Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The natural gonadotropin-releasing hormone (GnRH) is secreted by hypothalamic neurons and acts at the level of anterior pituitary gonadotrophs releasing the peptides luteinizing hormone and follicle-stimulating hormone. GnRH is a decapeptide sensitive to peptidases, resulting in a short half-life. The synthesis of highly potent analogues of GnRH provides peptides with a longer half-life and a higher affinity to the GnRH-receptor. The presently available GnRH analogues for clinical use act initially as agonists by upregulating GnRH receptors in the pituitary. A few days after continuous application of GnRH analogues down-regulation of receptors and desensitization of the pituitary occur. In addition to receptor mechanisms, a number of postreceptor actions at the level of second messengers (protein kinase C, leukotriene and inositol phosphates) are responsible for the inhibition of adequate gonadotropin secretion. This paradoxical entire fertility action of the analogues is the basic principle for its clinical use, resulting in a reversible suppression of pituitary and thereby ovarian function.
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PMID:[Gonadotropin releasing hormone and analogs. Physiology and pharmacology]. 132 31

The priming effect of LHRH in vitro (which results in increased responsiveness of gonadotropes to both LHRH receptor-mediated and receptor-independent stimuli) is brought about by an unknown mechanism. The present results indicate that induction of the LHRH priming effect is inhibited in a concentration-dependent manner by the protein kinase C (PKC) inhibitors staurosporine, K252a, H7 and by the novel highly-selective PKC inhibitor, Ro 31-8220. In contrast, a range of other compounds that are relatively selective inhibitors of other kinases such as tyrosine kinases and Ca2+/calmodulin-dependent kinases were unable to prevent priming. The PKC inhibitors prevented priming without affecting initial LHRH-induced gonadotropin secretion. Thus, the priming-elicited increment in secretion was selectively removed, restoring hormone release to the level measured during an initial response to LHRH. Similar results were obtained on different days of the estrous cycle where the magnitude of the priming effect varies. Experiments on the time course of PKC inhibitor action revealed that the critical period was in the induction of the priming effect, not its expression. The PKC inhibitors had neither acute nor delayed effects on gonadotropin secretion induced by ionomycin. Staurosporine, K252a and Ro 31-8220 inhibited LHRH priming with identical potencies to their inhibition of phorbol ester-induced gonadotropin secretion. The reduced potency of H7 seen on LHRH priming compared to phorbol ester-induced gonadotropin release parallels results seen with this inhibitor on phorbol ester-induced secretion of growth hormone (Johnson and Mitchell (1989) Biochem. Soc. Trans. 17, 751-752) and on the pharmacological characteristics of PKCs partially purified from anterior pituitary tissue. In all aspects of this study, effects on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion appeared to be entirely similar.
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PMID:The priming effect of luteinizing hormone-releasing hormone (LHRH) but not LHRH-induced gonadotropin release, can be prevented by certain protein kinase C inhibitors. 163 16

In Sertoli cells from 21-day-old rats, the expression of the mRNA encoding the alpha-subunit of inhibin, and the production of immunoreactive inhibin are stimulated by follicle-stimulating hormone (FSH). In contrast, the amount of beta B-subunit mRNA is not increased after FSH treatment of the cells, and the ratio between bioactive and immunoactive inhibin decreases after stimulation with FSH. These data suggest that the beta B-subunit is the limiting factor in the production of bioactive inhibin. The aim of the present experiments was to investigate the effect of changes in the amount of beta B-subunit mRNA on the production of bioactive and immunoreactive inhibin. During early postnatal testicular development, the relative amounts of the 4.2 kb and 3.5 kb mRNAs encoding the beta B-subunit of inhibin changed markedly. The meaning of this changing ratio between beta B-subunit mRNAs is not clear, since both mRNAs are actively translated, as demonstrated by polysomal analysis. The total amount of beta B-subunit mRNA correlated with the in vitro production of bioactive inhibin as published earlier. Prolonged stimulation of cultured Sertoli cells from 14-day-old rats with 4 beta-phorbol 12-myristate 13-acetate (PMA) caused a decreased expression of the beta B-subunit mRNAs, presumably by down-regulation of protein kinase C. A similar effect was obtained after addition of the calcium ionophore A23187. Concomitantly, a decreased production of bioactive inhibin was observed. Furthermore, Western blotting revealed that secretion of the 32 kDa inhibin alpha beta-dimer was decreased, whereas secretion of the combination of the C-terminal part with the pro-region of the alpha-subunit was increased. It is concluded that the level of the beta B-subunit of inhibin is rate-limiting for the production of bioactive inhibin in cultured Sertoli cells, and that its expression can be influenced by modulation of protein kinase C, and/or intracellular calcium levels.
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PMID:Regulation of inhibin beta B-subunit mRNA expression in rat Sertoli cells: consequences for the production of bioactive and immunoreactive inhibin. 163 19

Recent evidence has been presented that follicle-stimulating hormone (FSH) stimulates the induction of granulosa cell c-fos protooncogene mRNA in vivo (Pennybacker and Herman (1989) J. Cell Biol. 109, 151A; Delidow et al. (1990) Endocrinology 126, 2302-2306), yet the mechanisms by which FSH induces c-fos mRNA expression have not been delineated. To elucidate the mechanisms of FSH-dependent c-fos mRNA expression, we measured the time and dose dependence of c-fos mRNA levels using Northern blot analysis in intact ovaries and cultured granulosa cells in response to FSH. In intact ovaries, FSH-induced c-fos mRNA expression was time dependent with maximal expression at 90 min post FSH injection, while in cultures of granulosa cells obtained from estrogen-primed immature female rats, c-fos mRNA levels were highest after 30 min exposure to FSH and at a concentration of 100 ng/ml. Neither 8-bromo adenosine 3',5'-cyclic monophosphate (8-br-cAMP), at doses ranging from 0.1 to 10 mM, nor 100 microM forskolin (in the presence or absence of 200 microM isobutyl-methylxanthine) or luteinizing hormone (LH, 100 ng/ml) were able to mimic FSH-induced c-fos mRNA expression in granulosa cell cultures. However, tetradecanoyl-13-phorbol acetate (TPA, 200 nM) was able to induce c-fos mRNA expression. The protein kinase C (PKC) inhibitors H-7 (0.3-30 microM) and staurosporine (0.75 micrograms/ml) blocked FSH-induced c-fos mRNA expression in cultured granulosa cells while HA 1004, an inhibitor of cGMP- and cAMP-dependent protein kinases at 30 microM had no effect on TPA-induced c-fos expression, and only minimally inhibited FSH-induced c-fos expression. Both FSH (100 ng/ml) and forskolin (3 microM) increased progesterone production in cultured granulosa cells. These data support the hypothesis that FSH specifically induces c-fos mRNA expression by a PKC-dependent mechanism and that the cAMP arm of the FSH response pathway is operant in these cells.
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PMID:Follicle-stimulating hormone increases c-fos mRNA levels in rat granulosa cells via a protein kinase C-dependent mechanism. 165 43

The gene for the beta subunit of porcine LH (LH-beta) was cloned from a genomic library constructed in EMBL3. The nucleotide sequence was determined for the entire gene transcriptional unit of porcine LH-beta in addition to 1277 and 372 bp of the 5'- and 3'-flanking regions respectively. Southern blot analysis of the porcine genomic DNA indicated that the LH-beta gene is present as a single copy. The transcriptional unit of porcine LH-beta spanned 1107 bp and contained three exons interrupted by two introns of 326 and 289 bp. The short untranslated sequence in the first exon and the location of the exon/intron junctions at amino acid residues -16/-15 and +41/+42 were highly conserved in the rat, human and bovine LH-beta genes. In the 5'-flanking region, one TATA box and two CCAAT boxes were present. The steroid-responsive element was not found up to 1277 bases upstream of the transcription start site. The potential AP-2 factor-responsive elements appeared nine times within the sequence that was determined, and four of them were located in the 5'-flanking region. Two distal AP-2 elements were arranged in an inverted repeat forming a 16 bp palindromic sequence. This feature suggested that hypothalamic gonadotrophin-releasing hormone stimulates expression of the LH-beta gene, predominantly by a signal-transduction system with the protein kinase C cascade and a mediator, the AP-2 factor. A further characteristic feature of the porcine LH-beta gene was the presence of clusters of GC boxes and CACCC elements in the 5'-flanking region and the downstream sequence. Co-existence of these regulatory elements with other elements, such as the AP-2 element or CCAAT box, was also found. The porcine LH-beta gene shows a structure distinct from the porcine FSH-beta and common alpha genes, which are counterparts of the LH-beta gene, reflecting differential control of their synthesis during gametogenesis.
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PMID:The gene for the beta subunit of porcine LH: clusters of GC boxes and CACCC elements. 170 Oct 88

Gonadotropin-releasing hormone (GnRH) stimulates the release and biosynthesis of gonadotropins, luteinizing hormone, and follicle-stimulating hormone from the pituitary gland. Additionally, GnRH regulates the number of its own receptors on pituitary gonadotropes causing both up- and down-regulation of receptors as well as biosynthesis of GnRH receptors. After exposure to GnRH, gonadotropes become desensitized to further stimulation by GnRH. The mechanisms through which these actions of GnRH are mediated appear to differ. Effects dependent upon extracellular calcium include gonadotropin biosynthesis and release as well as up-regulation of GnRH receptors. Additional actions of GnRH, such as down-regulation of receptors, biosynthesis of receptors, and desensitization, appear to be independent of extracellular calcium. Subsequent studies have ascribed roles for calmodulin and protein kinase C in mediating specific effects of GnRH.
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PMID:The 1990 James A. F. Stevenson Memorial Lecture. Gonadotropin-releasing hormone and its actions. 205 7

The modulatory role of protein kinase C (PK-C)- and Gi-protein-mediated signal transduction systems was studied in the cyclic variation of follicle-stimulating hormone (FSH)-stimulated cAMP production of rat seminiferous tubules. FSH (Metrodin, Serono, 30 mg/l) stimulated cAMP production 10-fold (p less than 0.01) in a 3 h incubation of 5 mm segments of seminiferous tubules of stages II-VI of the epithelial cycle, but only 2-fold (p less than 0.01) in stages VII-VIII. The PK-C activator 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/l) suppressed the FSH effect on cAMP output by 50-70% (p less than 0.01) in stages II-VI, but had no effect in stages VII-VIII. If the tubular segments were preincubated for 3 h in the presence of pertussis toxin (PT, 100 micrograms/l), the FSH-stimulated cAMP production of stages VII-VIII increased by 100-200% (p less than 0.01), and now they also became responsive to the TPA suppression. Conversely, no effect of PT was observed in stages II-VI. Cholera toxin (CT, 100 micrograms/l) and forskolin (Fk, 100 mumol/l) nearly similarly stimulated the cAMP production in both stages studied (about 10-fold, p less than 0.01), and TPA and PT potentiated the effects in a non-additive fashion. In conclusion, both Gi-protein and PK-C-mediated mechanisms modulate cAMP production of rat seminiferous tubules. A clear cyclic variation can only be demonstrated in FSH-stimulated cAMP production, but not if the Gs-protein or adenylate cyclase are directly stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C and Gi-protein mediated modulation of cAMP production in different stages of the rat seminiferous epithelium. 216 36

The neurohormone gonadotropin-releasing hormone (GnRH) is a decapeptide which is synthesized in the hypothalamus and released into the hypophysial portal system in a pulsatile manner. GnRH exerts its effect on the anterior pituitary gonadotrophs where it regulates the secretion and synthesis of gonadotropins (luteinizing hormone and follicle-stimulating hormone) through receptor-mediated actions. The GnRH receptor has been characterized and shown to be coupled to the formation of 'second messengers' which participate in signal transduction mechanisms. GnRH stimulation of luteinizing hormone release is a Ca2(+)-dependent process. G protein, phosphoinositide hydrolysis, protein kinase C as well as arachidonic acid and some of its metabolites were identified as possible mediators in the process.
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PMID:The gonadotropin-releasing hormone receptor: signals involved in gonadotropin secretion and biosynthesis. 217 Feb 60

To elucidate the structure and control of expression of the porcine FSH-beta subunit gene, two genomic clones were isolated and the entire gene structure was determined to the extent of 10 kb, consisting of 6 kb of the 5'-flanking region and 4 kb of the transcriptional unit. The porcine FSH-beta gene consisted of three exons the same as the human and bovine genes, but the positions of both splicing sites of porcine intron-1 were unique. It is known that the synthesis of FSH is regulated by gonadal steroids, gonadotrophin-releasing hormone (GnRH) and inhibin. However, the consensus steroid-responsive element was unexpectedly absent in the 5'-flanking region of 6 kb. On the other hand, the potential binding sites for activator protein-1 (AP1) and AP2, which might be stimulated by the GnRH-protein kinase C cascade, were present at seven and five positions respectively. An imperfect cyclic AMP-responsive element was also present. Southern blot analyses, using the cDNA and genomic fragments as probes, gave smear patterns suggesting the presence of repetitive sequences in the porcine FSH-beta gene. A survey of homology with the repetitive sequences revealed that short interspersed repeated sequences (SINES)-type non-viral retroposons were present with about 250 bp length repeats twice in the 5'-flanking region and once each in intron-1 and the 3'-flanking region. Other SINES-like sequences were also found in intron-1, exon-2 and exon-3. In comparison with the 5'-flanking sequences of the porcine alpha and LH-beta genes, there were no significantly conserved regions, implying a lack of common modulation of the three subunit genes.
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PMID:The gene for the beta subunit of porcine FSH: absence of consensus oestrogen-responsive element and presence of retroposons. 217 41

Normal human melanocytes, unlike malignant melanoma cells, required at least three growth-promoting agents, i.e., phorbol ester for protein kinase C activation and the growth factors basic fibroblast growth factor (bFGF) and insulin, for growth in chemically defined W489 medium. Cell growth was further stimulated by addition of agents that increase intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) to the medium. Among these agents, the pituitary hormones alpha-melanocyte-stimulating hormone (alpha-MSH) and follicle-stimulating hormone were the most potent, whereas bacterial toxins, including cholera, tetanus, and pertussis toxin and their subunits either were less mitogenic or gave variable results depending on the culture tested. Medium containing phorbol ester PMA, growth factors bFGF and insulin (or insulin-like growth factor-I), and synthetic alpha-MSH supported melanocyte growth for more than 5 months with doubling times between 5 and 8 days. Two copper-binding proteins, ceruloplasmin and tyrosinase, were mitogenic when added to medium and ceruloplasmic induced a long bi- to tripolar-shape of cells. Addition of 1 mM dibutyryl cAMP to the medium led to the formation of dendrites in all cells, with an average of 28 extensions per cell. Although cell growth was inhibited by dibutyryl cAMP, cells were not terminally differentiated and continued to proliferate. Dendritic melanocytes showed a 2.2-fold increase in activity of the tyrosine kinase pp60c-src. The induction of dendritic processes in melanocytes by dibutyryl cAMP or sodium butyrate was reversible and appears to reflect the expression of the mature melanocytic phenotype in situ.
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PMID:Regulatory factors that determine growth and phenotype of normal human melanocytes. 246 9


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