Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AfsK, a protein serine/threonine kinase, autophosphorylates on serine and threonine residues and phosphorylates serine and threonine residues of AfsR, a transcriptional activator for afsS involved in secondary metabolism in Streptomyces coelicolor A3(2). pkaG encoding a 592-amino-acid protein and SCD10.09 (named afsL) encoding a 580-amino-acid protein, both of which encode an AfsK-like protein, were transcribed throughout growth. PkaG with a histidine-tag and the kinase catalytic domain of PkaG, produced in Escherichia coli, autophosphorylated dominantly on threonine and slightly on serine residues. In addition, these proteins phosphorylated AfsR on threonine and serine residues. The catalytic domain of AfsL also autophosphorylated and phosphorylated AfsR, on threonine and serine residues in both cases. AfsR was thus found to be phosphorylated by multiple kinases. Disruption of the chromosomal pkaG gene resulted in slightly reduced production of the pigmented antibiotic actinorhodin. These findings, together with the presence of about 40 AfsK homologues and at least five AfsR homologues in S. coelicolor A3(2), suggest that the regulatory networks via eukaryotic-type protein phosphorylation are more diverse and versatile than we have expected.
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PMID:Phosphorylation of AfsR by multiple serine/threonine kinases in Streptomyces coelicolor A3(2). 1525 55

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

Latent Epstein-Barr virus (EBV) infection is strongly associated with B-cell proliferative diseases such as Burkitt's lymphoma. Here we show that the oncogenic serine/threonine kinases Pim-1 and Pim-2 enhance the activity of the viral transcriptional activator EBNA2. During EBV infection of primary B-lymphocytes, the mRNA expression levels of pim genes, especially of pim-2, are upregulated and remain elevated in latently infected B-cell lines. Thus, EBV-induced upregulation of Pim kinases and Pim-stimulated EBNA2 transcriptional activity may contribute to the ability of EBV to immortalize B-cells and predispose them to malignant growth.
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PMID:Pim kinases are upregulated during Epstein-Barr virus infection and enhance EBNA2 activity. 1572 54

FCP1 (TFIIF-associated CTD phosphatase) is the first identified CTD-specific phosphatase required to recycle RNA polymerase II (RNAP II). FCP1 activity has been shown to be regulated by the general transcription factors TFIIF (RAP74) and TFIIB, protein kinase CK2 (CK2), and the HIV-1 transcriptional activator Tat. Phosphorylation of FCP1 by CK2 stimulates FCP1 phosphatase activity and enhances binding of RAP74 to FCP1. We have examined consensus CK2 phosphorylation sites (acidic residue n + 3 to serine or threonine residue) located immediately adjacent to both RAP74-binding sites of FCP1. We demonstrate that both of these consensus CK2 sites can be phosphorylated in vitro and that phosphorylation at either CK2 site results in enhanced binding of RAP74 to FCP1. The CK2 site adjacent to the RAP74-binding site in the central domain of FCP1 is phosphorylated at a single threonine site (T584). The CK2 site adjacent to the RAP74-binding site in the carboxyl-terminal domain can be phosphorylated at three successive serine residues (S942-S944), with phosphorylations at S942 and S944 both contributing to enhanced binding to RAP74. With the use of tandem Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR), we demonstrate that the phosphorylation of S942-S944 occurs in a semiordered fashion with the initial phosphorylation occurring at either S942 or S944 followed by a second phosphorylation to yield the S942/S944 diphosphorylated species. Using nuclear magnetic resonance (NMR) spectroscopy, we identify and map chemical shift changes onto the solution structure of the carboxyl-terminal domain of RAP74 (RAP74(436)(-)(517)) on complexation of RAP74(436)(-)(517) with phosphorylated FCP1 peptides. These results provide new functional and structural information on the role of phosphorylation in the recognition of acidic-rich activation domains involved in transcriptional regulation, and bring insights into how CK2 and TFIIF regulate FCP1 function.
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PMID:Enhanced binding of RNAP II CTD phosphatase FCP1 to RAP74 following CK2 phosphorylation. 1572 18

Phosphorylation of the mycobacterial transcriptional activator, EmbR, is essential for transcriptional regulation of the embCAB operon encoding cell wall arabinosyltransferases. This signaling pathway eventually affects the resistance to ethambutol (a frontline antimycobacterial drug) and the cell wall Lipoarabinomannan/Lipomannan ratio (an important determinant for averting the host immune response). In this study, further biochemical characterization revealed that EmbR, as a transcriptional regulator, interacts with RNA polymerase and possesses a phosphorylation-dependent ATPase activity that might play a role in forming an open complex between EmbR and RNA polymerase. EmbR was recently shown to be phosphorylated by the cognate mycobacterial serine/threonine (Ser/Thr) kinase, PknH. Using bioinformatic analysis and in vitro assays, we identified additional novel regulators of the signaling pathway leading to EmbR phosphorylation, namely the Ser/Thr protein kinases PknA and PknB. A previously unresolved question raised by this signaling scheme is the fate of phosphorylated kinases and EmbR at the end of the signaling cycle. Here we show that Mstp, a mycobacterial Ser/Thr phosphatase, antagonizes Ser/Thr protein kinase-EmbR signaling by dephosphorylating Ser/Thr protein kinases, as well as EmbR, in vitro. Additionally, dephosphorylation of EmbR reduced its ATPase activity, interaction with Ser/Thr protein kinases and DNA-binding activity, emphasizing the antagonistic role of Mstp in the EmbR-Ser/Thr protein kinase signaling system.
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PMID:EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis. 1681 99

The transcriptional regulator VIVIPA-ROUS1 (VP1) is composed of four functional domains that control different aspects of gene expression during seed development. The B2 domain is required for its role as a transcriptional activator, functioning at the site of transcription and/or for its transport into the nucleus. Previous work showed that the B2 domain was required for transactivation of the Em promoter. We demonstrate that VP1::GFP localizes to the nucleus of barley (Hordeum vulgare) aleurone cells, but when B2 is deleted, nuclear accumulation is lost. However, the B2 domain itself is not sufficient for nuclear localization of GFP::GUS. Using point mutagenesis on the putative NLS within B2, we show that the VP1::GFP still accumulates in the nucleus. Utilizing a comparative approach, through the alignment of B2 domains from various VP1/ABI3 proteins, oincluding the ABI3 orthologs from Physcomitrella patens, revealed the involvement of other conserved amino acids. Mutating VP1 at the conserved threonine on the N-terminal side of the putative NLS and at a conserved arginine-glutamine-arginine sequence on the C-terminal side prevented nuclear localization of VP1. A single amino acid change, from alanine to threonine, within this NLS found in the Arabidopsis abi3-7 mutant prevents transcription of AtEm1 and AtEm6 in vivo. We show that this same mutation in VP1 prevents transactivation of the Em-GUS reporter in barley aleurone but does not interfere with nuclear localization. Our data demonstrate that the B2 domain of VP1 is bifunctional in nature regulating both nuclear localization and transactivation.
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PMID:The B2 domain of VIVIPAROUS1 is bi-functional and regulates nuclear localization and transactivation. 1697 53

E2F-1 mediates apoptosis through transcriptional regulation of its targets. We report here that E2F-1 acts as a direct transcriptional regulator of dual specificity phosphatase 1 (DUSP1; CL100), a threonine and tyrosine phosphatase that inhibits mitogen-activated protein (MAP) kinases. We found that DUSP1 is transcriptionally induced by ectopic E2F-1 expression and that extracellular signal-regulated kinase 1/2 are dephosphorylated in the presence of E2F-1 and DUSP1. E2F-1 mediates apoptosis in the cellular response to oxidative stress. DUSP1 levels are significantly increased in an E2F-1-dependent manner following oxidative stress but not other stresses examined. DUSP1 mediates the cellular response to oxidative stress. We found that E2F-1 binds to chromatin encompassing the DUSP1 promoter and greatly stimulates the promoter activity of the DUSP1 gene. In particular, E2F-1 physically binds to an E2F-1 consensus sequence and a palindromic motif in the DUSP1 promoter. Interestingly, E2F-1 is acetylated following oxidative stress. Our findings show that E2F-1 is a transcriptional activator of DUSP1 and that DUSP1 is a link between E2F-1 and MAP kinases.
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PMID:Dual specificity phosphatase 1/CL100 is a direct transcriptional target of E2F-1 in the apoptotic response to oxidative stress. 1763 84

CREB is a cAMP- and calcium-responsive transcriptional activator that is required for islet beta cell proliferation and survival. Glucose and incretin hormones elicit beta cell insulin secretion and promote synergistic CREB activity by inducing the nuclear relocalization of TORC2 (also known as Crtc2), a coactivator for CREB. In islet cells under basal conditions when CREB activity is low, TORC2 is phosphorylated and sequestered in the cytoplasm by 14-3-3 proteins. In response to feeding stimuli, TORC2 is dephosphorylated, enters the nucleus, and binds to CREB located at target gene promoters. The dephosphorylation of TORC2 at Ser-171 in response to cAMP is insufficient to account for the dynamics of TORC2 localization and CREB activity in islet cells. Here, we identify Ser-275 of TORC2 as a 14-3-3 binding site that is phosphorylated under low glucose conditions and which becomes dephosphorylated by calcineurin in response to glucose influx. Dephosphorylation of Ser-275 is essential for both glucose and cAMP-mediated activation of CREB in beta cells and islets. Using a cell-based screen of 180 human protein kinases, we identified MARK2, a member of the AMPK family of Ser/Thr kinases, as a Ser-275 kinase that blocks TORC2:CREB activity. Taken together, these data provide the mechanistic underpinning for how cAMP and glucose cooperatively promote a transcriptional program critical for islet cell survival, and identifies MARK2 as a potential target for diabetes treatment.
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PMID:Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. 1862 18

Fruiting body development of Myxococcus xanthus is propelled by temporal gene expression directed via stage-specific intercellular signaling pathways. M. xanthus exhibits social behaviors during its complex life cycle and is a potential source for production of natural products such as secondary metabolites. The numerous signaling pathways of M. xanthus consist of not only the two-component His-Asp phosphorelay system (TCS) but also protein Ser/Thr kinases (PSTKs) that regulate gene expression, motility and multicellular development. Recent studies have uncovered the unique molecular regulatory mechanism of MrpC, a transcription factor essential for fruiting body development and sporulation. mrpC expression is activated early in development by MrpB, which belongs to the NtrC family of TCS. MrpC, is, in turn, a transcriptional activator of fruA that encodes another key transcription factor, FruA. FruA is essential for fruiting body development and sporulation and regulates positively and negatively the synthesis of many developmental proteins. In addition, expression of mrpC during vegetative growth is kept at a low level by the PSTK Pkn8-Pkn14 kinase cascade which negatively regulates MrpC-binding activity to its own promoter. Therefore, M. xanthus utilizes a novel dual system with both eukaryotic PSTK cascade and prokaryotic TCS signaling systems to tightly and precisely regulate MrpC levels, which activate timely fruA expression and propel fruiting body development and sporulation.
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PMID:Dual regulation with Ser/Thr kinase cascade and a His/Asp TCS in Myxococcus xanthus. 1879 84

EWS-Fli1, a fusion gene resulting from the chromosomal translocation t(11;22, q24;q12), encodes a transcriptional activator, promotes cellular transformation, and is often found in Ewing sarcoma and primitive neuroectodermal tumor. The Aurora A and Aurora B kinases belong to a highly conserved family of serine/threonine protein kinases, are tightly regulated during the cell cycle, and are overexpressed in many carcinomas. Because the relationship between the Aurora A and/or Aurora B genes and the EWS-Fli1 fusion gene is unknown, we investigated the regulatory mechanism(s) by which Aurora kinases are controlled. Knockdown of EWS-Fli1 by small interfering RNA reduced mRNA levels not only of EWS-Fli1 but also of Aurora A and Aurora B. Luciferase assay using Aurora A and Aurora B promoters showed up-regulated activities compared with those of an empty vector. Experiments with deletion and point mutants showed positive regulatory Ets-binding sites located -84 and -71 bp upstream of the transcription initiation sites in Aurora A and Aurora B, respectively. Moreover, chromatin immunoprecipitation assay revealed that EWS-Fli1 gene products interact with both the Aurora A and Aurora B promoters. These results strongly suggest that the mitotic kinases Aurora A and Aurora B are regulated by EWS-Fli1 fusion protein in Ewing sarcoma cells.
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PMID:EWS-Fli1 up-regulates expression of the Aurora A and Aurora B kinases. 1907 38


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