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)

Transcription of proto-oncogene fos is induced by elevated levels of intracellular cAMP. We report that human c-fos promoter recombinants transfected into rat pheochromocytoma cells (PC12) and human choriocarcinoma cells (JEG-3) are induced by stimulation of adenylate cyclase and that this induction is diminished considerably in the mutant PC12 cell line A126-1B2, which is deficient in cAMP-dependent protein kinase II. An element centered at position -60 of the c-fos promoter, which encompasses a consensus cAMP response element (CRE), is sufficient to confer cAMP responsiveness to a herpes thymidine kinase/CAT fusion gene. The specific binding of a nuclear protein to the c-fos CRE can be competed by the somatostatin and alpha-chorionic gonadotropin (alpha-CG) promoter regions that contain CREs. Gel mobility shift assays with double-stranded oligonucleotides containing either the wild-type or mutated c-fos CRE sequence have demonstrated that binding occurs only to the wild-type CRE. The nuclear factor binding to the c-fos CRE is likely to be transcription factor CREB (CRE nuclear binding protein), because an affinity-purified 43-kD CREB isolated from PC12 cells binds efficiently in a DNA footprinting assay. Thus, regulation of the c-fos gene transcription appears to involve a mechanism common to many genes that respond to cAMP as a second message leading to cell growth and differentiation.
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PMID:Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. 285 Sep 67

Purified testicular and ovarian luteinizing hormone/human chorionic gonadotropin (hCG) receptors are phosphorylated at serine and threonine residues by the catalytic subunit of the cAMP-dependent protein kinase (protein kinase A). Occupancy of the receptors by hCG significantly increased the rate but not the extent of phosphorylation. However, prolonged preincubation of receptors with hCG reduced the subsequent rate of receptor phosphorylation. Identical phosphopeptide maps were obtained for the phosphorylated ovarian and testicular receptors. The phosphorylated receptor, like the native receptor, bound to wheat germ lectin and hCG-Sepharose and migrated as a single band of Mr 90,000 (testis) and Mr 85,000 (ovary) on NaDodSO4/PAGE. Neuraminidase treatment of receptors caused reductions of molecular weight to 82,000 (testis) and 77,000 (ovary), and further treatment with O-Glycanase had minimal effect on molecular size. However, deglycosylation with N-Glycosidase and endoglycosidase F produced a single labeled polypeptide of Mr 59,000 for both gonadal receptors. Treatment of native receptors with neuraminidase caused no apparent change in binding of gonadotropin to blotted receptors, whereas deglycosylated receptors showed a major reduction in hormone binding. These results indicate that luteinizing hormone/hCG receptors are sialoglycoproteins with predominantly N-linked glycosyl residues that account for the size difference between testicular and ovarian receptors and that may participate in the interaction with gonadotropin. Receptor occupancy by agonist leads to a conformational change that facilitates its phosphorylation during initial binding and reduces the rate of phosphorylation after more prolonged exposure to hCG.
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PMID:Phosphorylation and glycosylation of the luteinizing hormone receptor. 292 94

The murine Leydig tumor cell line, MLTC-1, contains gonadotropin receptors and a gonadotropin-responsive adenylate cyclase system that became refractory (desensitized) when exposed to human chorionic gonadotropin (hCG). MLTC-1 cells also contain phorbol ester receptors with a Kd of 53 nM for [3H]phorbol dibutyrate. Exposing cells to 12-O-tetradecanoyl phorbol 13-acetate (TPA) also causes desensitization of the hCG response. TPA-induced desensitization was similar to hCG-induced desensitization by every criteria tested. Both TPA- and hCG-induced desensitization caused approximately 50% loss of the hormone response within 30 min. Neither TPA or hCG altered receptor affinity for hCG. The dose response of adenylate cyclase to hCG or GTP in isolated membranes was not affected by either hCG- or TPA-induced desensitization. Similarly the dose response to hCG of cAMP accumulation in intact cells was not altered by desensitization with hCG or TPA. It was determined that MLTC-1 cells have Ca2+/phospholipid-dependent protein kinase activity that displayed a dose-dependent response to TPA. The concentration of TPA required to activate the protein kinase was similar to that required for desensitization. Phorbol esters that were unable to activate protein kinase C were also unable to desensitize MLTC-1 cells. The protein kinase from MLTC-1 cells was also activated by diacylglycerol. In addition, diacylglycerols caused desensitization of the hCG response. TPA- and diacylglycerol-induced desensitization is probably mediated by protein kinase C, and the similarities between hCG- and TPA-induced refractoriness suggests a convergence of mechanisms at some point of MLTC-1 cell desensitization.
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PMID:Phorbol ester causes desensitization of gonadotropin-responsive adenylate cyclase in a murine Leydig tumor cell line. 298 73

Although estradiol is the established luteotropic hormone in the rabbit, the corpus luteum also contains a luteinizing hormone (LH)-activated adenylate cyclase system and cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase, which suggests that LH and cAMP may play a physiological role in regulating luteal progesterone production. The present study examined whether human chorionic gonadotropin (hCG) and cAMP derivatives stimulate progesterone production by dispersed rabbit luteal cells in static and perifusion incubations. Results of this study show that progesterone production by rabbit luteal cells is significantly stimulated (p less than 0.05) by hCG concentrations at or greater than 0.1 IU/ml or by dibutyryl cAMP concentrations at or greater than 5 mM. Both agents produce maximal stimulations of approximately 4-fold. However, neither prostaglandin E2 or F2 alpha at concentrations of 0.1-3.0 micrograms/ml altered progesterone secretion. When luteal cells were incubated with maximal concentrations of hCG and lipoproteins together, the resultant progesterone secretion was additive. This suggests that the effects of hCG and lipoprotein are independent. Both responses could be blocked completely by cycloheximide (10(-4) M), and thus appear to be dependent on protein synthesis. The cholesterol derivative 25-hydroxycholesterol (20 micrograms/ml) partially overcame the steroidogenic block by cycloheximide, suggesting that transport of cholesterol, regardless of its origin, into mitochondria was an essential protein-mediated event in these cells. Inhibition of the side-chain-cleavage enzyme by aminoglutethamide blocked progesterone production by rabbit luteal cells in vitro. Although estradiol may dominate in the regulation of luteal progesterone production physiologically, this study clearly demonstrates that potential mechanisms do exist in the rabbit corpus luteum for cAMP-mediated stimulation of progesterone production in the rabbit.
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PMID:The effect of human chorionic gonadotropin, dibutyryl cyclic adenosine 3',5'-monophosphate, prostaglandins, and 25-hydroxycholesterol on acute progesterone secretion by dissociated rabbit luteal cells in vitro: evidence for independent effect of human chorionic gonadotropins and lipoproteins. 303 63

Phosphorylation of secretory proteins is an uncommon event. In this manuscript, the phosphorylation of human chorionic gonadotropin, a glycoprotein hormone secreted by the JAR choriocarcinoma cell line, is described. Labeling of JAR cells with 32PO4 indicates that both the intracellular and the secreted forms of the free alpha subunit are phosphorylated. Although the secreted alpha beta dimer also incorporates 32PO4, there is little detectable phosphorylation of the intracellular precursors of alpha beta dimer, suggesting that dimer phosphorylation occurs as a late event in post-translational processing. In addition, phorbol 12-myristate 13-acetate markedly stimulates the phosphorylation of both intracellular and secreted forms of free alpha subunit and to a lesser extent of secreted alpha beta dimer. In vitro assays, using homogenates of JAR cells as a source of protein kinase activity, indicate that the uncombined alpha subunit is preferentially phosphorylated. The phosphorylation sites are on serine and threonine residues in the alpha subunit.
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PMID:Phosphorylation of the secreted, free alpha subunit of human chorionic gonadotropin. 346 19

Human chorionic gonadotropin (hCG) and its subunits were studied as substrates for cAMP-dependent protein kinase. Phosphorylated residues were identified in peptide fragments by sequence analysis following appropriate hydrolysis and purification. Only the free beta-subunit was phosphorylated. Intact beta subunit incorporated 1 mol of phosphate/mol of peptide. This was localized to Thr 97, within the sequence -Arg-Arg-Ser-Thr-, which resembles one type of acceptor site for cAMP-dependent phosphorylation. Since beta Thr 97 did not phosphorylate in native hCG, this residue may be masked by the alpha subunit. Reduced and carboxymethylated hCG beta phosphorylated to 2.8 mol of phosphate/mol of peptide. Besides Thr 97, phosphate was also found at Ser 66 and Ser 96. Ser 66 occurs within a segment recognized to be favored for phoshorylation with the general sequence -Arg-X-X-Arg-X-X-Ser-. The appearance of this site in the linearized peptide suggests that Ser 66 is "buried" in the native conformation of the beta subunit. Two synthetic peptides representing residues 93-102 of hCG beta were also examined. The disulfide form of the peptide phosphorylated at Thr 97 while the linear peptide phosphorylated at Ser 96. Conformation as well as primary structure can thus influence the site of phosphate incorporation.
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PMID:Phosphorylation of human choriogonadotropin. Stoichiometry and sites of phosphate incorporation. 619 63

The alteration in activities of multiple protein kinases has been studied in the endometrium of a rabbit treated with estrogen and progesterone. The administration of estrogen or progesterone to the castrated rabbit resulted in a remarkable increase of total activity in the cytosol fraction of the endometrium. The administration of estrogen caused an increase of type I adenosine-3',5'-monophosphate-dependent (cAMP-dependent) protein kinase and a slight decrease of type II cAMP-dependent protein kinase. In contrast, the treatment with progesterone after priming administration of estrogen brought about an increase of type II cAMP-dependent protein kinase and a decrease of type I cAMP-dependent protein kinase. Therefore, the activity ratio of type II to type I decreased by estrogen and increased by progesterone. The simultaneous administration of cycloheximide abolished the stimulatory effect of respective hormones on the level of each protein kinase. The activity profile of protein kinases on DEAE-cellulose column after ovulation caused by the administration of human chorionic gonadotropin to a non-castrated rabbit was similar to that of the rabbit treated with progesterone. The results presented demonstrate the specific regulation by the steroid hormones of de novo synthesis of protein kinases in the target organ.
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PMID:Specific regulation by steroid hormones of protein kinases in the endometrium. 1. Alteration by estrogen and progesterone in levels of protein kinases in rabbit endometrium. 624 54

The effect of human chorionic gonadotropin (CG) on protein kinase levels has been studied in rabbit endometrium. A good correlation was observed between alterations of total protein kinase activity and DNA content in the tissue. The level of type I cyclic AMP-dependent protein kinase had slightly increased by 6 h after human CG treatment, and then decreased later. In contrast, the type II enzyme gradually increased after 3 days. The increase of the activity at 7 days was mainly due to that of type II enzyme, and the ratio of type II to type I enzyme increased. The activity pattern at the later stage closely resembled that of treatment with progesterone.
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PMID:Regulation by human chorionic gonadotropin of protein kinases in rabbit endometrium. 627 Dec 46

The magnitude of activation of the type I and type II forms of cAMP-dependent protein kinase was investigated in estrous follicles and corpora lutea (CL) obtained from ovaries of control rabbits and rabbits injected acutely with human chorionic gonadotropin (hCG). To this end, a chromatographic technique which permitted quantitative evaluation of the in vivo activational state of the two forms of cAmP-dependent protein kinase was developed and verified. Results revealed that in follicles obtained from ovaries of untreated estrous rabbits, 15% of the soluble cAMP-dependent protein kinase, all of which exists as the type II isozyme, is activated. Intravenous administration of a single bolus of hCG promoted a concentration-dependent activation (in 10 min) of this protein kinase isozyme. In CL obtained from ovaries of control, 4-day pseudopregnant rabbits, 32% of the total soluble cAMP-dependent protein kinase exists as the type I form and 68% exists as the type II form. Both types of protein kinase are approximately 10% dissociated in CL from ovaries of untreated rabbits. Upon intravenous administration of hCG, only the type I form of cAMP-dependent protein kinase is further activated (in 10 min). Dissociation of this protein kinase is dependent upon the time and concentration of hCG. Preferential activation of the type I form of cAMP-dependent protein kinase in CL is also demonstrable in in vitro studies using exogenous cAMP. These data suggest that the physiological intracellular mediator of acute cAMP-regulated, hCG-triggered functions in rabbit ovarian follicles is the type II isozyme of cAMP-dependent protein kinase while in CL of 4-day pseudopregnant rabbits, it is the type I enzyme form.
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PMID:Selective activation of rabbit ovarian protein kinase isozymes in rabbit ovarian follicles and corpora lutea. 627 76

Using a 0-32% continuous metrizamide density gradient, interstitial cells could be separated into five distinct bands. Cells localized in bands 1 (B1), 2 (B2), and 3 (B3) were isolated and incubated for 1h with or without human chorionic gonadotropin (hCG). Both B2 and B3 cells responded to hCG with increased cyclic AMP formation, but only B3 cells produced significantly more testosterone. Protein kinase activity of B2 cells was found to be extremely low compared with B1 and B3 cells. Additional treatment of B3 cells with collagenase did not cause any change in protein kinase activity. These results indicate that decreased protein kinase activity may be responsible for impaired testosterone synthesis in B2 cells.
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PMID:Protein kinase activity of purified Leydig cells: low protein kinase activity causes impaired steroidogenesis by band two cells. 628 60


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