF directly acetylate the AR in vitro at a conserved KLKK motif. To determine the functional properties governed by AR acetylation, point mutations of the KLKK motif that abrogated acetylation were engineered and examined in vitro and in vivo. The AR acetylation site point mutants showed wild-type trans repression of NF-kappa B, AP-1, and Sp1 activity; wild-type sumoylation in vitro; wild-type ligand binding; and ligand-induced conformational changes. However, acetylation-deficient AR mutants were selectively defective in DHT-induced trans activation of androgen-responsive reporter genes and coactivation by SRC1, Ubc9, TIP60, and p300. The AR acetylation site mutant showed 10-fold increased binding of the N-CoR corepressor compared with the AR wild type in the presence of ligand. Furthermore, histone deacetylase 1 (HDAC1) bound the AR both in vivo and in cultured cells and HDAC1 binding to the AR was disengaged in a DHT-dependent manner. MEKK1 induced AR-dependent apoptosis in prostate cancer cells. The AR acetylation mutant was defective in MEKK1-induced apoptosis, suggesting that the conserved AR acetylation site contributes to a pathway governing prostate cancer cellular survival. As AR lysine residue mutations that abrogate acetylation correlate with enhanced binding of the N-CoR repressor in cultured cells, the conserved AR motif may directly or indirectly regulate ligand-dependent corepressor disengagement and, thereby, ligand-dependent trans activation.
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PMID:Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. 1197 70

Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anticancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element (CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity of CREB- binding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA stimulated an interaction between RA receptor-alpha and CBP/p300; a corresponding decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly, overexpressing CBP/p300 or dominant-negative RA receptor-alpha relieved the suppressive effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the mechanism by which carnosol inhibited COX-2 transcription, its effects on protein kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated induction of COX-2. By contrast, carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms.
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PMID:Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms. 1198 Jun 44

The Smad proteins are key intracellular effectors of transforming growth factor-beta (TGF-beta) cytokines. The ability of Smads to modulate transcription results from a functional cooperativity with the coactivators p300/cAMP-response element-binding protein-binding protein (CBP), or the corepressors TGIF and Ski. The c-Jun N-terminal kinase (JNK) pathway, another downstream target activated by TGF-beta receptors, has also been suggested to inhibit TGF-beta signaling through interaction of c-Jun with Smad2 and Smad3. Here we show that c-Jun directly interacts with Ski to enhance the association of Ski with Smad2 in the basal state. Interestingly, TGF-beta signaling induces dissociation of c-Jun from Ski, thereby relieving active repression by c-Jun. Moreover, activation of JNK pathway suppressed the ability of TGF-beta to induce dissociation of c-Jun from ski. Thus, the formation of a c-Jun/Ski complex maintains the repressed state of Smad2-responsive genes in the absence of ligand and participates in negative feedback regulation of TGF-beta signaling by the JNK cascade.
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PMID:c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity. 1203 30

Overexpression of the HER2/Neu receptor is correlated to a poor prognosis in tumor patients and leads to stimulation of mitogen-activated protein kinase (MAPK) signaling pathways, which in turn activate transcription factors, such as the ETS protein ER81. Here, we have analyzed whether, on the other hand, ER81 may regulate the Her2/neu gene. Indeed, ER81, together with its co-activators, p300 and CBP, activates the Her2/neu promoter, and this activation is enhanced upon stimulation of MAPK pathways as well as by oncogenic HER2/Neu protein. Furthermore, ER81 interacts with one ETS binding site in the Her2/neu promoter, whose mutation decreases ER81-mediated transcription. Activation of the Her2/neu promoter is also diminished upon mutation of MAPK-dependent phosphorylation sites in ER81 or upon deletion of ER81 transactivation domains. In addition, the ER81 DNA-binding domain on its own functions as a dominant-negative molecule, effectively repressing any stimulation of the Her2/neu promoter. Altogether, our results show that ER81 is a component of a positive regulatory feedback loop, in which the HER2/Neu protein activates ER81, as well as p300/CBP via MAPKs causing the upregulation of the Her2/neu gene.
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PMID:Regulation of Her2/neu promoter activity by the ETS transcription factor, ER81. 1211 28

Prostate cancer (PCa) begins as an androgen-dependent tumor that will eventually progress to an androgen-independent stage after androgen ablation. Although little is understood about this transition to androgen independence, the androgen receptor (AR) appears to be involved. The coactivator p300 has been shown to interact with the AR during its androgen-dependent transactivation. We show that p300 is involved downstream of the mitogen-activated protein kinase pathway during transactivation of the AR by interleukin-6 (IL-6). Furthermore, we demonstrate that sequestration of p300 with E1A inhibits the IL-6-dependent transactivation of the AR, and that increasing amounts of p300 reverse this inhibition. A mutant p300 that lacks histone acetyltransferase (HAT) activity did not reverse E1A-mediated inhibition. By using small-interference RNA designed to target p300 transcripts, we demonstrate that, after silencing p300, there was no induction of AR activity by IL-6. These findings reveal a unique role for p300 and its HAT activity, indicating that it is necessary for the ligand-independent transactivation of the AR in androgen-independent PCa cells.
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PMID:p300 mediates androgen-independent transactivation of the androgen receptor by interleukin 6. 1238 15

The transcription factor ER81 has been shown to be involved in ontogenesis and breast tumor formation. ER81 is activated by many signals through phosphorylation directly mediated by mitogen-activated protein kinases (MAPKs), but also by an unknown protein kinase(s). Here, mitogen- and stress-activated protein kinase 1 (MSK1), which itself is directly activated by distinct classes of MAPKs, is identified to regulate ER81 function. MSK1 expression enhances ER81-dependent transcription upon stimulation of especially the p38-MAPK pathway. Two serine residues in ER81 are phosphorylated by MSK1, and mutating these serine residues to alanines dramatically diminishes the ability of MSK1 to stimulate ER81. However, mutation of the MSK1 phosphorylation sites in ER81 does not completely abrogate the ability of MSK1 to activate ER81 function, suggesting that MSK1 may also target cofactors of ER81. Consistently, MSK1 interacts with two homologous coactivators of ER81, CBP and p300, and stimulates the transactivation domains of CBP. Thus, MSK1 may regulate ER81-dependent transcription via direct phosphorylation of ER81 as well as via stimulation of CBP/p300, which might be important for ER81's normal function and during mammary tumor formation.
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PMID:Regulation of the ER81 transcription factor and its coactivators by mitogen- and stress-activated protein kinase 1 (MSK1). 1256 67

Hypoxia-inducible factors (HIF) are a family of heterodimeric transcriptional regulators that play pivotal roles in the regulation of cellular utilization of oxygen and glucose and are essential transcriptional regulators of angiogenesis in solid tumor and ischemic disorders. The transactivation activity of HIF complexes requires the recruitment of p300/CREB-binding protein (CBP) by HIF-1 alpha and HIF-2 alpha that undergo oxygen-dependent degradation. HIF activation in tumors is caused by several factors including mitogen-activated protein kinase (MAPK) signaling. Here we investigated the molecular basis for HIF activation by MAPK. We show that MAPK is required for the transactivation activity of HIF-1 alpha. Furthermore, inhibition of MAPK disrupts the HIF-p300 interaction and suppresses the transactivation activity of p300. Overexpression of MEK1, an upstream MAPK activator, stimulates the transactivation of both p300 and HIF-1 alpha. Interestingly, the C-terminal transactivation domain of HIF-1 alpha is not a direct substrate of MAPK, and HIF-1 alpha phosphorylation is not required for HIF-CAD/p300 interaction. Taken together, our data suggest that MAPK signaling facilitates HIF activation through p300/CBP.
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PMID:MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. 1258 75

Ceramide, formed by sphingomyelinase, is involved in the expression of cyclooxygenase-2 (COX-2). This study examines the effect of C2-ceramide (C2), a cell-permeable ceramide analog, on the lipopolysaccharide (LPS)-inducible COX-2 expression and signaling pathways. C2 did not induce COX-2 but potentiated LPS-inducible COX-2 expression in Raw264.7 cells, whereas dihydro-C2 was inactive. Treatment of cells with C2 notably increased LPS-inducible CCAAT/enhancer binding protein (C/EBP) DNA binding. Antibody supershift experiments revealed that LPS-induced C/EBP DNA binding activity depended on C/EBP beta and C/EBP delta but not C/EBP alpha, C/EBP epsilon or CBP/p300. C/EBP beta contributed to C2-enhanced DNA binding activity. 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB203580), a p38 kinase inhibitor, completely inhibited LPS-inducible and C2-potentiated LPS-inducible COX-2 expression. Enhancement of LPS-inducible COX-2 expression and C/EBP DNA binding by C2 was abrogated in dominant-negative mutant of JNK1 [JNK1(-)] cells. 2'-Amino-3'-methoxyflavone (PD98059) or stable transfection with dominant-negative mutant of MKK1 decreased COX-2 induction by LPS but failed to inhibit C2-enhanced LPS induction of COX-2. Transfection with dominant-negative mutant of C/EBP inhibited the ability of C2 to potentiate the induction of COX-2 by LPS. In LPS-treated cells, C2 enhanced both the nuclear translocation and the expression of LPS-inducible C/EBP beta with an increase in AP-1 DNA binding activity. These enhancements were abolished by JNK1(-) transfection. AP-1 decoy oligonucleotide suppressed C2-potentiated C/EBP beta expression, indicating that AP-1 was responsible for C2-mediated C/EBP beta expression. These results demonstrate that C2 increases C/EBP beta-mediated COX-2 induction by LPS and that the pathway of JNK1 but not ERK1/2 is responsible for C/EBP beta activation involving activator protein-1-mediated enhanced C/EBP beta expression.
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PMID:Potentiation of lipopolysaccharide-inducible cyclooxygenase 2 expression by C2-ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer binding protein beta in macrophages. 1260 57

The regulated expression of the ETS transcription factor ER81 is a prerequisite for normal development, and its dysregulation contributes to neoplasia. Here, we demonstrate that ER81 is acetylated by two coactivators/acetyltransferases, p300 and p300- and CBP-associated factor (P/CAF) in vitro and in vivo. Whereas p300 acetylates two lysine residues (K33 and K116) within the ER81 N-terminal transactivation domain, P/CAF targets only K116. Acetylation of ER81 not only enhances its ability to transactivate but also increases its DNA binding activity and in vivo half-life. Furthermore, oncogenic HER2/Neu, which induces phosphorylation and thereby activation of ER81, was less able to activate acetylation-deficient ER81 mutants, indicating that both acetyltransferase and protein kinase-specific regulatory mechanisms control ER81 activity. Importantly, HER2/Neu overexpression stimulates the ability of p300 to acetylate ER81, likely by inducing phosphorylation of p300 through the Ras-->Raf-->mitogen-activated protein kinase pathway. This represents a novel mechanism by which oncogenic HER2/Neu, Ras, or Raf may promote tumor formation by enhancing acetylation not only of ER81 but also of other downstream effector transcription factors as well as histones.
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PMID:Acetylation-mediated transcriptional activation of the ETS protein ER81 by p300, P/CAF, and HER2/Neu. 1291 45

The development of myoblasts is regulated by various growth factors as well as by intrinsic muscle-specific transcriptional factors. In this study, we analyzed the roles for STAT3 in the growth and differentiation of myoblasts in terms of cell cycle regulation and interaction with MyoD using C2C12 cells. Here we found that STAT3 inhibited myogenic differentiation induced by low serum or MyoD as efficiently as the Ras/mitogen-activated protein kinase cascade. As for this mechanism, we found that STAT3 not only promoted cell cycle progression through the induction of c-myc but also inhibited MyoD activities through direct interaction. STAT3 inhibited not only DNA binding activities of MyoD but also its transcriptional activities. However, the inhibited transcriptional activities were restored by the supplement of p300/CBP and PCAF, suggesting that STAT3 might deprive MyoD of these transcriptional cofactors. In addition, we found that MyoD inhibited DNA binding activities of STAT3, thereby inhibiting STAT3-dependent cell growth and survival of Ba/F3 cells. These results suggest that the development of muscle cells is regulated by the coordination of cytokine signals and intrinsic transcription factors.
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PMID:Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts. 1294 15


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