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: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroidogenic factor-1 (SF-1) is a member of the nuclear receptor superfamily that plays essential roles in the development of endocrine organs. Steroid receptor coactivator 1 and transcription intermediary factor 2 (TIF2) belong to the p160 coactivator family that mediates transcriptional activation by several nuclear receptors, including SF-1. Here, it is reported that another of the p160 coactivators, p/CIP, interacts with SF-1 through the activation function-2 domain. Both p300/CBP/cointegrator-associated protein (p/CIP) and TIF2 potentiated SF-1-mediated transcription from two reporter gene constructs in transfected nonsteroidogenic COS-1 cells and in adrenocortical Y1 cells. PKA was shown to stimulate SF-1 transcriptional activity, and coexpression of p/CIP together with the PKA catalytic subunit stimulated SF-1-mediated transactivation even further. In contrast, PKA catalytic subunit overexpression impaired the ability of TIF2 to potentiate SF-1-dependent transcription. Activation of PKA also inhibited the TIF2-mediated coactivation of other nuclear receptors such as PPAR alpha/-gamma and liver X receptor-alpha. The TIF2 mRNA levels were not affected by PKA, but instead we found that PKA activation led to a decrease in the levels of TIF2 protein. Moreover, the C-terminal activation domain 2 of TIF2 was required for the inhibitory effect of PKA, suggesting that this region is the target for the PKA-mediated down-regulation. Thus, in contrast to the regulation of p/CIP and steroid receptor coactivator 1, we suggest that activation of PKA leads to selective down-regulation of TIF2 and subsequently repression of TIF2 coactivator function.
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PMID:The nuclear receptor coactivators p300/CBP/cointegrator-associated protein (p/CIP) and transcription intermediary factor 2 (TIF2) differentially regulate PKA-stimulated transcriptional activity of steroidogenic factor 1. 1192 73

Estrogen biosynthesis from C(19) steroids is catalyzed by aromatase cytochrome P450. Aromatase is expressed in breast adipose tissue through the use of a distal, cytokine-responsive promoter (promoter I.4). Breast tumors, however, secrete soluble factors that stimulate aromatase expression through an alternative proximal promoter, promoter II. In other estrogenic tissues such as ovaries, transcription from promoter II requires the presence of the Ftz-F1 homologue steroidogenic factor-1 (SF-1); adipose tissue, however, does not express SF-1. We have explored the hypothesis that in adipose tissue, an alternative Ftz-F1 family member, liver receptor homologue-1 (LRH-1), substitutes for SF-1 in driving transcription from promoter II. In transient transfection assays using 3T3-L1 preadipocytes, promoter II reporter constructs were modestly (2-3-fold) stimulated by either treatment with activators of protein kinases A or C (PKA/C) or by cotransfection with LRH-1. In combination, these treatments synergistically activated promoter II (>30-fold). Induction by LRH-1 (but not by PKA/C) required an AGGTCA motif at -130 base pairs, to which LRH-1 bound in gel shift assays. Activity of GAL4-LRH-1 fusion proteins was not altered by activators of PKA or PKC. Quantitative real-time PCR revealed that LRH-1 (but not SF-1) is expressed in the preadipocyte fraction of human adipose tissue at levels comparable with that of liver. Differentiation of cultured human preadipocytes into mature adipocytes was associated with a time-dependent induction of peroxisome proliferator-activated receptor-gamma (PPARgamma), and rapid loss of LRH-1 and aromatase expression. We conclude that LRH-1 is a preadipocyte-specific nuclear receptor that regulates expression of aromatase in adipose tissue. Alterations in LRH-1 expression and/or activity in adipose tissue could therefore have considerable effects on local estrogen production and breast cancer development.
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PMID:Liver receptor homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. 1192 88

Members of the nuclear receptor superfamily, including retinoic acid receptors (RARs), retinoid X receptors (RXRs), and vitamin D receptors (VDRs), are transcription factors that control many important cellular functions, and their ligands are widely used in several clinical indications. The latest family member is the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is highly expressed in normal monocytes, different leukemias, and epithelial malignancies. PPARgamma ligands have been developed and signal differentiation, growth arrest, and apoptosis. PPARgamma forms heterodimers with RXR, and ligation of both receptors is required for maximal signaling. PPARgamma signaling, its expression in hematologic malignancies, and role in differentiation are discussed. Interactions of PPARgamma with X-RARalpha, protein kinase R (PKR), PTEN, and mitogen-activated protein kinase (MAPK) have been described. PPARgamma ligands have been developed for the management of diabetes, but new and more potent ligands, including triterpenoids, are being investigated as therapeutic agents for epithelial and hematologic malignancies.
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PMID:Role of peroxisome proliferator-activated receptor-gamma in hematologic malignancies. 1204 3

Chondrogenesis is a multistep process culminating in the establishment of a precisely patterned template for bone formation. Previously, we identified a loss in retinoid receptor-mediated signaling as being necessary and sufficient for expression of the chondroblast phenotype (Weston et al., 2000. J. Cell Biol. 148:679-690). Here we demonstrate a close association between retinoic acid receptor (RAR) activity and the transcriptional activity of Sox9, a transcription factor required for cartilage formation. Specifically, inhibition of RAR-mediated signaling in primary cultures of mouse limb mesenchyme results in increased Sox9 expression and activity. This induction is attenuated by the histone deacetylase inhibitor, trichostatin A, and by coexpression of a dominant negative nuclear receptor corepressor-1, indicating an unexpected requirement for RAR-mediated repression in skeletal progenitor differentiation. Inhibition of RAR activity results in activation of the p38 mitogen-activated protein kinase (MAPK) and protein kinase A (PKA) pathways, indicating their potential role in the regulation of chondrogenesis by RAR repression. Accordingly, activation of RAR signaling, which attenuates differentiation, can be rescued by activation of p38 MAPK or PKA. In summary, these findings demonstrate a novel role for active RAR-mediated gene repression in chondrogenesis and establish a hierarchical network whereby RAR-mediated signaling functions upstream of the p38 MAPK and PKA signaling pathways to regulate emergence of the chondroblast phenotype.
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PMID:Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. 1210 81

Nuclear histone acetyltransferases, DNA-dependent ATPases, and transcriptional intermediary factors (TIFs) all harbor a distinct structural module known as the bromodomain (BrD). Although the BrD can interact with histones H3 and H4 and their acetylated N-terminal tails in vitro, its function in a chromosomal environment remains elusive. We used the nuclear receptor coregulator TIF1alpha, a protein kinase that associates tightly with euchromatin, to analyze the properties of the BrD in a nucleosomal environment in vitro. Here, we report that TIF1alpha-chromatin association is direct and involves DNA and nucleosome interactions mediated by the BrD. Mutation of the BrD signature peptide, PMDL, abolishes DNA binding and disrupts BrD-nucleosome interactions. Based on our results, we propose that the BrD plays a critical role in vivo by directing transregulators to their cognate location on nucleosomal DNA.
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PMID:The bromodomain mediates transcriptional intermediary factor 1alpha -nucleosome interactions. 1238 11

We originally discovered the serum and glucocorticoid inducible protein kinase, SGK, as a novel protein kinase that is under acute transcriptional control by serum and glucocorticoids. An expanding set of cell surface receptor, nuclear receptor, and cellular stress pathways has been shown to target SGK, which has implicated this regulated signaling molecule in a variety of biological functions. Compared to most other protein kinases, a distinguishing feature of SGK is the stringent stimulus-dependent regulation of its transcription, subcellular localization and enzymatic activity. In addition, SGK expression is regulated during discrete developmental stages, and during normal and abnormal physiological function. An analysis of the SGK promoter reveals many potential transcription factor sites that potentially account for the stimulus-dependent changes in SGK transcript expression observed in a variety of cell systems, although, the direct stimulus regulation of SGK promoter activity has been established only for glucocorticoids, p53 tumor suppressor protein, hyperosmotic stress and follicle stimulating hormone. In the systems tested to date, hormones, growth factors and environmental cues induce expression of a catalytically active SGK. It is now well established that the enzymatic activity of SGK is controlled by the PI 3-kinase cascade which produces a hyperphosphorylated active SGK. A critical third level of regulation is the stimulus-dependent control of SGK subcellular localization. The nuclear-cytoplasmic shuttling of SGK is regulated by a nuclear localization signal (NLS) that binds to the importin-alpha nuclear import receptor. Modeling of the 3-D structure of the central region of SGK that includes the kinase domain predicts that the NLS is located at an external surface of the molecule. Thus, multiple signal transduction pathways converge on SGK to control its availability, function and access to its substrates and non-substrate targets.
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PMID:Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. 1264 97

Regulation of GnRH receptor (GnRHR) expression levels in the pituitary is a crucial control point in reproduction. The promoter of the mouse GnRHR gene contains nuclear receptor half-sites (NRS) at -244/-236 and -15/-7 relative to the translation start site. Although binding of steroidogenic factor-1 (SF-1) to the -244/-236NRS is implicated in mediating basal and gonadotrope-specific expression, no function or protein-DNA interactions have previously been described for the -15/-7NRS. We report that levels of the endogenous GnRHR mRNA in alpha T3-1 cells are stimulated by forskolin and 8-bromo-cAMP. We also show that the orphan nuclear receptor Nur77 is expressed in alpha T3-1 cells, and that both SF-1 and Nur77 bind to the -15/-7NRS and -244/-236NRS in vitro. We show that the activity of the proximal (-579/+1) mouse GnRHR promoter is up-regulated by protein kinase A, via a mechanism that is modulated by SF-1, both positively and negatively, through binding to the -244/-236NRS or the -15/-7NRS, respectively. Nur77 appears to be capable of acting as a negative regulator of this response, via the -15/-7NRS. Furthermore, we show that forskolin up-regulates SF-1 mRNA levels in alpha T3-1 cells, indicating that the levels of SF-1 play a role in modulating the protein kinase A response.
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PMID:Expression of the mouse gonadotropin-releasing hormone receptor gene in alpha T3-1 gonadotrope cells is stimulated by cyclic 3',5'-adenosine monophosphate and protein kinase A, and is modulated by Steroidogenic factor-1 and Nur77. 1269 3

The action of a variety of peptide hormones is critical for proper growth and differentiation of the urogenital ridge, which ultimately gives rise to the kidney, adrenal cortex, and gonad. One such class of peptides is the Wnt family of secreted glycoproteins that is classically involved in development of cell polarity and cell fate determination. Notably, alterations in Wnt-4 expression in mice and humans result in profound defects in urogenital ridge development, including dysregulation of kidney, gonadal, and adrenal growth. The nuclear receptor steroidogenic factor-1 (SF-1) has been implicated as a downstream effector of peptide hormone signaling during urogenital ridge development as evidenced by both the activation of SF-1-dependent transcription in the adrenal cortex by signaling molecules such as protein kinase A and by the adrenal and gonadal agenesis in mice with null mutations in SF-1. We hypothesized that Wnt-dependent signaling cascades regulate SF-1-dependent transcription of genes required for adreno-gonadal development. Specifically, the data demonstrate that beta-catenin synergizes with SF-1 to activate the alpha-inhibin promoter through formation of a transcriptional complex. The activation requires an intact SF-1 RE and is independent of TCF/Lef. These data support the recent observation that beta-catenin can participate in nuclear receptor-mediated transcriptional activation and extend the findings to the monomer binding class of orphan nuclear receptors.
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PMID:Convergence of Wnt signaling and steroidogenic factor-1 (SF-1) on transcription of the rat inhibin alpha gene. 1273 19

The mechanism through which protein kinase A (PKA) potentiates the transactivation ability of adrenal 4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) is currently unclear. In the present study, we investigated the mechanism by applying laser confocal microscopy and fluorescence recovery after photobleaching technique. In KGN cells, forskolin (a PKA stimulator) could reorganize wild-type Ad4BP/SF-1, but not mutant Ad4BP/SF-1 (G35E), from a diffuse distribution pattern to foci formation in the nucleus. The subcellular distributions of GCN5 (general control nonderepressed) and TRRAP (transformation/transcription domain-associated protein), both of which were recently proved to be working in the same complex as the third class of nuclear receptor coactivators, were unexpectedly diffuse inside and outside the nucleus, respectively, when they were separately transfected. However TRRAP was translocated into the nucleus in the presence of GCN5, and together with GCN5 colocalized with Ad4BP/SF-1 in the same foci when PKA was activated. A luciferase assay also indicated that these two cofactors enhanced Ad4BP/SF-1 transactivation.Dosage-sensitive sex reversal (DAX-1) interacts with and thus inhibits Ad4BP/SF-1 transactivation. The coexistence of the two proteins dramatically altered their respective subnuclear distributions. They colocalized extensively, suggestive of binding, and Ad4BP/SF-1 was sharply immobilized when DAX-1 was coexpressed, whereas PKA could maintain mobility, as evidenced by Fluorescence Recovery After Photobleaching showing that Ad4BP/SF-1 mobility recovered after forskolin treatment.Therefore, the PKA signal pathway may modify the interaction between Ad4BP/SF-1 and its activators and repressor (GCN5 and TRRAP are integrated, whereas DAX-1 is disassociated), and thus stimulate the Ad4BP/SF-1 transactivation.
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PMID:Protein kinase A potentiates adrenal 4 binding protein/steroidogenic factor 1 transactivation by reintegrating the subcellular dynamic interactions of the nuclear receptor with its cofactors, general control nonderepressed-5/transformation/transcription domain-associated protein, and suppressor, dosage-sensitive sex reversal-1: a laser confocal imaging study in living KGN cells. 1455 13

The transcriptional repressor REST/NRSF (RE-1 silencing transcription factor/neuron-restrictive silencer factor) and the transcriptional regulator REST4 share an N-terminal zinc finger domain structure involved in nuclear targeting. Using this domain as bait in a yeast two-hybrid screen, a novel protein that contains three LIM domains, putative nuclear localization sequences, protein kinase A phosphorylation sites, and a CAAX prenylation motif was isolated. This protein, which is localized around the nucleus, is involved in determining the nuclear localization of REST4 and REST/NRSF. We propose the name RILP, for REST/NRSF-interacting LIM domain protein, to label this novel protein. RILP appears to serve as a nuclear receptor for REST/NRSF, REST4, and possibly other transcription factors.
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PMID:REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor. 1464 15


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