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: UNIPROT:P51532 (transcriptional activator)
6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GCN2 is a protein kinase in Saccharomyces cerevisiae that is required for increased expression of the transcriptional activator GCN4 in amino acid-starved cells. GCN2 stimulates GCN4 synthesis at the translational level by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2). We identified a truncated form of the GLC7 gene, encoding the catalytic subunit of a type 1 protein phosphatase, by its ability to restore derepression of GCN4 expression in a strain containing the partially defective gcn2-507 allele. Genetic analysis suggests that the truncated GLC7 allele has a dominant negative phenotype, reducing the level of native type 1 protein phosphatase activity in the cell. The truncated form of GLC7 does not suppress the regulatory defect associated with a gcn2 deletion or a mutation in the phosphorylation site of eIF-2 alpha (Ser-51). In addition, the presence of multiple copies of wild-type GLC7 impairs the derepression of GCN4 that occurs in response to amino acid starvation or dominant-activating mutations in GCN2. These findings suggest that the phosphatase activity of GLC7 acts in opposition to the kinase activity of GCN2 in modulating the level of eIF-2 alpha phosphorylation and the translational efficiency of GCN4 mRNA. This conclusion is supported by biochemical studies showing that the truncated GLC7 allele increases the level of eIF-2 alpha phosphorylation in the gcn2-507 mutant to a level approaching that seen in wild-type cells under starvation conditions. The truncated GLC7 allele also leads to reduced glycogen accumulation, indicating that this protein phosphatase is involved in regulating diverse metabolic pathways in yeast cells.
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PMID:Truncated protein phosphatase GLC7 restores translational activation of GCN4 expression in yeast mutants defective for the eIF-2 alpha kinase GCN2. 133 44

The plant hormone abscisic acid (ABA) regulates the development and germination of seeds, as well as the adaptation of vegetative tissues to conditions of environmental stress. During the past year, considerable insights have been gained into the molecular nature of the complex signaling network that mediates the actions of ABA. Biophysical studies indicate that at least some of the effects of ABA in stomatal guard cells involve intracellular receptors. Also, increasing evidence supports the view that guard cells contain redundant ABA transduction pathways, and that cytoplasmic Ca2+ acts as a second messenger in at least one of these pathways. Finally, mutational analysis in Arabidopsis indicates that the multiple effects of ABA at the whole plant level are mediated by overlapping branches of a highly ramified signaling network. Two Arabidopsis loci that determine ABA sensitivity have already been cloned and found to encode a protein phosphatase and a transcriptional activator.
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PMID:Abscisic acid signaling. 761 76

Ceramide is known to induce pRb (retinoblastoma gene product) dephosphorylation through the activation of ceramide-activated protein phosphatase (CAPP) during G1 arrest, but other molecular mechanisms linked to regulation of pRb dephosphorylation during ceramide-induced G1 arrest are poorly understood. In this paper, we investigated whether p21, a cdk (cyclin-dependent kinase) inhibitor, is involved in the induction of pRb dephosphorylation during ceramide-induced G1 arrest. In SK-Hep-1 cells, the addition of ceramide resulted in pRb dephosphorylation and G1 arrest. The activity of cdk2 was inhibited in response to ceramide during this process. p21 protein and mRNA were remarkably induced, while the protein level of p53, known as a transcriptional activator of p21, was not elevated at the same condition. p21 induction was also observed in the Hep3B cells lacking a functional p53 after exposure to ceramide. Although p21 is induced in ceramide-treated Hep3B cells, Hep3B cells do not induce G1 arrest, because Hep3B cells are deficient in a functional pRb protein. To confirm that pRb is a critical target for the induction of G1 arrest by inhibiting cdk2 activity through p53-independent p21, pRb-expressing vector was transfected into Hep3B cells. After treatment with ceramide, pRb-expressing cells (pRb+/+), but not pRb-/- cells, were arrested in G1 phase. In pRb+/+ cells, ceramide-mediated G1 arrest was accompanied by the accumulation of hypophosphorylated pRb and p21 associated with cdk2. Together, these results suggest that p21, induced through p53-independent pathway, participates in the induction of pRb dephosphorylation by inhibiting cdk2 activity during ceramide-mediated G1 arrest in hepatocarcinoma cells.
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PMID:Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells. 1087 74

cis,trans-Abscisic acid (ABA) plays an important role in plant growth and development, regulation of seed maturation, germination, and adaptation to environmental stresses. Knowledge of ABA mechanisms of action and the interactions of components required for ABA signal transduction is far from complete. Using transient gene expression in rice protoplasts, we observed additive and inhibitory effects between maize VP1 (Viviparous-1, a transcriptional activator) and a dominant-negative mutant protein phosphatase, ABI1-1 (ABA-insensitive-1-1), from Arabidopsis. Lanthanide ions were shown to be specific agonists of ABA-inducible gene expression and to interact synergistically with ABA and overexpressed VP1. Both VP1 and lanthanum activities could be antagonized by coexpression of ABI1-1, which demonstrates the specific ABA dependence of these effectors on ABA-regulated gene expression. We obtained pharmacological evidence that phospholipase D (PLD) functions in ABA-inducible gene expression in rice. Antagonism of ABA, VP1, and lanthanum synergy by 1-butanol, a specific inhibitor of PLD, was similar to the inhibition by coexpression of ABI1-1. These results demonstrate that ABA, VP1, lanthanum, PLD, and ABI1 are all involved in ABA-regulated gene expression and are consistent with an integrated model whereby La(3+) acts upstream of PLD.
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PMID:Functional interactions of lanthanum and phospholipase D with the abscisic acid signaling effectors VP1 and ABI1-1 in rice protoplasts. 1113 77

The subcellular localization of Msn2, a transcriptional activator of STRE (stress response element)-regulated genes, is modulated by carbon source availability. In cells growing in glucose, Msn2 is located mainly in the cytosol, whereas in carbon source-starved cells, Msn2 is located largely inside the nucleus. However, in cells lacking Reg1 (the regulatory subunit of the Reg1/Glc7 protein phosphatase complex), the regulation of subcellular distribution is absent, Msn2 being constitutively present in the cytosol. The localization defect in these mutants is specific for carbon starvation stress, and it is because of the presence of an abnormally active Snf1 protein kinase that inhibits the nuclear localization of Msn2 upon carbon starvation. Active Snf1 kinase is also able to avoid the effects of rapamycin, a drug that by inhibiting the TOR kinase pathway leads to a nuclear localization of Msn2 in wild type cells. Therefore, active Snf1 and the TOR kinase pathway may affect similar cytosolic steps in the regulation of the subcellular localization of Msn2.
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PMID:Convergence of the target of rapamycin and the Snf1 protein kinase pathways in the regulation of the subcellular localization of Msn2, a transcriptional activator of STRE (Stress Response Element)-regulated genes. 1209 9

The yeast transcriptional activator Adr1 controls the expression of genes required for ethanol, glycerol, and fatty acid utilization. We show that Adr1 acts directly on the promoters of ADH2, ACS1, GUT1, CTA1, and POT1 using chromatin immunoprecipitation assays. The yeast homolog of the AMP-activated protein kinase, Snf1, promotes Adr1 chromatin binding in the absence of glucose, and the protein phosphatase complex, Glc7.Reg1, represses its binding in the presence of glucose. A post-translational process is implicated in the regulation of Adr1 binding activity. Chromatin binding by Adr1 is not the only step in ADH2 transcription that is regulated by glucose repression. Adr1 can bind to chromatin in repressed conditions in the presence of hyperacetylated histones. To study steps subsequent to promoter binding we utilized miniAdr1 transcription factors to characterize Adr1-dependent transcription in vitro. Yeast nuclear extracts prepared from glucose-repressed and glucose-derepressed cells are equally capable of supporting miniAdr1-dependent transcription and pre-initiation complex formation. Nuclear extracts prepared from a snf1 mutant support miniAdr1-dependent transcription but are partially defective in the formation of pre-initiation complexes with Mediator components being particularly depleted. We conclude that Snf1 regulates Adr1-dependent transcription primarily at the level of chromatin binding.
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PMID:Snf1 protein kinase regulates Adr1 binding to chromatin but not transcription activation. 1216 49

In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.
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PMID:Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. 1472 79

Skeletal muscle adapts to different patterns of motor nerve activity by alterations in gene expression that match specialized properties of contraction, metabolism, and muscle mass to changing work demands (muscle plasticity). Calcineurin, a calcium/calmodulin-dependent, serine-threonine protein phosphatase, has been shown to control programs of gene expression in skeletal muscles, as in other cell types, through the transcription factor nuclear factor of activated T cells (NFAT). This study provides evidence that the function of NFAT as a transcriptional activator is regulated by neuromuscular stimulation in muscles of intact animals and that calcium influx from the transient receptor potential (TRPC3) channel is an important determinant of NFAT activity. Expression of TRPC3 channels in skeletal myocytes is up-regulated by neuromuscular activity in a calcineurin-dependent manner. These data suggest a mechanism for cellular memory in skeletal muscles whereby repeated bouts of contractile activity drive progressively greater remodeling events.
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PMID:TRPC3 channels confer cellular memory of recent neuromuscular activity. 1519 80

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

In yeast, glucose depletion elicits a quick response in the transcription of stress-related genes. The main transcriptional activator that orchestrates this response is Msn2, whose nuclear localization and DNA binding are negatively controlled by the cAMP-dependent protein kinase (PKA). Msn2 activation by sudden glucose depletion correlates with a fast but transient decrease in phosphorylation of several sites in its nuclear localization signal (NLS). Here we show that protein phosphatase 1 (PP1) is the direct antagonist of PKA-dependent phosphorylation at the Msn2 nuclear import domain and therefore a potential mediator of glucose starvation signals that target this transcription factor. Apart from PKA, the protein kinase Snf1 can also directly modify one of the Msn2 phosphorylation sites (S582) and thereby repress Msn2 function. Consequently, in snf1 mutants, rephosphorylation of the NLS happens to be much slower during prolonged starvation. Thus, a second, Reg1-dependent form of PP1 indirectly influences Msn2 functionality by modulating Snf1 kinase activation and repression. Different activities of PP1 are therefore involved in shaping induction and adaptation of the transcriptional stress response during acute glucose starvation.
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PMID:A dual role for PP1 in shaping the Msn2-dependent transcriptional response to glucose starvation. 1628 Oct 53


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