Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NGFI-B is an immediate early gene and orphan member of the nuclear receptor superfamily. It is induced in several tissues, including brain, and in cultured cerebellar granule cells in response to different stimuli. Since both the induction of its mRNA as well as the level and function of its gene product are under the control of the inducing stimulus, we wanted to study the final outcome of the stimulus, i.e., transcriptional activity, by means of a specific, artificial reporter gene in cultured CNS cells. Cultured cerebellar granule cells and astrocytes were transfected with an NGFI-B responsive reporter gene to study the role of NGFI-B as a transcriptional activator after stimulation of the protein kinase A and C pathways. In both cell types, stimulation of either protein kinase A or C with forskolin (10 microM) or phorbol 12-myristate 13-acetate (0.1 microM), respectively, gave up to fivefold induction of the reporter gene. In the granule cells a combined treatment gave a strong synergistic induction of the reporter gene. The astrocytes showed only weak synergy, indicating cell-specific regulation of the target gene by the two kinases.
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PMID:Activation of a reporter gene responsive to NGFI-B in cultured neurons and astrocytes. 874 51

We identified a region in the human Ran GTPase-binding protein RanBP1 that shares similarities to the nuclear export signal of the inhibitor of the cAMP-dependent protein kinase. Mutational analysis confirmed that this region is responsible for the cytoplasmic accumulation of RanBP1 and can functionally replace the nuclear export signal of Rev of human immunodeficiency virus type 1. We showed that RanBP1 interferes with Rev-mediated expression of human immunodeficiency virus type 1, whereas the RanBP1 with inactivated nuclear export signal abrogates Rev function. Expression of a Rev-independent molecular clone, which is regulated via the constitutive transport element (CTE) of the simian retrovirus type 1, is not affected. These findings indicate that Rev and RanBP1 compete for the same nuclear export pathway, whereas Rev- and the CTE-mediated pathways are distinct. The inhibition of Rev function is independent of the ability of RanBP1 to associate with Ran and therefore, it is not likely a result of interference with Ran function. These data suggest that RanBP1 interacts with Rev at the putative nuclear receptor and, hence, shares a step in posttranscriptional pathway with Rev.
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PMID:Mutations in the nuclear export signal of human ran-binding protein RanBP1 block the Rev-mediated posttranscriptional regulation of human immunodeficiency virus type 1. 911 Oct 43

Hepatocyte nuclear factor 4 (HNF4), a liver-enriched transcription factor of the nuclear receptor superfamily, is critical for development and liver-specific gene expression. Here, we demonstrate that its DNA-binding activity is modulated posttranslationally by phosphorylation in vivo, ex vivo, and in vitro. In vivo, HNF4 DNA-binding activity is reduced by fasting and by inducers of intracellular cyclic AMP (cAMP) accumulation. A consensus protein kinase A (PKA) phosphorylation site located within the A box of its DNA-binding domain has been identified, and its role in phosphorylation-dependent inhibition of HNF4 DNA-binding activity has been investigated. Mutants of HNF4 in which two potentially phosphorylatable serines have been replaced by either neutral or charged amino acids were able to bind DNA in vitro with affinity similar to that of the wild-type protein. However, phosphorylation by PKA strongly repressed the binding affinity of the wild-type factor but not that of HNF4 mutants. Accordingly, in transfection assays, expression vectors for the mutated HNF4 proteins activated transcription more efficiently than that for the wild-type protein-when cotransfected with the PKA catalytic subunit expression vector. Therefore, HNF4 is a direct target of PKA which might be involved in the transcriptional inhibition of liver genes by cAMP inducers.
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PMID:Protein kinase A-dependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4. 923 78

The human neuroblastoma cell line SK-N-SH has been used as a model system to study the interactions of the human estrogen receptor (hER) with neurotransmitters. We have successfully transfected these cells using an adenoviral delivery system and have reconstituted ligand-dependent responses to estradiol and ligand-independent responses to a series of dopamine D1 receptor agonists. The full agonist for the D1 receptor, SKF 82958, shows a robust activation of hER, comparable to that induced by estradiol. This activation is blocked by the protein kinase A inhibitor H-89, is mimicked by forskolin, and is therefore thought to be mediated in part through the cAMP/protein kinase A pathway. We have examined deletion mutants of hER for activation by SKF 82958 and find that both its transactivation domains, AF-1 and AF-2, must cooperate to impart the full response to the agonist. Significantly, an agonist of the muscarinic acetylcholine receptor, carbachol, though not active by itself, synergistically activates hER in conjunction with suboptimal doses of SKF 82958. This is the first reported instance of two neurotransmitters synergizing to activate a member of the nuclear receptor superfamily, and might predict a role for multiple neural inputs modulating the effects of these receptors in the central nervous system.
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PMID:Neurotransmitters activate the human estrogen receptor in a neuroblastoma cell line. 932 4

Functional domains of the androgen receptor (AR) have been localized through a combination of studies on naturally occurring AR gene mutations, in vitro mutagenesis studies and comparison with the structure of other members of the steroid/nuclear receptor superfamily. Two activation domains exist within the amino-terminal domain, and a ligand-dependent activation domain is present in the ligand binding domain. The poly(Gln) stretch within the amino-terminal domain may inhibit the transactivation function of the receptor. Different ligands or binding to different promoters may recruit the use of different activation domains, which may provide promoter-specific effects of receptor action. Co-activator proteins that modulate or enhance AR action have been identified, many of which interact with the ligand binding domain of the AR. Tissue-specific expression of such co-activators, and promoter-specific protein interactions, may also help control the specificity of androgen action. Target Ser residues for phosphorylation have been identified, which may be the site of action for cross-talk from protein kinase signalling pathways. However, the role of phosphorylation in AR function in general is still unclear. It is now clear that interactions occur between receptor domains, modulating functions including ligand dissociation, dimerization and transactivation. By studying the functional domains of the AR, and how they control receptor function in response to different activation signals, we are beginning to understand the mechanisms controlling the specificity of receptor action.
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PMID:Localization of functional domains in the androgen receptor. 940 77

Steroidogenic factor-1 (SF-1) is a nuclear receptor that is essential for the proper development and function of steroid hormone-producing cells. The activation function-2 (AF-2) domain in SF-1 is a short alpha-helix in the C terminus that is conserved with respect to other nuclear receptors and is important for transactivation of target genes. In order to investigate the possible role of the AF-2 domain of SF-1 in cAMP-dependent transcriptional regulation of the bovine steroid hydroxylase gene CYP17, mutations were introduced and the effects were characterized. The mutant SF-1 proteins were expressed at comparable levels in nonsteroidogenic Cos-1 cells that lack SF-1, and their abilities to bind an SF-1 site from the CYP17 gene were not affected. Transient transfections of wild-type and mutant SF-1 in Cos-1 cells showed that the capacity to transactivate a reporter gene under the control of the SF-1 site from CYP17 was reduced by the mutations in the AF-2 domain of SF-1. A point mutation in the AF-2 region, E454A, resulted in a relative reporter gene activity that was 21% of that observed with wild-type SF-1. Co-transfections of adrenocortical Y-1 cells, which express endogenous SF-1, with the catalytic subunit of cAMP-dependent protein kinase (PKA-C) and the SF-1-dependent reporter gene showed on average a 16-fold increase in activity in the presence of PKA-C. Introduction of the AF-2 mutants of SF-1 into Y-1 cells completely abolished the PKA-C-mediated stimulation of the reporter gene. The transdominant negative effect of the mutant SF-1 proteins suggests that the AF-2 domain is essential for the activation of SF-1 by the cAMP-dependent protein kinase-dependent signaling pathway.
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PMID:Mutations in the activation function-2 core domain of steroidogenic factor-1 dominantly suppresses PKA-dependent transactivation of the bovine CYP17 gene. 959 68

Ligand-induced gene activation by nuclear receptors (NRs) is a complex process requiring dissociation of corepressors and recruitment of coactivators. The putative transcriptional intermediary factor TIF1alpha has been previously characterized as a nuclear protein that interacts directly with the AF-2 ligand-dependent activating domain present in the ligand-binding domain of numerous steroid and nonsteroid receptors, including the estrogen (ERalpha) and retinoid X (RXRalpha) receptors. We report here that TIF1alpha is both a phosphoprotein and a protein kinase. TIF1alpha coexpressed in COS-1 cells with RXRalpha or ERalpha is phosphorylated and becomes hyperphosphorylated upon ligand treatment. This hyperphosphorylation requires the binding of TIF1alpha to transcriptionally active NRs since it is prevented by mutations either in the core (alpha-helix 12 of the ligand-binding domain) of the AF-2 activating domains of RXRalpha and ERalpha or in the NR box of TIF1alpha that are known to prevent TIF1alpha-NR interactions. Thus, TIF1alpha is a phosphoprotein that undergoes ligand-dependent hyperphosphorylation as a consequence of nuclear receptor binding. We further show that purified recombinant TIF1alpha possesses intrinsic kinase activity and that, in addition to autophosphorylation, TIF1alpha selectively phosphorylates the transcription factors TFIIEalpha, TAFII28, and TAFII55 in vitro. These latter results raise the possibility that TIF1alpha may act, at least in part, by phosphorylating and modifying the activity of components of the transcriptional machinery.
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PMID:The putative cofactor TIF1alpha is a protein kinase that is hyperphosphorylated upon interaction with liganded nuclear receptors. 963 76

Androgen receptor (AR) belongs to the nuclear receptor superfamily and mediates the biological actions of male sex steroids. In this work, we have characterized a novel 130-kDa Ser/Thr protein kinase ANPK that interacts with the zinc finger region of AR in vivo and in vitro. The catalytic kinase domain of ANPK shares considerable sequence similarity with the minibrain gene product, a protein kinase suggested to contribute to learning defects associated with Down syndrome. However, the rest of ANPK sequence, including the AR-interacting interface, exhibits no apparent homology with other proteins. ANPK is a nuclear protein that is widely expressed in mammalian tissues. Its overexpression enhances AR-dependent transcription in various cell lines. In addition to the zinc finger region, ligand-binding domain and activation function AF1 of AR are needed, as the activity of AR mutants devoid of these domains was not influenced by ANPK. The receptor protein does not appear to be a substrate for ANPK in vitro, and overexpression of ANPK does not increase the extent of AR phosphorylation in vivo. In view of this, it is likely that ANPK-mediated activation of AR function is exerted through modification of AR-associated proteins, such as coregulatory factors, and/or through stabilization of the receptor protein against degradation.
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PMID:Activation of androgen receptor function by a novel nuclear protein kinase. 972 10

The use of steroid hormones in postmenopausal replacement therapy has been associated with prevention of cardiovascular disease. Although the contribution of estradiol to endothelial cell function has been addressed, little information is available on the effect of progestins on this cell type. Here, we provide direct evidence for the presence of functional nuclear progesterone receptor in endothelial cells and demonstrate that physiological levels of progesterone inhibit proliferation through a nuclear receptor-mediated mechanism. The effects of progesterone were blocked by pretreatment with a progesterone receptor antagonist, and progesterone receptor-deficient endothelial cells failed to respond to the hormone. We evaluated the effect of progesterone by analysis of aorta re-endothelialization experiments in wild-type and progesterone receptor knockout mice. The rate of re-endothelialization was significantly decreased in wild-type mice when in the presence of progesterone, whereas there was no difference between control and progesterone-treated progesterone receptor knockout mice. FACS analysis showed that progestins arrest endothelial cell cycle in G1. The lag in cell cycle progression involved reduction in cyclin-dependent kinase activity, as shown by down-regulation in retinoblastoma protein phosphorylation. In addition, treatment of endothelial cells with progestins altered the expression of cyclin E and A in accordance with G1 arrest. These results have important implications to our current knowledge of the effect of steroids on endothelial cell function and to the overall contribution of progesterone to vascular repair.
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PMID:Progesterone regulates proliferation of endothelial cells. 989 Sep 81

Nuclear steroid/thyroid/retinoid receptors and c-erbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple c-erbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via cross-connected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and c-erbB-2, and between ER and retinoic acid receptor(RAR)-alpha have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12-O-tetradecanoylphorbol-13-acetate, TPA), on growth and expression of c-erbB and RARs in MCF-7 breast cancer cells, which contain high levels of RAR-alpha and -gamma, and which express significant amounts of c-erbB-2 and -3. All trans-retinoic acid (tRA), the anti-estrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17beta-estradiol (E2) stimulated cell growth. Flow cytometry revealed that tRA and E2 reduced c-erbB-2 and -3, whereas tamoxifen, Forsk and TPA up-regulated c-erbB-2. c-erbB-3 was co-regulated with c-erbB-2. Northern analysis demonstrated that RAR-alpha was down-regulated by dexamethasone, ICI, and TPA, whereas vitamin D3 and E2 up-regulated RAR-alpha. RAR-gamma expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and c-erbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.
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PMID:Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c-erbB and retinoic acid receptor expression in MCF-7 breast cancer cells. 1067 83


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