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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Porcine granulosa cells (GC) produce insulin-like growth factor (IGF) binding protein (BP)-3 and IGFBP-2 in culture. A gonadotropin, follicle-stimulating hormone (FSH), dramatically inhibited GC production of these IGFBPs in control cultures and in cultures stimulated by insulin plus epidermal growth factor (EGF) or IGF-I plus EGF. Stimulators of adenylate cyclase (forskolin, cholera toxin) and a derivative of adenosine 3',5'-cyclic monophosphate (cAMP), 8-bromoadenosine 3',5'-cyclic monophosphate, inhibited IGFBP synthesis in a manner similar to FSH. In contrast, the antagonist of cAMP action, (R)-p-adenosine 3',5'-cyclic phosphorothioate [(R)-p-cAMPS], significantly stimulated production of IGFBP-3 and IGFBP-2 compared with controls. This stimulatory effect of (R)-p-cAMPS was counteracted by cotreatment with FSH in a dose-dependent manner. Finally, treatment of GC cultures with FSH plus 3-isobutyl-1-methylxanthine resulted in a significant reduction in cellular content of mRNA coding for IGFBP-3 with no change in IGFBP-2 mRNA. In summary, agents that elevate intracellular cAMP were found to mimic the effects of FSH on IGFBP production.
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PMID:Gonadotropin and cAMP modulation of IGE binding protein production in ovarian granulosa cells. 137 63

Thyrotropin (TSH) is an important regulator of thyroid follicular cells. While its role in the maintenance of differentiated functions is undisputed, its role as a mitogen is less clear. TSH induces DNA synthesis and cell proliferation in some cells, while in others, TSH is mitogenic only in the presence of additional growth factors such as insulin-like growth factor-1. TSH causes elevations in intracellular cAMP and is thought to utilize this second messenger system in its mitogenic action. We studied TSH as a mitogen in Wistar rat thyroid cells (WRT) (Brandi, M. L., Rotella, C. M., Mavilia, C., Franceschelli, F., Tanini, A., and Toccafondi, R. (1987) Mol. Cell. Endocrinol. 54, 91-103) and examined the role of the guanine nucleotide binding protein, Gs, in its mitogenic action. WRT cells synthesized DNA in response to TSH and elevations in cAMP. In addition, TSH caused a rapid stimulation of an indicator gene whose expression is regulated by cAMP response elements. Following microinjection of an inhibitory polyclonal antibody raised against the Gs protein, both TSH-induced changes in gene expression and DNA synthesis were significantly reduced. These results demonstrate that virtually all of the mitogenic action of TSH is transduced through the Gs protein in WRT cells, presumably through the regulation of adenylate cyclase. Whether all or only part of TSH action is mediated by cAMP and the cAMP-dependent protein kinase remains to be determined.
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PMID:Inhibition of thyrotropin-induced DNA synthesis in thyroid follicular cells by microinjection of an antibody to the stimulatory G protein of adenylate cyclase, Gs. 137 81

Growth factors are prime candidates to mediate and modulate the functions of the mesangium. Mesangial cells are effector cells producing a number of growth factors that act in an autocrine manner to regulate their own function. Mesangial cells are also targets for growth factors released from neighboring glomerular cells or infiltrating cells and platelets. Growth factors may promote hypertrophy, proliferation, matrix metabolism, and immune-inflammatory and vasoactive properties of mesangial cells. These peptides represent important mediators of mesangial cell responses to injury. Platelet-derived growth factor mediates predominantly cell proliferation, whereas transforming growth factor beta mediates mesangial cell matrix expansion. Mesangial cells may also modulate some of the hemodynamic effects of growth factors, such as the increased renal vascular resistance in response to platelet-derived growth factor and epidermal growth factor or the increased RBF and GFR in response to insulin-like growth factor-1. Changes in the expression of growth factors of their receptors during the course of glomerular injury point to a potential role in mediating some of the pathologic changes in vivo. Several agents appear to antagonize the mitogenic and perhaps other effects of growth factors in mesangial cells. Such agents include adenylate cyclase as well as guanylate cyclase agonists. Recent studies also suggest that some traditional vasoactive agents may activate metabolic processes in mesangial cells similar to peptide growth factors. Collectively, these studies point to the interaction of both hemodynamic and metabolic factors in the response and contribution of glomerular and specifically mesangial cells to injury.
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PMID:Growth factors and the mesangium. 160 Jan 35

We have shown that for anatomically intact murine cartilage, insulin-like growth factor-1 (IGF-1) is the major anabolic stimulus. Using an experimental arthritis model, we found that cartilage from an arthritic joint could not be stimulated in vitro with IGF-1. This nonresponsiveness was not caused by a generalized disturbance of chondrocyte metabolism since forskolin, an activator of adenylate cyclase, could stimulate cartilage from arthritic joints. To investigate whether hydrogen peroxide may cause IGF-1 nonresponsiveness, we exposed normal murine cartilage to H2O2 in vitro as well as in vivo. We found that cartilage, in which chondrocyte proteoglycan synthesis was inhibited due to H2O2 action in vitro, showed a normal response to IGF-1 after 24-h tissue culture. A time dependent but full recovery was found. In contrast, cartilage which was longterm exposed to H2O2 in vivo after injection of amidated glucoseoxidase (aGO) showed only a moderate IGF-1 response. This lack of total recovery was not due to chondrocyte death or to retained aGO producing extra H2O2 during tissue culture. Further studies with isolated bovine chondrocytes revealed that H2O2 did not damage the IGF-1 receptor. Binding of radiolabelled IGF-1 to H2O2 treated chondrocytes was unimpaired. Our data indicate that H2O2 inhibits chondrocyte proteoglycan synthesis via a mechanism not related to disturbance of IGF-1 signalling. Transient chondrocyte IGF-1 nonresponsiveness found after H2O2 exposure is not related to IGF receptor damage, and contrasts with the complete nonresponsiveness found in arthritic cartilage.
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PMID:Transient chondrocyte nonresponsiveness to insulin-like growth factor-1 upon H2O2 exposure is not related to IGF receptor damage. 164 17

PC-3 human prostatic tumor sublines have been previously isolated which exhibit striking differences in their invasive and metastatic phenotypes. This work has been extended here to measure and compare the levels of kinesin, a microtubule-dependent translocator molecule, in the PC-3 sublines. Western blots, slot blots, radiolabeling, and immunoprecipitation analysis showed that kinesin was expressed in the highly invasive and metastatic sublines at levels which were elevated above the base-line levels observed in the parent PC-3 cells. In comparison, kinesin was not expressed in detectable amounts in the noninvasive cell lines. The conditioned medium of the metastatic PC-3 sublines contained a heat- and trypsin-sensitive protein which exhibited a dosage-dependent capacity to stimulate increased kinesin expression, type IV collagenase secretion, and invasion of Matrigel by the metastatic sublines. The noninvasive sublines failed to secrete a similar stimulatory factor(s) or respond to the conditioned medium of metastatic sublines. Various growth factors and cytokines tested (platelet-derived growth factor, epidermal growth factor, insulin-like growth factor, formylmethionineleucinephenylalanine) had no significant effect on either kinesin expression or protease secretion and invasion. Pertussis toxin blocked the stimulatory effects of the conditioned medium, but other agents known to interfere with adenylate cyclase pathways (i.e., cholera toxin, forskolin, 8-bromoadenosine) failed to block stimulation. The data show for the first time that kinesin, protease secretion, and the resulting invasion process may be regulated in a coordinated manner by an autocrine factor(s) which activates G-protein-dependent processes.
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PMID:Regulation of kinesin expression and type IV collagenase secretion in invasive human prostate PC-3 tumor sublines. 165 72

Human follicular fluid contains the insulin-like growth factor-binding protein (IGFBP-1) synthesized by ovarian granulosa cells. We studied the regulation of IGFBP-1 production by the granulosa-luteal cells from the hyperstimulated follicles of patients attending an in vitro fertilization program. The cells were first allowed to attach and recover from the hyperstimulation for 2 days. Then, a protein kinase-C activator, 12-O-tetradecanoyl phorbol-13-acetate (TPA), and adenylate cyclase activators, gonadotropins, FSH, hCG, cholera toxin, or prostaglandin E2 (PGE2) were added to the cells. The gonadotropins failed to increase IGFBP-1 production, whereas it was enhanced by TPA and to a lesser extent by cholera toxin and PGE2. The maximal response to TPA occurred at the concentration of 1.0 ng/mL, and the enhancing effect of TPA was detected at 24 h. PGE2 stimulated IGFBP-1 production; the lowest effective concentration was 10(-8) mol/L. The mean highest response was 4.3-fold and occurred at the PGE2 concentration of 10(-5) mol/L. The effect of PGE2 on IGFBP-1 production became detectable at 24 h, and it continued to increase up to 72 h. PGE2 also increased granulosa-luteal cell progesterone production in a dose- and time-dependent manner. Incorporation of [35S]methionine into immunoreactive IGFBP-1, as detected by sodium dodecyl sulfate-polyacrylamide electrophoresis and fluorography, was also increased by TPA. This suggests that TPA accelerated the synthesis of IGFBP-1. Our results indicate that the production of IGFBP-1 by human granulosa-luteal cells can be regulated both via protein kinase-C- and adenylate cyclase-dependent pathways.
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PMID:Regulation of insulin-like growth factor-binding protein-1 production in human granulosa-luteal cells. 255 84

Characterization of insulin and type I insulin-like growth factor (IGF-I) receptors and the effects of insulin and IGF-I on steroidogenesis were evaluated by using purified adult Leydig cells from Sprague-Dawley rats. Purified Leydig cells were found to contain both high and low affinity binding sites for insulin, with Ka values of 1.08 X 10(9) and 1.1 X 10(7) M-1, respectively. Using affinity cross-linking of [125I]iodoinsulin to plasma membrane insulin receptor, several bands were identified by autoradiography under nonreduced conditions with mol wt of 230,000, 280,000, and 300,000. After reduction with 50 mM dithiothreitol, only one band was identified with a mol wt of 130,000, consistent with the alpha-subunit of insulin receptor. Purified Leydig cells also contain specific type I IGF receptors with estimated binding affinity of 0.6 X 10(9) M-1. Multiple high mol wt bands (greater than 250,000) were identified under nonreduced conditions by affinity cross-linking. Under reduced conditions, one band with an approximate mol wt of 135,000 was identified. Purified Leydig cells (10(5) cells/ml) were cultured in Dulbecco's Modified Eagle's Medium-Ham's F-12 Nutrient Mixture (1:1) containing 0.1% fetal calf serum at 37 C in a humidified atmosphere of 5% CO2-95% air. Insulin and IGF-I stimulated testosterone formation as early as 3 h after administration, and their effects were completely blocked by the addition of a protein synthesis inhibitor, cycloheximide (1 microgram/ml). Insulin and IGF-I also significantly potentiated hCG-and 8-bromo-cAMP-induced testosterone formation. Furthermore, insulin and IGF-I potentiated hCG-stimulated cAMP formation. This suggests that insulin and IGF-I have effects at both the LH receptor sites and the steps beyond adenylate cyclase. The ED50 values of insulin and IGF-I-stimulated testosterone formation were comparable (25 ng/ml). In conclusion, we found that Leydig cells contain specific insulin and type I IGF receptors, and both insulin and IGF-I are capable of modulating Leydig cell steroidogenesis.
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PMID:Characterization of insulin and insulin-like growth factor I receptors of purified Leydig cells and their role in steroidogenesis in primary culture: a comparative study. 294 38

We have previously shown that insulin-like growth factor (IGF-I) suppresses basal and GHRH-induced GH gene transcription. cAMP is a putative intracellular mediator of GHRH action. We, therefore, studied the mechanism of IGF-I action on the somatotroph with or without cAMP activators. Primary rat pituitary cells growing in serum-free medium were treated with IGF-I. GH secretion was measured by RIA, and mRNA levels were measured by hybridization to [32P]GH cDNA. 8-Bromo-cAMP (8-Br-cAMP; 0.625 mM) stimulated GH mRNA levels after 72 h by 238%. IGF-I (6.5 nM) caused a 64% inhibition of 8-Br-cAMP-stimulated GH mRNA levels and a similar inhibition of GH secretion. This inhibition was time and dose dependent, with maximal (71%) suppression of cAMP-induced GH achieved with 13 nM IGF-I after 72 h. Forskolin (1 microM), a stimulator of adenylate cyclase, stimulated GH secretion (198%) which was inhibited by IGF-I by 42%. 12-O-Tetradecanoylphorbol 13-acetate, (a phorbol ester; 50 nM), a potent activator of protein kinase C, strongly stimulated GH secretion (347%), which was similarly suppressed by IGF-I by 51%. The suppressive action of IGF-I on somatotroph gene expression is unimpaired by direct activation of both cAMP and protein kinase C, suggesting that IGF-I acts upon the GH gene by a mechanism that is not altered by these second messengers. The negative feedback inhibition of physiological concentrations of IGF-I on GH, therefore, appears to override the potent stimulation of GH by these intracellular messengers.
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PMID:Insulin-like growth factor I action on rat anterior pituitary cells: effects of intracellular messengers on growth hormone secretion and messenger ribonucleic acid levels. 367 37

Stage 5-6 Xenopus laevis oocytes are arrested in prophase of the first meiotic division, and can be studied in vitro after removal from their follicle cell environment. While they do not mature spontaneously, they demonstrate germinal vesicle (nucleus) breakdown (GVBD) if exposed to approximately 1 microM-progesterone (the hormone released in vivo at the time of ovulation and maturation). The oocytes' then become eggs ready to be fertilized. The progesterone-oocyte interaction, contrary to what is observed in all endocrine steroid target organs so far studied, takes place at the surface membrane level and is not narrowly progesterone-specific, since other hormones such as cortisol or testosterone can also cause resumption of meiosis in vitro. This is the first description of such a paracrine steroid system, which depends however on a receptor mechanism, as indicated by physicochemical experiments, studies with antagonistic (competitive) steroids, and cell-free specific inhibitory effects on membrane-bound adenylate cyclase. It was found that insulin and related growth factors (mitosis-stimulating activity, MSA; insulin-like growth factor, IGF) are also reinitiators of meiosis. Insulin also potentiates the effects of low progesterone concentration (approximately 1 nM) in completely denuded oocytes (free of the vitelline membrane). From these observations it is suggested that there may be a physiological, cooperative involvement of a steroid (progesterone) and an insulin-like peptide factor within the ovaries which promotes oocyte maturation in vivo. The molecular mechanisms of the hormone-dependent changes in cyclic AMP and Ca2+ remain to be elucidated in detail, as well as the respective roles of these two sets of metabolic events.
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PMID:Steroid and peptide control mechanisms in membrane of Xenopus laevis oocytes resuming meiotic division. 631 17

Induction of the ovalbumin gene in chicken oviduct explant cultures requires the presence of a serum component in addition to estrogen. Previous studies have demonstrated that either insulin or related peptides, such as proinsulin or insulin-like growth factor, can eliminate the requirement for serum. In the present study, we determined that half-maximal binding of [125I]iodoinsulin to oviduct cell membranes occurs with 5 X 10(-10) M insulin, and proinsulin is 10-fold less effective than insulin as a competitor. Induction of the ovalbumin gene is half-maximal with 10(-9) M insulin, and both proinsulin and insulin-like growth factor are 10-fold less potent. These results suggest that insulin is the physiological hormone that is required in addition to estrogen to stimulate transcription of the ovalbumin gene. In an effort to understand the mechanism by which insulin regulates the steroid response in this system, we searched for agents that could substitute for insulin. We found that cyclic nucleotide derivatives, such as 8-bromo-cAMP, can mimic the effect of insulin on ovalbumin gene expression and that the phosphodiesterase inhibitor isobutylmethylxanthine can potentiate this response to 8-bromo-cAMP. Activation of oviduct adenylate cyclase with either forskolin or cholera toxin also allows the estrogen-mediated induction of mRNA, and both of these agents produce a dramatic rise in intracellular cAMP. Although these results suggest that the effect of insulin on gene regulation might depend on a cAMP-mediated mechanism, we are unable to detect any change in cellular cAMP levels in response to insulin. We conclude that insulin and cAMP are producing their effects on activation of the ovalbumin gene via convergent pathways. The involvement of an activator of protein kinase, cAMP, strongly suggests that protein phosphorylation events play a regulatory role in the expression of the ovalbumin gene.
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PMID:Regulation of the ovalbumin gene: effects of insulin, adenosine 3',5'-monophosphate, and estrogen. 632 59


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