UNIPROT:P51532 - FACTA Search

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

CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase). A specific inhibitor of p38 MAP kinase, SB203580, abolished the stress-inducible in vivo phosphorylation of CHOP. Phosphorylation of CHOP on these residues enhanced its ability to function as a transcriptional activator and was also required for the full inhibitory effect of CHOP on adipose cell differentiation. CHOP thus serves as a link between a specific stress-activated protein kinase, p38, and cellular growth and differentiation.
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PMID:Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. 865 May 47

NF-kappa B is a ubiquitous transcription factor that contributes to the induction of many genes playing a central role in immune and inflammatory responses. The NF-kappa B proteins are subject to multiple regulatory influences including post-translational modifications such as phosphorylation and proteolytic processing. A very important component of this regulation is the control of their subcellular localization: cytoplasmic retention of NF-kappa B is achieved through interaction with I kappa B molecules. In response to extracellular signals, these molecules undergo degradation, NF-kappa B translocates to the nucleus and activates its target genes. To investigate novel proteins involved in this dynamic response, we have reconstituted the NF-kappa B/I kappa Beta system in the yeast Saccharomyces cerevisiae. We have successively introduced p65, the main transcriptional activator of the NF-kappa B family, which leads to the activation of two reporter genes controlled by kappa B sites, and the I kappa B alpha inhibitory protein, which abolishes this activation. By transforming such a yeast strain with a cDNA library we have performed a genetic screen for cDNAs encoding proteins capable of either dissociating the p65/I kappa B alpha complex or directly transactivating the expression of the reporter genes. The efficiency of our screen was demonstrated by the isolation of a cDNA encoding the p105 precursor of the p50 subunit of NF-kappa B. We also used this system to test stimuli known to activate signalling pathways in yeast, in order to investigate whether the related mammalian cascades might be involved in NF-kappa B activation. We showed that yeast endogenous kinase cascades activated by pheromone, hypo- or hyperosmotic shock cannot modulate NF-kappa B activity in our system, and that the p38 human MAP kinase does not act directly on the p65/I kappa B alpha complex.
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PMID:Reconstitution of the NF-kappa B system in Saccharomyces cerevisiae for isolation of effectors by phenotype modulation. 920 Aug 10

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

Recent studies have established an essential role for p38 MAP kinase in UV activation of human immunodeficiency virus (HIV) gene expression. However, p38 MAP kinase is not involved in activation of NF-kappa B, a key transcriptional activator of HIV gene expression, in response to UV, suggesting that NF-kappa B acts independently of p38 MAP kinase. In this study, we have investigated whether activation of HIV gene expression occurs when p38 MAP kinase and NF-kappa B are activated by separate stress-causing treatments, each relatively specific for activating only one of the factors. Treatment of cells with sorbitol (hyperosmotic shock) strongly activates p38 MAP kinase, whereas the cytokine TNF-alpha is a poor activator of p38 MAP kinase. On the other hand, TNF-alpha is a strong activator of NF-kappa B whereas sorbitol is not. Sorbitol, however, activates AP-1 DNA binding activity in a manner similar to that of UV. Most importantly, both sorbitol and TNF-alpha are poor activators of HIV gene expression in HeLa cells stably transfected with an HIVcat reporter gene, whereas UV elicits a strong response. The combined treatment with UV and hyperosmotic shock produces an additive effect on HIV gene expression, suggesting that these agents activate at least in part by different mechanisms. The combined treatment with sorbitol and TNF-alpha activates p38 and NF-kappa B to levels similar to those with UV, yet only results in 25-30% of the CAT levels elicited by UV. Inhibition of NF-kappa B activation by the protease inhibitor N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) prevents UV activation of HIV gene expression, but does not inhibit p38 MAP kinase activation. We conclude that whereas both p38 MAP kinase and NF-kappa B are important for UV activation of HIV gene expression they act independently from each other and activation of both factors is not sufficient for triggering a full HIV gene expression response. Activation of HIV gene expression by UV must therefore involve additional cellular processes, such as those triggered by DNA damage, for generation of a full gene expression response.
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PMID:Activation of NF-kappa B and p38 MAP kinase is not sufficient for triggering efficient HIV gene expression in response to stress. 1067 19

Nontypeable Hemophilus influenzae (NTHi) is an important human pathogen in both children and adults. In children, it causes otitis media, the most common childhood infection and the leading cause of conductive hearing loss in the United States. In adults, it causes lower respiratory tract infections in the setting of chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. The molecular mechanisms underlying the pathogenesis of NTHi-induced infections remain undefined, but they may involve activation of NF-kappa B, a transcriptional activator of multiple host defense genes involved in immune and inflammatory responses. Here, we show that NTHi strongly activates NF-kappa B in human epithelial cells via two distinct signaling pathways, NF-kappa B translocation-dependent and -independent pathways. The NF-kappa B translocation-dependent pathway involves activation of NF-kappa B inducing kinase (NIK)--IKK alpha/beta complex leading to I kappa B alpha phosphorylation and degradation, whereas the NF-kappa B translocation-independent pathway involves activation of MKK3/6--p38 mitogen-activated protein (MAP) kinase pathway. Bifurcation of NTHi-induced NIK-IKK alpha/beta-I kappa B alpha and MKK3/6--p38 MAP kinase pathways may occur at transforming growth factor-beta activated kinase 1 (TAK1). Furthermore, we show that toll-like receptor 2 (TLR2) is required for NTHi-induced NF-kappa B activation. In addition, several key inflammatory mediators including IL-1 beta, IL-8, and tumor necrosis factor-alpha are up-regulated by NTHi. Finally, P6, a 16-kDa lipoprotein highly conserved in the outer membrane of all NTHi and H. influenzae type b strains, appears to also activate NF-kappa B via similar signaling pathways. Taken together, our results demonstrate that NTHi activates NF-kappa B via TLR2-TAK1-dependent NIK--IKK alpha/beta-I kappa B alpha and MKK3/6--p38 MAP kinase signaling pathways. These studies may bring new insights into molecular pathogenesis of NTHi-induced infections and open up new therapeutic targets for these diseases.
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PMID:Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. 1143

Mirk/Dyrk1B is an arginine-directed serine/threonine protein kinase that is expressed at low levels in most normal tissues but at elevated levels in many tumor cell lines and in normal skeletal muscle. Colon carcinoma cell lines stably overexpressing Mirk proliferated in serum-free medium, but the mechanism of Mirk action is unknown. DCoHm (dimerization cofactor of hepatocyte nuclear factor 1alpha ( HNF1alpha) from muscle), a novel gene of the DCoH family with 78% amino acid identity to DCoH, was identified as a Mirk-binding protein by yeast two-hybrid analysis and cloned. Mirk co-immunoprecipitated with DCoHm and bound to DCoHm in glutathione S-transferase pull-down assays. DCoH stabilizes HNF1alpha as a dimer and enhances its transcriptional activity on the beta-fibrinogen promoter reporter, and DCoHm had similar activity. Mirk enhanced HNF1alpha transcriptional activity in a dose-dependent manner, whereas two kinase-inactive Mirk mutants and a Mirk N-terminal deletion mutant did not. Mirk, DCoHm, and HNF1alpha formed a complex. Mirk bound to a specific region within the CREB-binding protein-binding region of HNF1alpha and phosphorylated HNF1alpha at a site adjacent to the Mirk-binding region. Conversely, the HNF1alpha binding domain was located within the first five conserved kinase subdomains of Mirk. Mirk co-immunoprecipitated with the MAPK kinase MKK3, an upstream activator of p38. MKK3 enhanced Mirk kinase activity and the transcriptional activation of HNF1alpha by Mirk, suggesting that Mirk, like p38, is activated by certain environmental stress agents. The Mirk-binding protein DCoH has been shown to be selectively expressed in colon carcinomas but not in normal tissue. Mirk may function as an HNF1alpha transcriptional activator in response to an MKK3-mediated stress signal, and the selective expression of DCoH could restrict the Mirk response to carcinoma cells.
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PMID:Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1alpha. 1198 Sep 10

Mirk/Dyrk1B protein kinase was shown in an earlier study to function as a transcriptional activator of HNF1alpha, which Mirk phosphorylates at Ser(249) within its CREB (cAMP-response element-binding protein)-binding protein (CBP) binding domain (). The MAPK kinase MKK3 was also shown to activate Mirk as a protein kinase, implicating Mirk in the biological response to certain stress agents. Another MKK3 substrate, p38MAPK, is now shown to inhibit the function of Mirk as a transcriptional activator in a kinase-independent manner. Co-immunoprecipitation experiments demonstrated that kinase-inactive p38AF, as well as wild-type p38, sequestered Mirk and prevented its association with MKK3. Only the p38alpha and p38beta isoforms, but not the gamma or delta isoforms, complexed with Mirk. p38alphaMAPK blocked Mirk activation of HNF1alpha in a dose-dependent manner, with high levels of kinase-inactive p38alphaAF completely suppressing the activity of Mirk. Size fractionation by fast protein liquid chromatography on Superdex 200 demonstrated that Mirk is not found as a monomer in vivo, but is found within 150-700 kDa subnuclear complexes, which co-migrate with the nuclear body scaffolding protein PML. Endogenous Mirk, p38, and MKK3 co-migrate within 500-700-kDa protein complexes, which accumulate when nuclear export is blocked by leptomycin B. Stable overexpression of Mirk increases the fraction of Mirk protein and p38 protein within these 500-700 kDa complexes, suggesting that the complexes act as nuclear depots for Mirk and p38. Sequestration of Mirk by p38 may occur within these subnuclear complexes. Synchronization experiments demonstrated that Mirk levels fluctuate about 10-fold within the cell cycle, while p38 levels do not, leading to the speculation that endogenous p38 could only block Mirk function when Mirk levels were low in S phase and not when Mirk levels were elevated in G(0)/G(1). These data suggest a novel cell cycle-dependent function for p38, suppression of the function of Mirk as a transcriptional activator only when cells are proliferating, and thus limiting Mirk function to growth-arrested cells.
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PMID:The transcriptional activator Mirk/Dyrk1B is sequestered by p38alpha/beta MAP kinase. 1238 4

Cholinergic differentiation factors (CDFs) suppress noradrenergic properties and induce cholinergic properties in sympathetic neurons. The CDFs leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) bind to a LIFR.gp130 receptor complex to activate Jak/signal transducers and activators of transcription and Ras/mitogen-activated protein kinases signaling pathways. Little is known about how these differentiation factors suppress noradrenergic properties. We used sympathetic neurons and SK-N-BE(2)M17 neuroblastoma cells to investigate CDF down-regulation of the norepinephrine synthetic enzyme dopamine-beta-hydroxylase (DBH). LIF and CNTF activated extracellular signal-regulated kinases (ERKs) 1 and 2 but not p38 or Jun N-terminal kinases in both cell types. Preventing ERK activation with PD98059 blocked CNTF suppression of DBH protein in sympathetic neurons but did not prevent the loss of DBH mRNA. CNTF decreased transcription of a DBH promoter-luciferase reporter construct in SK-N-BE(2)M17 cells, and this was also ERK-independent. Cytokine inhibition of DBH promoter activity did not require a silencer element but was prevented by overexpression of the transcriptional activator Phox2a. Inhibiting ERK activation increased basal DBH transcription in SK-N-BE(2)M17 cells, and DBH mRNA in sympathetic neurons. Transfection of Phox2a into PD98059-treated M17 cells resulted in a synergistic increase in DBH promoter activity compared with Phox2a or PD98059 alone. These data suggest that CDFs down-regulate DBH protein via an ERK-dependent pathway but inhibit DBH gene expression through an ERK-independent pathway. They further suggest that ERK activity inhibits basal DBH gene expression.
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PMID:Cytokine suppression of dopamine-beta-hydroxylase by extracellular signal-regulated kinase-dependent and -independent pathways. 1260 84

p38 is associated with a macromolecular tRNA synthetase complex. It has an essential role as a scaffold for the complex, and genetic disruption of p38 in mice causes neonatal lethality. Here we investigated the molecular mechanisms underlying lethality of p38-mutant mice. p38-deficient mice showed defects in lung differentiation and respiratory distress syndrome. p38 was found to interact with FUSE-binding protein (FBP), a transcriptional activator of c-myc. Binding of p38 stimulated ubiquitination and degradation of FBP, leading to downregulation of c-myc, which is required for differentiation of functional alveolar type II cells. Transforming growth factor-beta (TGF-beta) induced p38 expression and promoted its translocation to nuclei for the regulation of FBP and c-myc. Thus, this work identified a new activity of p38 as a mediator of TGF-beta signaling and its functional importance in the control of c-myc during lung differentiation.
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PMID:Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation. 1281 82

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

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