Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this program of studies we have characterized in detail the translocation (assessed by Triton-insolubility) and phosphorylation (using serine-45 or -59 phosphospecific antibodies) of alphaB crystallin during myocardial ischemia [both with or without ischemic preconditioning (IPC)]. Pharmacological activators and inhibitors allowed us to characterize the signaling pathways involved in alphaB crystallin phosphorylation during ischemia. Ischemic preconditioning alone caused 30% of the heart's alphaB crystallin pool to translocate, providing a significant translocation 'head-start' in protected tissue. This enhanced translocation is coupled with increased (3-fold) alphaB crystallin phosphorylation at both serine residues. The possible role of alphaB crystallin in the protection afforded by ischemic preconditioning is supported by the signal transduction data; which showed preconditioning-induced alphaB crystallin phosphorylation can be blocked by tyrosine kinase inhibition (using genistein) and by p38 MAP kinase or PKC inhibition (using SB203580 or bisindolylmaleimide, respectively). The activation of both p38 MAP kinase and PKC are recognized requirements for the induction of preconditioning and their inhibition is known to block protection. Western immunoblotting analysis after isoelectric focusing electrophoresis, confirmed the observations made with the phosphospecific antibodies; but also showed that 27+/-4% of total cardiac crystallin was phosphorylated after 30 min of ischemia. AlphaB crystallin exists as large polymeric aggregates in cardiac tissue under basal conditions (approximately 1 MDa as determined by gel filtration chromatography). We induced phosphorylation of alphaB crystallin during aerobic perfusion by the administration of phenylephrine. However this treatment did not alter the molecular aggregate size of alphaB crystallin. It appears that alphaB crystallin molecular aggregate size is not simply regulated by phosphorylation. AlphaB crystallin may have a role to play in the myocardial protection induced by ischemic preconditioning, as both translocation and phosphorylation are both accelerated and enhanced by ischemic preconditioning.
J Mol Cell Cardiol 2001 Sep
PMID:AlphaB crystallin translocation and phosphorylation: signal transduction pathways and preconditioning in the isolated rat heart. 1154 45

Acetaminophen (AAP), a widely used analgesic drug, can damage various organs when taken in large doses. In this study, we investigate whether AAP causes cell damage by altering the early signaling pathways associated with cell death and survival. AAP caused time- and concentration-dependent apoptosis and DNA fragmentation of C6 glioma cells used as a model. AAP activated c-Jun N-terminal protein kinase (JNK) by 5.3-fold within 15 min. The elevated JNK activity persisted for up to 4 h before it returned to the basal level at 8 h. In contrast, activities of other mitogen-activated protein (MAP) kinases and the level of Akt phosphorylation in the cell survival pathway remained unchanged throughout the treatment. Wortmannin, an inhibitor of phosphatidylinositol-3 kinase, or SB203580, an inhibitor of p38 MAP kinase, did not reduce AAP-induced toxicity, indicating that these enzymes do not play a major role in cell toxicity. AAP-induced apoptosis was preceded by the sequential elevation of the pro-apoptotic Bax protein, cytochrome c release, and caspase-3 activity. Treatment with caspase inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK) significantly reduced AAP-induced caspase-3 activation and cytotoxicity. Transfection of cDNA for the dominant-negative mutant JNK-KR or stress-activated protein kinase kinase-1 Lys-->Arg mutant (SEK1-KR), an immediate upstream kinase of JNK, significantly reduced AAP-induced JNK activation and cell death rate. The noncytotoxic analog of AAP, 3-hydroxyacetanilide, neither increased JNK activity nor caused apoptosis. Pretreatment with YH439, an inhibitor of CYP2E1 gene transcription, markedly reduced CYP2E1 mRNA, protein content, and activity, as well as the rate of AAP-induced JNK activation and cell death. These data indicate that AAP can cause cell damage by activating the JNK-related cell death pathway, providing a new mechanism for AAP-induced cytotoxicity.
Mol Pharmacol 2001 Oct
PMID:Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway. 1156 48

Mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) has been shown to play a critical role in mediating the feedback control of MAP kinase cascades in a variety of cellular processes, including proliferation and stress responsiveness. Although MKP-1 expression is induced by a broad array of extracellular stimuli, the mechanisms mediating its induction remain poorly understood. Here we show that MKP-1 mRNA was potently induced by arsenite and ultraviolet light and modestly increased by heat shock and hydrogen peroxide. Interestingly, arsenite also dramatically induces phosphorylation-acetylation of histone H3 at a global level which precedes the induction of MKP-1 mRNA. The transcriptional induction of MKP-1, histone H3 modification, and elevation in MKP-1 mRNA in response to arsenite are all partially prevented by the p38 MAP kinase inhibitor SB203580, suggesting that the p38 pathway is involved in these processes. Finally, analysis of the DNA brought down by chromatin immunoprecipitation (ChIP) reveals that arsenite induces phosphorylation-acetylation of histone H3 associated with the MKP-1 gene and enhances binding of RNA polymerase II to MKP-1 chromatin. ChIP assays following exposure to other stress agents reveal various degrees of histone H3 modification at the MKP-1 chromatin. The differential contribution of p38 and ERK MAP kinases in mediating MKP-1 induction by different stress agents further illustrates the complexity and versatility of stress-induced MKP-1 expression. Our results strongly suggest that chromatin remodeling after stress contributes to the transcriptional induction of MKP-1.
Mol Cell Biol 2001 Dec
PMID:Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. 1168 10

Cachexia is a chronic state of negative energy balance and muscle wasting that is a severe complication of cancer and chronic infection. While cytokines such as IL-1alpha, IL-1beta, and TNFalpha can mediate cachectic states, how these molecules affect energy expenditure is unknown. We show here that many cytokines activate the transcriptional PPAR gamma coactivator-1 (PGC-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of PGC-1 protein. Cytokine or lipopolysaccharide (LPS)-induced activation of PGC-1 in cultured muscle cells or muscle in vivo causes increased respiration and expression of genes linked to mitochondrial uncoupling and energy expenditure. These data illustrate a direct thermogenic action of cytokines and p38 MAP kinase through the transcriptional coactivator PGC-1.
Mol Cell 2001 Nov
PMID:Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. 1174 33

We tested the hypothesis that mechanical plasticity of airway smooth muscle may be mediated in part by the p38 mitogen-activated protein (MAP) kinase pathway. Bovine tracheal smooth muscle (TSM) strips were mounted in a muscle bath and set to their optimal length, where the active force was maximal (F(o)). Each strip was then contracted isotonically (at 0.32 F(o)) with ACh (maintained at 10(-4) M) and allowed to shorten for 180 min, by which time shortening was completed and the static equilibrium length was established. To simulate the action of breathing, we then superimposed on this steady distending force a sinusoidal force fluctuation with zero mean, at a frequency of 0.2 Hz, and measured incremental changes in muscle length. We found that TSM strips incubated in 10 microM SB-203580-HCl, an inhibitor of the p38 MAP kinase pathway, demonstrated a greater degree of fluctuation-driven lengthening than did control strips, and upon removal of the force fluctuations they remained at a greater length. We also found that the force fluctuations themselves activated the p38 MAP kinase pathway. These findings are consistent with the hypothesis that inhibition of the p38 MAP kinase pathway destabilizes muscle length during physiological loading.
Am J Physiol Lung Cell Mol Physiol 2002 May
PMID:Inhibition of the p38 MAP kinase pathway destabilizes smooth muscle length during physiological loading. 1194 78

Nuclear factor of activated T cells (NFAT) is implicated in multiple biological processes, including cytokine gene expression, cardiac hypertrophy, and adipocyte differentiation. A conserved NFAT homology domain is identified in all NFAT members. Dephosphorylation of the NFAT homology region is critical for NFAT nuclear translocation and transcriptional activation. Here we demonstrate that NFATc4 is phosphorylated by p38 mitogen-activated protein (MAP) kinase but not by JNK. The p38 MAP kinase phosphorylates multiple residues, including Ser(168) and Ser(170), in the NFAT homology domain of NFATc4. Replacement of Ser(168,170) with Ala promotes nuclear localization of NFATc4 and increases NFAT-mediated transcription activity. Stable expression of Ala(168,170) NFATc4, but not of wild-type NFATc4, in NIH 3T3 cells promotes adipocyte formation under differentiation conditions. Molecular analysis indicates that peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2) is a target of NFAT. Two distinct NFAT binding elements are located in the PPAR gamma 2 gene promoter. Stable expression of Ala(168,170) NFATc4, but not of wild-type NFATc4, increases the expression of PPAR gamma, which contributes in part to increased adipocyte formation. Thus, NFAT regulates PPAR gamma gene expression and has a direct role in adipocyte differentiation.
Mol Cell Biol 2002 Jun
PMID:Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. 1199 22

Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.
Mol Cell Biol 2002 Jun
PMID:Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade. 1202 21

The immunomodulatory effect of hyperbaric oxygen, involving altered cytokine release by macrophages, is well described. Importantly, however, it is not known what the relative contribution is of the hyperbaric environment of the cells vs. increased oxygen tension on these hyperbaric oxygen-dependent effects. We compared, therefore, cytokine release by murine macrophages under hyperbaric oxygen, hyperpressure of normal air and normobaric conditions. We observed that hyperbaric oxygen enhanced cytokine release of both unstimulated as well as lipopolysaccharide (LPS)-challenged macrophages. Hyperpressure of normal air, however, enhanced LPS-induced cytokine production but did not elicit cytokine release in unstimulated macrophages. To further investigate the molecular details underlying the effects of hyperbaric oxygen, we investigated the effect of the p42/p44 mitogen-activated protein (MAP) kinase inhibitor PD98059 and the p38 MAP kinase inhibitor SB203580. Neither inhibitor, however, had a significant effect on the modulatory effects of hyperbaric oxygen on cytokine release. We concluded that the immunomodulatory effect of hyperbaric oxygen contains a component for which hyperpressure is sufficient and a component that apart from hyperpressure also requires hyperoxygenation.
Comp Biochem Physiol A Mol Integr Physiol 2002 May
PMID:Immunomodulatory effect of oxygen and pressure. 1206 9

Small molecule inhibitors have proven extremely useful for investigating signal transduction pathways and have the potential for development into therapeutics for inhibiting signal transduction pathways whose activities contribute to human diseases. Transforming growth factor beta (TGF-beta) is a member of a large family of pleiotropic cytokines that are involved in many biological processes, including growth control, differentiation, migration, cell survival, adhesion, and specification of developmental fate, in both normal and diseased states. TGF-beta superfamily members signal through a receptor complex comprising a type II and type I receptor, both serine/threonine kinases. Here, we characterize a small molecule inhibitor (SB-431542) that was identified as an inhibitor of activin receptor-like kinase (ALK)5 (the TGF-beta type I receptor). We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are very highly related to ALK5 in their kinase domains. It has no effect on the other, more divergent ALK family members that recognize bone morphogenetic proteins (BMPs). Consistent with this, we demonstrate that SB-431542 is a selective inhibitor of endogenous activin and TGF-beta signaling but has no effect on BMP signaling. To demonstrate the specificity of SB-431542, we tested its effect on several other signal transduction pathways whose activities depend on the concerted activation of multiple kinases. SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways or on components of the signaling pathways activated in response to serum.
Mol Pharmacol 2002 Jul
PMID:SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. 1206 56

5-Lipoxygenase (5-LO) catalyzes the transformation of arachidonic acid to leukotrienes (LT). In stimulated human PMN, activation of 5-LO involves calcium, p38 MAP kinase (p38) phosphorylation, and translocation of 5-LO from the cytosol to nuclear membranes containing the 5-LO activating protein (FLAP). In this study, cAMP-elevating agents such as isoproterenol, prostaglandin E(2), CGS-21680 (an adenosine A(2a) receptor agonist), the type IV phosphodiesterase inhibitor RO 20-1724, the adenylate cyclase activator forskolin, and the Gs-protein activator cholera toxin all inhibited LT biosynthesis and 5-LO translocation to the nucleus in cytokine-primed human PMN stimulated with platelet-activating factor and in human PMN stimulated with the endomembrane Ca(2+)-ATPase blocker thapsigargin. Furthermore, monophosphorothioate analogs of cAMP, which activate protein kinase A (PKA), also inhibited LT biosynthesis and 5-LO translocation in stimulated cells. Treatment of PMN with CGS-21680 also prevented the phosphorylation of p38 by thapsigargin. Treatment of PMN with the PKA inhibitors H-89 and KT-5720 prevented the inhibitory effect of cAMP-elevating agents on LT biosynthesis, 5-LO translocation, and p38 phosphorylation, whereas the p38 inhibitor SB 203,580 dose-dependently inhibited arachidonic acid-induced LT biosynthesis. The 5-LO translocation was also inhibitable by the FLAP antagonist MK-0591 and correlated with LT biosynthesis in all experimental conditions tested. These results indicate that cAMP-mediated PKA activation in PMN results in the concomitant inhibition of 5-LO translocation and LT biosynthesis and support a role of p38 in the signaling pathway involved. This represents the first physiological down-regulation mechanism of 5-LO translocation in human PMN.
Mol Pharmacol 2002 Aug
PMID:Cyclic AMP-mediated inhibition of 5-lipoxygenase translocation and leukotriene biosynthesis in human neutrophils. 1213 Jun 75


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