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)

After a single injection of oestradiol benzoate (1.5 mg/kg) to oestrogen-withdrawn chickens, there was an increase in magnum wet weight, DNA polymerase alpha activity, adenosine-3',5'-monophosphate-dependent protein-kinase activity and estrogen-receptor concentration, as measured over 36 h. Besides these intracellular proteins, the secretory proteins ovalbumin and conalbumin were also augmented, and detailed time-course studies were performed. Early induction kinetics for ovalbumin and conalbumin synthesis, which differed for each protein, were independent of the dose of oestradiol benzoate injected if it exceeded 0.1 mg/kg. After 6 h for ovalbumin and 2 h for conalbumin, the induction curves diverged according to the dose of hormone administered and in correlation with the persistence of elevated nuclear oestrogen-receptor concentrations, a result confirmed with 11 beta-methoxy-17 alpha-ethynyloestradiol (R 2858), a powerful synthetic oestrogen. When oestradiol benzoate (1 mg/kg) and progesterone (3 mg/kg) were injected simultaneously, the rate of conalbumin sythesis, during the first 6-8 h, was lower than that observed in animals injected with oestradiol benzoate alone. However at later times conalbumin synthesis was greater in animals receiving both hormones than with oestradiol alone. In contrast, the rate of ovalbumin synthesis after the combined injection was higher than that induced by either hormone alone throughout the entire experimental period. In order to study further the synergistic and antagonistic activities of these two hormones, a single injection of progesterone (3 mg/kg) was administered 6, 12 or 18 h after 1.5 mg/kg oestradiol benzoate. Progesterone administration resulted in a reduction in cytoplasmic, nuclear and total oestrogen receptor concentration for at least 6 h when compared with the values in birds treated with oestrogen alone. DNA polymerase and protein kinase activities were also reduced during this period. Subsequently, all parameters increased, and by 18-24 h after progesterone treatment, reached values higher than those observed in animals receiving oestrogen alone.
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PMID:Steroid receptors and effects of oestradiol and progesterone on chick oviduct proteins. 624 83

Microinjection of cAMP-dependent protein kinase inhibitor (1.8 microM) increases the cAMP level of Xenopus oocyte. Its effect was observed in full-grown (stage VI) as well as in vitellogenic (stage IV) oocytes. In contrast the inhibitor I1 of protein phosphatase-1 blocks cAMP accumulation. Progesterone (1 microM) decreases the cAMP level in control and in PKI-treated oocytes of both stages. These results show that cAMP concentration is regulated by a cAMP-dependent phosphorylation indicating the presence of a feedback mechanism. The feedback control is disrupted when oocyte is induced to mature by progesterone.
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PMID:cAMP-dependent protein kinase regulates in ovo cAMP level of the Xenopus oocyte: evidence for an intracellular feedback mechanism. 630 83

Progesterone (P4) production by the bovine placenta differs from that of other steroidogenic tissue in two important respects: 1) it is calcium-dependent but cyclic nucleotide-independent and 2) it is suppressed by an endogenous inhibitor for most of the life span of the placenta. This natural refractory state of the placenta can be overcome in in vitro incubations of fetal cotyledon cells by agents that increase intracellular calcium (3-isobutylmethylxanthine [MIX], calcium ionophore (A23187), addition of substrate (pregnenolone, hydroxycholesterol), and stimulators of protein kinase C (PKC) such as phorbol ester (TPA). We therefore tested, in cultures of cotyledonary cells, two compounds that have been reported to inhibit protein kinases: 1) staurosporine (STA), an inhibitor of PKC, cAMP-dependent kinase, tyrosine kinase (TK), and the epidermal growth factor (EGF) receptor TK, and 2) genistein, an inhibitor of TK. It was found that STA stimulated steroidogenesis in a dose-dependent manner in both the absence and presence of added calcium. STA (10(-9) M) stimulated at least a twofold increase in P4 production by cultured fetal cotyledon cells throughout the first half of gestation (50-130 days). EGF was also found to cause a twofold stimulation of P4 production, and the effect was additive to that of STA. Both basal and EGF- or STA-stimulated production were inhibited by genistein. In contrast, two inhibitors of PKC and PKA (H-7, H-8) had no effect on P4 production. We conclude that STA-induced steroidogenesis in the bovine placenta is not related to its reported ability to inhibit PKC, TK, or EGF receptor TK.
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PMID:Staurosporine stimulates progesterone production by bovine placental cells. 791 70

The inhibition of Ca2+ channel currents by endogenous brain steroids was examined in freshly dissociated pyramidal neurons from the adult guinea pig hippocampal CA1 region. The steady-state inhibition of the peak Ca2+ channel current evoked by depolarizing steps from -80 to -10 mV occurred in a concentration-dependent manner with the following IC50 values: pregnenolone sulfate (PES), 11 nM; pregnenolone (PE), 130 nM; and allotetrahydrocorticosterone (THCC), 298 nM. THCC, PE, and PES depressed a fraction of the Ca2+ channel current with a maximal inhibition of 60% of the total current. However, substitution of an acetate group for the sulfate group on PES resulted in a complete loss of activity. Progesterone had no effect (4% inhibition at 100 microM). Intracellular dialysis of PES had no effect on the Ca2+ current; concomitant extracellular perfusion of PES showed normal inhibitory activity, suggesting that the steroid binding site can only be accessed extracellularly. Analysis of tail currents at -80 mV demonstrated that THCC and PES slowed the rate of Ca2+ current activation and deactivation with no change in the voltage dependence of activation. Inhibition of the Ca2+ channel current by THCC and PES was voltage dependent. THCC primarily inhibits the omega-conotoxin (CgTX)-sensitive or N-type Ca2+ channel current. PE was nonselective in inhibiting both the CgTX- and the nifedipine (NIF)-sensitive Ca2+ channel current. These neurosteroids had no effect on the CgTX/NIF-insensitive current. In neurons isolated from pertussis toxin (PTX)-treated animals by chronic intracerebroventricular infusion (1000 ng/24 hr for 48 hr), the Ca2+ channel current inhibition by PES, PE, and THCC was significantly diminished. Intracellular dialysis with GDP-beta-S (500 microM) also significantly diminished the neurosteroid inhibition of the Ca2+ channel current. Intracellular dialysis with the general kinase inhibitors H-7 (100 microM), staurosporine (400 nM), and a 20 amino acid protein kinase inhibitor (1 microM) also significantly prevented the THCC and PES inhibition of the Ca2+ channel current. Intracellular dialysis with the more specific inhibitors of protein kinase C (PKC), the pseudosubstrate inhibitor (PKCI 19-36) (1-2 microM) and bisindolylmaleimide (1 microM) significantly diminished the THCC and PE inhibition of the Ca2+ channel current. Rp- cAMP (100 microM), a specific inhibitor of cAMP-dependent protein kinase (PKA), had no effect on the THCC and PE inhibition of the Ca2+ current.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism. 815 51

When steroid hormone antagonists have inappropriate agonist effects, the clinical consequences are grave. Progesterone antagonists bind to two naturally occurring isoforms of human progesterone receptors (hPR), hPRB and the NH2-terminally truncated hPRA, and usually inhibit agonist-stimulated transcription. It is shown here that elevation of cAMP levels in a human breast cancer cell line leads to the functional reversal of progesterone antagonist action. While hPR occupied by the antagonists RU486 and ZK112993 are transcriptionally inactive, the antagonist-occupied receptors become strong activators of transcription in the presence of 8-Br-cAMP. However, this functional switch does not occur with the progesterone antagonist ZK98299, which, unlike RU486 and ZK112993, is unable to induce hPR binding to DNA. This suggests that the 8-Br-cAMP-induced transcriptional reversal requires that the antagonist-occupied receptors be bound to DNA. Even with agonist-occupied hPR, addition of 8-Br-cAMP results in a synergistic increase in transcriptional activity. When hPRA alone are transiently expressed in COS-1 cells, transcription of a reporter gene is stimulated by the agonist R5020 and by 8-Br-cAMP and is synergistic when both are present; but the 8-Br-cAMP-dependent component of transcription proceeds in the absence of hPRA, in the absence of the progesterone response element, and in the presence of a DNA-binding domain mutant of hPRA that cannot bind to the progesterone response element. Additionally, under the intracellular conditions in which 8-Br-cAMP activates antagonist-hPR complexes, there is no protein kinase A-mediated phosphorylation of the receptors. We discuss a model in which a gene that is independently transcribed by cAMP-responsive factors and by hPR can be selected for positive or negative regulation on the transcription complex due to additive or cooperative interactions between the two DNA-bound factors.
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PMID:Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists by cAMP. 838 87

Diethylumbelliferyl phosphate (DEUP) is an organophosphate cholesteryl ester hydrolase inhibitor that blocks steroidogenesis mainly by preventing cholesterol transport into the mitochondria of steroidogenic cells. In the present study, we show that DEUP blocks the cAMP-stimulated mitochondrial accumulation of the 30-kDa mitochondrial proteins (recently named steroidogenic acute regulatory StAR proteins) that are believed to be the cycloheximide-sensitive factors induced by trophic hormones and cAMP. Inhibition of mitochondrial StAR accumulation by DEUP is dose dependent and closely parallels inhibition of progesterone synthesis. Stimulated lactate production, another cAMP-dependent process in MA-10 cells, is also inhibited by DEUP. Inhibition of protein kinase A (PKA) action would explain the inhibition of these two unrelated processes. However, the cytosolic PKA activity of DEUP-treated MA-10 10 cells was normal. Moreover, the activity of purified PKA was unaffected by DEUP. The inhibition of StAR synthesis was not caused by a direct effect of DEUP on the labile proteins since DEUP-treated cells required more than 24 h to recover steroidogenic capacity after DEUP treatment. Further evidence that the synthesis of StAR was not directly affected was obtained using the constitutively active R2C cells. Progesterone synthesis by these cells also involves StAR, but neither StAR synthesis or steroid synthesis is sensitive to DEUP. Lactate formation in dibutyryl-cAMP-stimulated R2C cells is, however, sensitive to inhibition by DEUP. These data can be best explained by DEUP acting on a long-lived factor involved in the cAMP/PKA response pathway, but not involved in constitutive steroidogenesis.
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PMID:Diethylumbelliferyl phosphate inhibits steroidogenesis by interfering with a long-lived factor acting between protein kinase A activation and induction of the steroidogenic acute regulatory protein (StAR). 853 19

Progestin antagonists inhibit the proliferation of progesterone receptor-positive cells, including breast cancer cells, by G1 phase-specific actions, but the molecular targets involved are not defined. Reduced phosphorylation of pRB, a substrate for G1 cyclin-dependent kinases (CDKs) in vivo, was apparent after 9 h treatment of T-47D breast cancer cells with the antiprogestins RU 486 or ORG 31710, accompanying changes in S phase fraction. Although the abundance of cyclin D1, Cdk4, and Cdk6 did not decrease cyclin D1-associated kinase activity was reduced by approximately 50% at 9-18 h. Similarly, cyclin E-associated kinase activity decreased by approximately 60% at 12-24 h in the absence of significant changes in the abundance of cyclin E and Cdk2. The CDK inhibitor p21 increased in mRNA and protein abundance and was present at increased levels in cyclin D1 and cyclin E complexes at times when their kinase activity was decreased. Increased p21 protein abundance was observed in another antiprogestin-sensitive cell line, BT 474, but not in two breast cancer cell lines insensitive to antiprogestins. These data suggest increased p21 abundance and concurrent inhibition of CDK activity as a mechanism for antiprogestin induction of growth arrest. Antiprogestin effects on proliferation were markedly reduced after ectopic expression of cyclin D1, indicating that inhibition of cyclin D1 function is a critical element in antiprogestin inhibition of proliferation. However, these data also implicate regulation of cyclin E function in antiprogestin regulation of cell cycle progression.
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PMID:Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21. 899 88

Progesterone synthesis in the corpus luteum is regulated primarily by luteinizing hormone which acts via the adenylate cyclase/cyclic AMP/protein kinase A signalling cascade. Protein phosphorylation therefore plays a key role in the regulation of steroidogenesis, but there are relatively few studies of the in situ phosphorylation of luteal cell substrates. This may in part reflect the difficulties inherent in measuring changes in protein phosphorylation in intact cells preloaded with 32P and difficulties in interpreting data obtained using broken cell preparations. We have now applied a method of stable permeabilization of luteal cell plasma membranes by exposure of cell populations to a high intensity electric field. Under optimum conditions (5 kV/cm, six discharges) electrical permeabilization reproducibly produced populations of luteal cells in which 70-80% of the cells were permeabilized, as assessed by Trypan blue exclusion and [14C] sucrose space measurements. Pores were stable for at least 1 h, and there were no ultrastructural changes to the cells that could be detected by transmission electron microscopy. Permeabilized cells showed rapid cyclic AMP-induced changes in phosphorylation of endogenous proteins when provided with [gamma - 32 P] ATP. Our results demonstrate that the electricity permeabilized luteal cell offers a useful model for studying intracellular events in steroidogenic stimulus-response coupling cascades.
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PMID:Electrical permeabilization of rat luteal cells: in situ phosphorylation of endogenous protein. 925 93

Depending on the tissue, progesterone is classified as a proliferative or a differentiative hormone. To explain this paradox, and to simplify analysis of its effects, we used a breast cancer cell line (T47D-YB) that constitutively expresses the B isoform of progesterone receptors. These cells are resistant to the proliferative effects of epidermal growth factor (EGF). Progesterone treatment accelerates T47D-YB cells through the first mitotic cell cycle, but arrests them in late G1 of the second cycle. This arrest is accompanied by decreased levels of cyclins D1, D3, and E, disappearance of cyclins A and B, and sequential induction of the cyclin-dependent kinase (cdk) inhibitors p21 and p27(Kip1). The retinoblastoma protein is hypophosphorylated and extensively down-regulated. The activity of the cell cycle-dependent protein kinase, cdk2, is regulated biphasically by progesterone: it increases initially, then decreases. This is consistent with the biphasic proliferative increase followed by arrest produced by one pulse of progesterone. A second treatment with progesterone cannot restart proliferation despite adequate levels of transcriptionally competent PR. Instead, a second progesterone dose delays the fall of p21 and enhances the rise of p27(Kip1), thereby intensifying the progesterone resistance in an autoinhibitory loop. However, during the progesterone-induced arrest, the cell cycling machinery is poised to restart. The first dose of progesterone increases the levels of EGF receptors and transiently sensitizes the cells to the proliferative effects of EGF. We conclude that progesterone is neither inherently proliferative nor antiproliferative, but that it is capable of stimulating or inhibiting cell growth depending on whether treatment is transient or continuous. We also suggest that the G1 arrest after progesterone treatment is accompanied by cellular changes that permit other, possibly tissue-specific, factors to influence the final proliferative or differentiative state.
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PMID:Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). 932 42

Progesterone is a key factor in regulating endometrial cell decidualization, but the signal transduction pathways involved in mediating the effects of progesterone are not known. A role of the cAMP pathway in decidualization has been suggested by in vitro studies demonstrating that cAMP agonists can stimulate decidualization, in the absence of sex steroids. In this article, we have used an in vitro culture model of progesterone-dependent decidualization of human endometrial stromal cells to examine whether progesterone-induced decidualization is associated with activation of the cAMP signal transduction pathway in which the prolactin gene expression is a marker of decidualization. Following a lag period of approx 3 d, progesterone induced prolactin secretion and elevated intracellular cAMP levels. By d 15, cAMP and prolactin levels were approx 10- and 60-fold greater, respectively, than those on d 3. Changes in cAMP levels showed a positive correlation with prolactin secretion. Prostaglandin E2 (PGE2), which enhances progesterone-dependent decidualization, also increased both prolactin secretion and cAMP levels approx two- to fourfold on d 15 compared with d 3, whereas PGE2 alone, which does not induce decidualization, did not stimulate prolactin secretion or intracellular cAMP accumulation. Conversely, all-trans retinoic acid, which attenuates progesterone-dependent decidualization, significantly (p < 0.05) decreased both prolactin secretion and cAMP levels. Furthermore, the protein kinase A (PKA) inhibitor, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, significantly (p < 0.05) suppressed progesterone-dependent prolactin expression. Since activation of the PGE2 receptor subtype EP2 stimulates adenylate cyclase, reverse transcription-polymerase chain reaction (RT-PCR) analysis of endometrial cells was undertaken. Expression of EP2 mRNA was induced in cells treated with progesterone and estradiol alone or with PGE2, compared with untreated controls. The data suggest that the cAMP signal transduction cascade is activated during progesterone-dependent decidualization.
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PMID:Progesterone-dependent decidualization of the human endometrium is mediated by cAMP. 936 87


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