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)

Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor and the insulin signaling pathway. 3-phosphoinositide-dependent protein kinase-1 (PDK1) serves as a critical regulatory point in insulin signaling through its ability to phosphorylate the activation loop of several protein kinase families. The present study was undertaken to determine the interrelationships between the PDK1 and PPARgamma signaling pathways, and their association with adipocyte differentiation. Coexpression of PDK1 and PPARgamma1 in 293T cells stimulated PPARgamma response element-dependent reporter gene activity in either the presence or absence of ligand. PDK1-mediated stimulation of PPARgamma1 activity was comparable in magnitude to the coactivator activated in breast cancer-1, and was blocked by either the corepressor silencing mediator of retinoid and thyroid hormone receptor or dominant-negative PAX8-PPARgamma1. Heterologous Gal4-PPARgamma1 assays indicated that PDK1 interacted with the ligand binding domain, and physically associated with PPARgamma1; however, PDK1-mediated stimulation was not dependent on phosphorylation of PPARgamma1 by PDK1. PDK1 stimulatory activity was eliminated by mutation of the alpha-helical hydrophobic motifs in PDK1, L(268)XII, and V(313)XXLL, and expression of the alpha-helical region encompassing these motifs stimulated PPARgamma response element-dependent transcription. PDK1-PPARgamma interaction was confirmed by chromatin immunoprecipitation analysis of the lipoprotein lipase and adipocyte fatty acid-binding protein promoters. In cells expressing PDK1 and PPARgamma, binding to PPARgamma response elements occurred, which was enhanced by treatment with a PPARgamma agonist. Expression of PDK1 in 3T3-L1 or COMMA-1D mammary epithelial cells promoted adipocyte differentiation in the presence of a PPARgamma agonist that was comparable to the response of PPARgamma1-transfected cells in the presence of agonist; expression of PDK1 and PPARgamma resulted in a synergistic effect. Adipocyte differentiation in the presence of a PPARgamma agonist was markedly attenuated in PDK1 null cells. These results suggest that PDK1 can function as a PPARgamma1 coactivator independently of its catalytic activity and establishes an important mechanistic link between adipocyte differentiation and the insulin signaling pathway.
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PMID:3-phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor-gamma and promotes adipocyte differentiation. 1615 Aug 67

In addition to their role in cell cycle progression, new data reveal an emerging role of D-type cyclins in transcriptional regulation and cellular differentiation processes. Using 3T3-L1 cell lines to study adipogenesis, we observed an up-regulation of cyclin D3 expression throughout the differentiation process. Surprisingly, cyclin D3 was only minimally expressed during the initial stages of adipogenesis, when mitotic division is prevalent. This seemingly paradoxical expression led us to investigate a potential cell cycle-independent role for cyclin D3 during adipogenesis. We show here a direct interaction between cyclin D3 and the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). Our experiments reveal cyclin D3 acts as a ligand-dependent PPARgamma coactivator, which, together with its cyclin-dependent kinase partner, phosphorylates the A-B domain of the nuclear receptor. Overexpression and knockdown studies with cyclin D3 had marked effects on PPARgamma activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPARgamma target genes. We show that cyclin D3 mutant mice are protected from diet-induced obesity, display smaller adipocytes, have reduced adipogenic gene expression, and are insulin sensitive. Our results indicate that cyclin D3 is an important factor governing adipogenesis and obesity.
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PMID:Cyclin D3 promotes adipogenesis through activation of peroxisome proliferator-activated receptor gamma. 1626 Jun 12

Although 1,25-dihydroxyvitamin D3 (1,25D3) and retinoic acid (RA) have distinct developmental and physiological roles, both regulate the cell cycle. We provide molecular and genomic evidence that their cognate nuclear receptors regulate common genes through everted repeat TGA(C/T)TPyN8PuG(G/T)TCA (ER8) response elements. ER8 motifs were found in the promoters of several target genes of 1,25D3 and/or RA. Notably, an element was characterized in the cyclin-dependent kinase (CDK) inhibitor p19ink4d gene, and 1,25D3- or RA-induced p19INK4D) expression. P19ink4d knockdown together with depletion of p27kip1, another CDK inhibitor regulated by 1,25D3 and RA, rendered cells resistant to ligand-induced growth arrest. Remarkably, p19INK4D-deficient cells showed increased autophagic cell death, which was markedly enhanced by 1,25D3, but not RA, and attenuated by loss of p27KIP1. These results show a limited crosstalk between 1,25D3 and RA signalling by means of overlapping nuclear receptor DNA binding specificities, and uncover a role for p19INK4D in control of cell survival.
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PMID:Convergence of vitamin D and retinoic acid signalling at a common hormone response element. 1632 58

The classical mechanism of estradiol (E2) action is mediated by the nuclear estrogen receptors ERalpha and ERbeta, which function as ligand-dependent transcription factors that regulate transcription of target genes containing the consensus estrogen response element (ERE) in their promoter regions. However, accumulating evidence indicates that E2 can also exert its actions through a unique membrane estrogen receptor (mER). Upon activation of the mER, various signaling pathways (i.e. Ca(2+), cAMP, protein kinase cascades) are rapidly activated and ultimately influence downstream transcription factors. Some target genes of the mER pathway may be activated independently of the nuclear estrogen receptor (nER). Additionally, it has been shown that classical nER action can be modulated by mER-initiated signaling through phosphorylation of nER and its coactivators, and by induction of third messengers (i.e. cyclin D1 and c-fos). Based on current evidence, we propose a model for E2 action integrating distinct membrane receptor and nuclear receptor signaling. This membrane receptor-nuclear receptor interaction is likely to exist for other hormones. Steroid hormones and other hormones acting through hormone receptors in the steroid receptor superfamily (i.e. thyroid hormones) also activate many of the same intracellular signaling cascades, which provides the basis for extensive crosstalk networks between hormones. The model proposed serves as a framework to investigate the diverse actions of hormones and endocrine disrupting chemicals (EDCs).
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PMID:Integration of membrane and nuclear estrogen receptor signaling. 1651 16

INK4 proteins are members of a family of cyclin-dependent kinase (CDK) inhibitors that function in G(1) to block the activity of CDKs 4 and 6. While they share clear structural similarities, numerous studies have shown that INK4 proteins differ in their expression patterns during development and in the adult, and have differing roles in tumor suppression. A recent study from our laboratory showed that expression of the gene encoding p19(INK4D) is induced by the hormonal form of vitamin D(3) and by retinoids, both of which signal through related nuclear receptor transcription factors. Although vitamin D(3) and retinoids have distinct developmental and physiological functions, both regulate the cell cycle and have been shown to have chemopreventive effects in a range of studies. Induction of p19(INK4D) expression contributed to cell cycle arrest by both ligands. However, knockdown of p19(INK4D) rendered cells sensitive to autophagic cell death, a remarkable phenotype given the hyperproliferative responses to loss of other INK4 proteins. We discuss the relevance of our studies and recent findings of others to the cell death observed in p19(INK4D)-deficient animals and to a possible role for p19(INK4D) induction in chemoprevention.
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PMID:p19INK4D and cell death. 1658 18

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds including the thiazolidinediones. In addition to being a target for diabetes, PPARgamma activation state has recently been shown to modulate beta-amyloid peptide (Abeta) production in cellular models relevant to Alzheimer's disease. Here, we report the effect of troglitazone, a thiazolidinedione, in cells expressing 4-repeat tau. A 24 h treatment with troglitazone significantly reduced phosphorylation of tau at Ser202 and Ser396/404, residues of early and later stages of neurofibrillary tangle accumulation in Alzheimer's disease and other neurodegenerative disorders. Under the same experimental conditions the level of tau did not change. In our cellular model, troglitazone appeared to enhance 3'-phosphoinositide-dependent protein kinase 1 (PDK1) nuclear translocation, resulting in a decrease in cytosolic phosphorylated 70 kDa ribosomal protein kinase (p70S6) and phosphorylated mammalian target of rapamycin (mTor). Furthermore, PPARgamma transcriptional activity did not appear to be responsible for decreased phosphorylation of tau. Thus, we believe that the thiazolidinedione regulates tau phosphorylation through a PPARgamma-dependent/independent mechanism involving an Akt/glycogen synthase kinase-3(GSK-3beta)-independent signalling cascade: PDK1/p70S6K/mTor.
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PMID:Troglitazone, a peroxisome proliferator-activated receptor-gamma agonist, decreases tau phosphorylation in CHOtau4R cells. 1678 14

Inhibin alpha is the common subunit of the dimeric inhibin proteins known for their role in suppressing pituitary FSH secretion. In this study, we have examined the role of GATA factors and the nuclear receptor, LRH-1/NR5A2, in the regulation of inhibin alpha-subunit promoter activity. The inhibin alpha promoter contains two GATA-binding motifs that can be activated by GATA4 or GATA6. The GATA-dependence of the promoter was demonstrated by downregulating GATA expression in MA-10 cells using siRNA technology. We next examined whether GATA factors could cooperate with LRH-1, a factor recently proposed to be an important regulator of inhibin alpha-subunit transcription. Both GATA4 and GATA6 strongly synergized with LRH-1. Consistent with the cAMP-dependence of the inhibin alpha-subunit promoter, GATA/LRH-1 synergism was markedly enhanced by PKA and the co-activator protein CBP. Thus, our results identify LRH-1 as a new transcriptional partner for GATA factors in the regulation of inhibin alpha-subunit gene expression.
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PMID:LRH-1/NR5A2 cooperates with GATA factors to regulate inhibin alpha-subunit promoter activity. 1689 4

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.
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PMID:Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. 1713 41

Prostacyclin (PGI2) and its analogues exert cardioprotective effects via the rhodopsin type membrane PGI2 receptor, IP. Peroxisome proliferator-activated receptor (PPAR) delta is a nuclear receptor abundantly expressed in cardiomyocytes and plays a pivotal role in maintaining constitutive mitochondrial fatty acid beta-oxidation (FAO). Recently, a novel signaling pathway of PGI2 via PPARdelta has been demonstrated in non-cardiac tissues. We therefore examined whether carbacyclin (cPGI2), a PGI2 analogue, up-regulates transcriptional expression of carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme in mitochondrial FAO, via PPARdelta in cardiomyocytes. Intraperitoneal injection of cPGI2 increased CPT-1 mRNA expression in murine hearts. Transcriptional activity was evaluated by PPAR responsive element (PPRE)-luciferase reporter gene assay in cultured neonatal rat cardiomyocytes. CPT-1 mRNA expression and PPRE promoter activity were significantly increased by cPGI2 in a concentration-dependent manner, where PPRE has been mapped to the promoter region of the CPT-1 gene. Moreover, the elevation of CPT-1 mRNA expression and PPRE promoter activity by cPGI2 was not abolished by H-89, a potent protein kinase A inhibitor, but was significantly inhibited in cardiomyocytes over-expressing a dominant-negative type of PPARdelta. Furthermore, electrophoretic mobility shift assays demonstrated that binding of PPARdelta to PPRE in the CPT-1 gene promoter is enhanced in response to cPGI2 stimulation. In addition, down-regulation of CPT-1 mRNA expression in cardiomyocytes subjected to hypoxia was attenuated by cPGI2. These results indicate that cPGI2 induces CPT-1 mRNA expression through PPARdelta, independent of the IP receptor signaling pathway, suggesting a possibility that cPGI2 modulates cardiac energy metabolism by activating FAO via PPARdelta.
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PMID:Carbacyclin induces carnitine palmitoyltransferase-1 in cardiomyocytes via peroxisome proliferator-activated receptor (PPAR) delta independent of the IP receptor signaling pathway. 1754 Apr 3

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. Three subtypes of this receptor have been discovered (PPARalpha, beta and gamma), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK- and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.
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PMID:Modulation of PPAR activity via phosphorylation. 1756 Aug 26


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