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)

Progesterone (P) has an inhibitory effect on the contractility of gastrointestinal smooth muscle, including the gallbladder. Since P levels are elevated during pregnancy, a biliary stasis may develop during pregnancy that is characterized by an increase in the fasting and residual volumes and by a decrease in emptying capacity. This study investigates the effect of P and two metabolites on contraction in guinea pig gallbladder strips. P induced a concentration-dependent relaxation in guinea pig gallbladder strips precontracted with cholecystokinin octapeptide (CCK). Pretreatment of gallbladder strips with P (50 microM) also reduced the amount of CCK-induced tension. Nifedipine (1 microM) produced a similar effect. Pretreatment of the strips with PKA inhibitor 14--22 amide myristolated (180 nM) or the PKG inhibitor KT5823 (1.2 microM) either separately or in combination significantly reduced the amount of P-induced relaxation. Rp-cAMPs (0.1mM) or H-89 (10 microM) separately or in combination significantly reduced the P-effect; however, the combination of agents produced the largest reduction. Genistein (1 microM), an inhibitor of protein tyrosine kinases, significantly (p<0.01) reduced the amount of P-induced relaxation. The use of strontium in the Kreb's solution as a substitute for Ca(2+) significantly (p<0.01) reduced the amount of CCK-induced tension. Pretreatment of the strips with 2-APB (26 microM), an inhibitor of IP(3,) induced Ca(2+) release, produced a significant (p<0.01) reduction in P-induced relaxation. We conclude that P inhibits gallbladder motility rapidly by nongenomic actions of the hormone. Several pathways that include tyrosine kinase and PKA/cAMP activity may mediate this effect.
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PMID:Progesterone inhibits gallbladder motility through multiple signaling pathways. 1591 87

We investigated, using guinea-pig spermatozoa as a model, whether phospholipase A2 (PLA2) is involved in progesterone or zona pellucida (ZP)-stimulated acrosomal exocytosis, if progesterone enhances ZP-induced activation of PLA2, and mechanisms underlying PLA2 regulation. Spermatozoa were capacitated and labeled in low Ca2+ medium with [14C]choline chloride or [14C]arachidonic acid, washed, and then exposed to millimolar Ca2+ and progesterone and/or ZP. Each agonist stimulated decrease of phosphatidylcholine (PC) and release of arachidonic acid and lysoPC, indicative of PLA2 activation. Aristolochic acid (a PLA2 inhibitor) abrogated lipid changes and exocytosis, indicating that these lipid changes are essential for exocytosis. Exposure of spermatozoa to submaximal concentrations of both progesterone and ZP resulted in a synergistic increase of arachidonic acid and lysoPC releases, and exocytosis, suggesting that, under natural conditions, both agonists interact to bring about acrosomal exocytosis. Progesterone-induced PLA2 activation appears to be mediated by a GABA(A)-like receptor, because bicuculline (a GABA(A) receptor antagonist) blocked arachidonic acid release and exocytosis. In agreement with this, GABA mimicked progesterone actions. ZP-induced activation of PLA2 seemed to be transduced via G(i) proteins because pertussis toxin blocked arachidonic acid release and acrosomal exocytosis. PLA2 may be regulated by PKC because progesterone- or ZP-induced release of arachidonic acid was blocked by the PKC inhibitors staurosporine or chelerythrine chloride. PLA2 could also be regulated by the cAMP-PKA pathway; inclusion of the PKA inhibitor 14-22 amide or H-89 led to a reduction in arachidonic acid release or exocytosis after progesterone or ZP. Taken together, these results suggest that PLA2 plays an essential role in progesterone or ZP-stimulated exocytosis with progesterone priming ZP action.
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PMID:Progesterone primes zona pellucida-induced activation of phospholipase A2 during acrosomal exocytosis in guinea pig spermatozoa. 1596 49

Di-n-butyl phthalate (DBP) is one of the most dominant phthalate esters and is widely distributed environmental contaminant. Although previous studies have demonstrated that DBP led to a variety of male reproductive abnormalities similar to those caused by androgen receptor antagonists, DBP and its active metabolite, mono-butyl phthalate (MBP), have been demonstrated no affinity for the androgen receptor, but rather exert anti-androgenic effect by altering testosterone biosynthesis. Furthermore, all these results were obtained from very high administrations of DBP or MBP. The purpose of this study was to determine the onset and the site of action of relatively low concentration of MBP on steroidogenesis in vitro. The mouse Leydig tumor cells (MLTC-1) was employed as a cellular model to investigate the effect of MBP on steroidogenesis. Various concentrations of MBP (1, 10, 100 and 1000nmol/l) and its solvent dimethyl sulfoxide (DMSO) were added to the medium for 24h followed by stimulation of some compounds such as human chorionic gonadotrophin (hCG), cholera toxin (CT), forskolin, cAMP analog 8-Br-cAMP, 22(R)-hydroxycholesterol (22R-HC) and pregnenolone. Progesterone in the medium and amounts of intracellular cAMP were measured by RIA. Expression of steroidogenic acute regulatory protein (StAR) was monitored by real-time PCR and Western blotting. The results revealed that the increases of progesterone production in the presence of hCG, CT, forskolin and 8-Br-cAMP were augmented by MBP. In contrast, the levels of intracellular cAMP exhibited no statistical significance when MLTC-1 cells were treated as above. These results implied that the site in the steroid biosynthesis pathway affected by MBP occurs after PKA activation in MLTC-1 cells. Moreover, supplementing the medium with 22R-HC and pregnenolone as progesterone precursors for P450 side chain cleavage enzyme (P450scc) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD), respectively, resulted in no rise in progesterone production, making clear that MBP did not influence the P450scc and 3beta-HSD but on the rate-limiting step, cholesterol transportation into mitochondria. In fact, the above results were confirmed by the upgraded StAR expression in MBP-treated cells. These data support that MBP promotes steroid hormone production by facilitating StAR expression in MLTC-1 cells.
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PMID:Low concentrations mono-butyl phthalate stimulates steroidogenesis by facilitating steroidogenic acute regulatory protein expression in mouse Leydig tumor cells (MLTC-1). 1699 44

Progesterone (P), acting through progesterone receptor (PR) isoforms A and B, plays an important role in normal mammary gland development and is implicated in the etiology of breast cancer. Because of significant similarities between human and rat mammary gland development and hormonal responsiveness of mammary cancers, we investigated P action in the rat mammary gland. By immunohistochemical methods we determined PRA and PRB expression at puberty, sexual maturity, pregnancy, and lactation and after postlactational involution and their functional roles in the regulation of proliferation. PRA expression was restricted to luminal epithelial cells, whereas PRB was expressed in both luminal and myoepithelial cells, indicating a novel role of PRB in myoepithelial cell regulation. The majority of PRA-positive (PRA+) cells coexpressed PRB. In the pubertal and adult virgin mammary gland, PRA+PRB+ cells also expressed nuclear cyclin D1 but did not contain the proliferation marker bromodeoxyuridine. Based on a lack of phosphorylated retinoblastoma protein expression and the expression patterns of the cyclin-dependent kinase inhibitors p21 and p27 in these cells, we conclude that PRA+PRB+ cells appear to be cell cycle arrested and do not proliferate. PRA+ cells were decreased in the adult gland and during and after pregnancy. The percentage of PRB+ cells was relatively constant throughout development, and in a significant proportion of cells, only PRB was detected. During development, and especially during pregnancy, a high percentage of PRB+ cells were positive for bromodeoxyuridine. From this observation, we conclude that these cells proliferate and that P acting through PRB may directly stimulate proliferation.
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PMID:Progesterone receptor isoforms and proliferation in the rat mammary gland during development. 1733 59

Progestin-facilitated lordosis of hamsters and rats is enhanced by activation of dopamine type 1 (D1) or GABAA/benzodiazepine receptor complexes (GBRs) in the ventral tegmental area (VTA) and these effects involve G-proteins and second messengers, such as adenosine 3',5'-monophosphate (cAMP). We examined whether D1- and/or GBR-mediated increases in progestin-facilitated lordosis of female hamsters and rats involve the cAMP-dependent protein kinase, protein kinase A (PKA), in the VTA. In experiment 1, ovariectomized hamsters, primed with estradiol (E2; 10 microg at h 0) + progesterone (P; 100 microg at h 45), were first pre-tested for lordosis and motor behavior (h 48) and then infused with the PKA inhibitor, Rp-cAMP (100 ng/side), or vehicle. Thirty minutes later, hamsters were retested and then received infusions of the D1 agonist, SKF38393 (100 ng/side), the GBR agonist, muscimol (100 ng/side), or vehicle to the VTA. Hamsters were post-tested for lordosis and motor behavior 30 min later. In Experiment 2, ovariectomized rats, primed with E2 (10 microg at h 0), were first pre-tested for lordosis and then infused with Rp-cAMP (100 ng/side) or vehicle to the VTA at h 44. Immediately after testing, rats received infusions of SKF38393 (100 ng/side), muscimol (100 ng/side), or vehicle and were retested for lordosis. Rats were then infused with the neurosteroid, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP; 100 or 200 ng/side), or beta-cyclodextrin vehicle and were post-tested for lordosis and motor behavior 10 and 60 min later. The enhancing effects of progestins or progestins plus D1 or GBR activation on lordosis of E2-primed hamsters and rats were blocked by the PKA inhibitor, Rp-cAMP. Thus, in the VTA, progestins' membrane actions involving D1 or GBRs are mediated, in part, by PKA.
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PMID:In the ventral tegmental area, progestins' membrane-mediated actions for lordosis of hamsters and rats involve protein kinase A. 1738 17

The mechanisms responsible for the increased basal rates of progesterone secretion from large steroidogenic luteal cells (LLC) relative to small steroidogenic luteal cells (SLC) have not been clearly defined. To determine if protein kinase A (PKA) is tonically active in LLC, the adenylate cyclase activator forskolin and a specific PKA inhibitor (PKI) were utilized in a 2 x 2 factorial treatment with each steroidogenic cell type. Progesterone and cAMP production were quantified after the different treatments. In addition, the effects of the treatments on the concentrations and relative phosphorylation status of the steroidogenic acute regulatory (STAR) protein in the two cell types were determined as a measure of PKA activity. Treatment with PKI blocked forskolin-induced increases in progesterone secretion by SLC without affecting the production of cAMP. The treatment of LLC with PKI significantly decreased basal progesterone secretion in the presence or absence of forskolin, indicating that the high level of steroidogenesis in this cell type requires PKA activity. There were no differences in the steady-state concentrations of STAR protein in either cell type after treatment. However, the percentage of relative STAR phosphorylation was higher in the LLC than in SLC, and PKI treatment significantly decreased the phosphorylation of STAR in the LLC. The relative phosphorylation status of STAR and the concentrations of progesterone in the media were significantly correlated with the treatments in both cell types. The amount of progesterone secreted per picogram of cAMP was higher in the LLC than in the SLC, and this was accompanied by a significant increase in the ratio of relative STAR phosphorylation to the steady-state concentration of STAR protein. These data are compatible with the theory that LLC are constitutively steroidogenic, partly because they have tonically active PKA. In addition, the phosphorylation of STAR appears to be a primary activity of PKA in both types of ovine steroidogenic luteal cells.
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PMID:Constitutive steroidogenesis in ovine large luteal cells may be mediated by tonically active protein kinase A. 1740 73

Progesterone exerts a variety of actions in the brain, where it is rapidly metabolized to 5alpha-dihydroprogesterone (DHP) and 3alpha,5alpha-tetrahydroprogesterone (THP). The effect of progesterone and its metabolites on the expression and phosphorylation of the microtubule-associated protein Tau and glycogen synthase kinase 3beta (GSK3beta), a kinase involved in Tau phosphorylation, were assessed in two progesterone-sensitive brain areas: the hypothalamus and the cerebellum. Administration of progesterone, DHP, and THP to ovariectomized rats did not affect Tau and GSK3beta assessed in whole hypothalamic homogenates. In contrast, progesterone and its metabolites resulted in a significant decrease in the expression of Tau and GSK3beta in the cerebellum. Furthermore, progesterone administration resulted in an increase in the phosphorylation of two epitopes of Tau (Tau-1 and PHF-1) phosphorylated by GSK3beta, but did not affect the phosphorylation of an epitope of Tau (Ser262) that is GSK3beta insensitive. These effects were accompanied by a decrease in the phosphorylation of GSK3beta in serine, which is associated to an increase in its activity, suggesting that the effect of progesterone on Tau-1 and PHF-1 phosphorylation in the cerebellum is mediated by GSK3beta. The regulation of Tau expression and phosphorylation by progesterone may contribute to the hormonal regulation of cerebellar function by the modification of neuronal cytoskeleton.
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PMID:Effects of progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, on the expression and phosphorylation of glycogen synthase kinase-3 and the microtubule-associated protein tau in the rat cerebellum. 1744 5

Mast cells proliferate in vivo in areas of active fibrosis, during parasite infestations, in response to repeated immediate hypersensitivity reactions and in patients with mastocytosis. We investigated how progesterone reduces the proliferation of HMC-1(560) mast cells that proliferate spontaneously in culture. Cells were incubated with 1 microM to 1 nM progesterone for 24-48 h. Progesterone (1 microM) reduced the spontaneous proliferation of HMC-1(560) mast cells to half that of cells cultured without hormone. [(3)H] thymidine incorporation was only 50% of control; there were fewer cells in G2/M and more cells in G0/G1. The amounts of phospho-Raf-1 (Tyr 340-341) and phospho-p42/p44 MAPK proteins were also reduced. In contrast progesterone had no effect on MAP kinase-phosphatase-1. The Raf/MAPK pathway, which depends on Src kinase activity, is implicated in the control of cell proliferation. HMC-1(560) cells incubated with the tyrosine kinase inhibitor PP1 proliferated more slowly than controls and had less phospho-Raf-1 (Tyr 340-341) and phospho-p42/p44 MAPK. The Csk homologous kinase (CHK), an endogenous inhibitor of Src protein tyrosine kinases, was also enhanced in progesterone-treated cells. In contrast, progesterone had no effect on the growth of cells transfected with siRNA CHK. We conclude that progesterone increases the amount of csk homologous kinase, which in turn reduces HMC-1(560) mast cell proliferation. This effect parallels decreases in the phosphorylated forms of Raf-1 and p42/44 MAPK, as their production depends on Src kinase activity.
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PMID:Progesterone increases csk homologous kinase in HMC-1560 human mast cells and reduces cell proliferation. 1749 61

Progesterone receptors (PRs) mediate proliferation during breast development and contribute to breast cancer progression, in part by synergizing with peptide growth factors. We have previously identified PR Ser294 as a key site for direct regulation of PR location, activity, and turnover in response to phosphorylation events. Herein, we sought to better understand how hormonal cross talk alters PR function. We demonstrate that progestins (R5020 and RU486) induce rapid (15 min) sumoylation of PR Lys388; sumoylation represses PR transcriptional activity on selected progesterone response element-driven and endogenous promoters and retards ligand-induced PR down-regulation. Consistent with this finding, we show that stabilized but weakly active phospho-mutant S294A PRs are heavily sumoylated. Conversely, desumoylated PR, created by mutation of PR Lys388 (K388R) or by overexpression of sentrin (SUMO)-specific protease desumoylating enzymes, are hypersensitive to low progestin concentrations. Combination of K388R and S294A mutations (KRSA double-mutant PR) rescues both transcription and turnover of impaired phospho-mutant (S294A) receptors. Notably, phosphorylation events antagonize PR-B but not PR-A sumoylation. Treatment of cells with epidermal growth factor or transient expression of activated mitogen-activated protein/ERK kinase kinase or cyclin-dependent protein kinase 2 induces PR-B Ser294 phosphorylation and blocks PR-B sumoylation, thereby derepressing receptor activity; PR-A is resistant to these events. Modulation of reversible PR sumoylation in response to diverse hormonal signals provides a mechanism for rapid isoform-specific changes in hormone responsiveness. In the context of elevated protein kinase activities, such as during mammary gland development or breast cancer progression, phosphorylated PR-B may be undersumoylated, transcriptionally hyperactive, and unstable/undetectable.
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PMID:Phosphorylation-dependent antagonism of sumoylation derepresses progesterone receptor action in breast cancer cells. 1771 77

It is well known that gonadal steroid hormones influence the level of plasma calcitonin (CT), but the mechanism by which progesterone affects CT secretion is not clear. Immortalized TT cells are a reliable model system for studying the endocrine function of human parafollicular cells. In the present study, the effects of progesterone on CT secretion were examined in TT cells. TT cells were incubated in medium containing vehicle (DMSO), progesterone or BSA-progesterone for 60 or 150 min, and then the levels of CT in the medium, progesterone receptors, cAMP accumulation and CT mRNA expression were measured. To study the correlation between progesterone effects and the cAMP-dependent protein kinase A (PKA) pathway, cell lysates or cells in 24-well plates were treated with either vehicle or progesterone plus RU486, SQ22536, KT5720, or 3-isobutyl-1-methylxanthine. Then, adenylyl cyclase and protein kinase A (PKA) activities were measured in the cell lysates, and the CT levels were measured in the medium from the 24-well plate. The activated cAMP response element binding protein (P-CREB) was also measured by immunofluorescence. Administration of 1 microM progesterone or 500 nM BSA-progesterone increased the secretion of CT by 381% and 100%, respectively. Progesterone receptors A and B were downregulated by progesterone treatment. The cAMP concentration, adenylyl cyclase and PKA activity, CT mRNA expression, and nuclear P-CREB concentrations all showed an increase after progesterone treatment. RU486, SQ22536 and KT5720 inhibited the progesterone-stimulated effects. These results suggest that a cAMP-dependent PKA pathway is involved in progesterone-stimulated effects on CT secretion from TT cells.
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PMID:The cyclic AMP-dependent protein kinase A pathway is involved in progesterone effects on calcitonin secretion from TT cells. 1796 87


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