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)

The presence of mRNA transcripts and/or immunoreactivity for PTH-related protein (PTHrP) in several normal mammalian tissues suggests a possible paracrine or autocrine role for this hormone. Since immunohistochemical studies of human ovary demonstrate the presence PTHrP immunoreactivity in this tissue, we wondered if ovarian follicular fluid (OVFF) might contain PTHrP. We retrospectively analyzed 28 OVFF samples obtained at ova harvest in 21 women undergoing in vitro fertilization. Fourteen samples contained significant adenylate cyclase-stimulating activity in a PTHrP-sensitive bioassay. In a subsequent prospective analysis, 41 of 45 freshly obtained OVFF samples demonstrated significant activity. This bioactivity was completely neutralized by antisera to PTHrP, but was unaffected by antisera to PTH. Fifteen OVFF samples were also analyzed in a sensitive 2-site immunoradiometric assay for PTHrP, and all 15 demonstrated significant levels of the hormone. The PTHrP levels did not correlate with the presence of an ovum in the follicle or with follicular fluid calcium. Short term (24- to 48-h) cultures of granulosa-luteal cells established from 5 OVFF samples demonstrated constitutive secretion of PTHrP using the immunoradiometric assay. Neither progesterone nor estrogen affected basal secretion. RNase protection analysis of cellular RNA prepared from cultured granulosa-luteal cells demonstrated the presence of mRNA for PTHrP in these cells. We conclude that 1) human OVFF obtained after stimulation with FSH and LH contain high concentrations of PTHrP; and 2) the granulosa-luteal cell is capable of secreting PTHrP both in vivo and in vitro.
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PMID:Human granulosa-luteal cells secrete parathyroid hormone-related protein in vivo and in vitro. 849 23

The expression of parathyroid hormone-related protein (PTHrP) was studied in a range of cell cultures representative of the osteoblast lineage and in rat calvarial sections. Primary newborn rat calvarial cells, a rat preosteoblastic cell line (UMR 201), a mouse stromal cell line (ST 2), a mouse calvaria-derived osteoblastic cell line (KS 4), and rat osteosarcoma cell lines (UMR 106-01 and -06), all expressed PTHrP when examined by reverse transcription polymerase chain reaction (RT-PCR). Using a radioimmunoassay we also demonstrated PTHrP in the conditioned medium of the cultured cells, with the exception of UMR 106-01 and -06 cells. Treatment of UMR 201 cells with all-trans-retinoic acid which induces them to acquire a more differentiated phenotype, also led to a time-dependent decrease in PTHrP mRNA levels as determined by RT-PCR, Northern blot analysis, and in situ hybridization. Decreased PTHrP levels in the conditioned medium of the treated cells was also observed. These results suggested that PTHrP production might be greater in less mature osteoblasts. Examination of the populations obtained from newborn rat calvariae by sequential collagenase digestion revealed that the early digests exhibited low ALP activity, low expression of PTH/PTHrP receptor mRNA, and no adenylate cyclase response to PTHrP(1-34). These populations showed the highest level of mRNA and production of PTHrP. Cells from later digests, the "osteoblast-rich" populations, had reduced PTHrP expression. Immunohistochemistry and in situ hybridization in sections of newborn rat calvariae showed PTHrP expression in cuboidal osteoblasts located adjacent to bone and in spindle-shaped cells in the periosteal region. It is concluded that PTHrP is produced by cells of the osteoblast lineage, supporting the hypothesis that PTHrP may function physiologically as a paracrine factor in bone.
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PMID:Expression of parathyroid hormone-related protein in cells of osteoblast lineage. 855 80

Parathyroid hormone (PTH) activates both adenylate cyclase and phospholipase C in target cells, and cloned PTH/PTH-related protein (PTHrP) receptor can mediate both responses when expressed in host cells such as LLC-PK1 renal epithelial cells. Because calcitonin (CT) is known to augment 70-kDa heat shock protein (HSP70) mRNA by an adenosine 3',5'-cyclic monophosphate (cAMP)-independent mechanism in LLC-PK1 cells, we examined regulation of HSP70 transcription by PTH in these cells. Like CT, human PTH-(1-34) [hPTH-(1-34); 10(-10) to 10(-7) M)] increased porcine HSP70 mRNA and human HSP70 promoter-chloramphenicol acetyltransferase (CAT) expression within 4 h in LLC-PK1 cells that stably express > or = 100,000 PTH/PTHrP receptors per cell. The effect of PTH on HSP70 mRNA was not mimicked by cAMP analogues, forskolin, phorbol esters, Ca2+ ionophores, or alpha-thrombin; was insensitive to pertussis toxin; and was not due to increased mRNA stability. The upregulation of HSP70 gene transcription by hPTH (and CT) was clearly observed even after deletion of the functional heat shock consensus element in the promoter region of the human HSP70/CAT reporter. Upregulation of HSP70 transcription via endogenous PTH receptors also was observed in the osteoblastic cell lines SaOS-2 and ROS 17/2.8. Regulation of HSP70 gene transcription by PTH may be a common cellular response to the hormone, which, in some cells, may not be mediated by activation of adenylate cyclase or protein kinase C.
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PMID:Regulation of HSP70 by PTH: a model of gene regulation not mediated by changes in cAMP levels. 876 37

We have previously shown that the response of osteoblasts to parathyroid hormone (PTH) can be influenced at the receptor level by growth on the physiological substrate, type I collagen, or by treatment with retinoic acid. We have also shown differential expression of genes when cells of the osteoblast lineage are grown on type I collagen. The aim of this study was therefore to examine the effect of retinoic acid and growth on type I collagen on PTH/PTH-related protein (PTHrP) receptor mRNA expression in the osteosarcoma osteoblast-like cell line UMR 106-06. PTH/PTHrP receptor mRNA levels, as assessed by Northern blot, of cells grown on collagen were increased up to 2-fold compared with cells on plastic and in a concentration-dependent manner with respect to collagen. An increase was seen as early as 6 h and was maintained over a 24 h period. This was not due to increased mRNA stability. Retinoic acid decreased the level of receptor mRNA on both plastic and collagen at each time but did not alter mRNA stability. For all treatments PTH/PTHrP receptor mRNA abundance, relative to glyceraldehyde-3-phosphate dehydrogenase, increased steadily over 24 h after subculture of cells. In contrast, PTHrP mRNA levels were reduced in cells on collagen, compared with plastic. PTH-stimulated cAMP levels of cells grown on collagen were increased compared with plastic at 24 h, but not earlier. Consistent with the mRNA data, retinoic acid decreased the amplitude of cAMP responses in cells on plastic and collagen. There was no evidence for changes in adenylate cyclase per se, since forskolin-induced cAMP levels did not change with either treatment. This study shows that known modulators of osteoblast maturation also affect signal transduction in these cells by regulating gene expression of the PTH/PTHrP receptor as well as the PTHrP ligand.
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PMID:A type I collagen substrate increases PTH/PTHrP receptor mRNA expression and suppresses PTHrP mRNA expression in UMR106-06 osteoblast-like cells. 886 96

Available data indicate that the mRNAs of the PTH-PTH-related protein (PTH-PTHrP) receptor in the kidney, liver and heart are down-regulated in chronic renal failure (CRF). This is due, in major part, to the elevation of cytosolic calcium ([Ca2+]i) in the cells of these organs. If elevation in [Ca2+]i is indeed the culprit, one should be able to demonstrate down-regulation of the mRNA of the PTH-PTHrP receptor in situations without CRF and with low levels of PTH but with elevated [Ca2+]i. Such a combination of events occurs in phosphate depletion (PD). To test this hypothesis, we examined the [Ca2+]i and the concentration of the mRNA of the PTH-PTHrP receptor in the kidneys from 1, 3 and 6 weeks PD, pair-weighed (PW) rats and PD and PW rats treated with verapamil (PD-V, PW-V). To evaluate the effect of a potential rise in [Ca2+]i on urinary phosphate excretion, we also measured the phosphaturic response to PTH and cAMP in all groups of rats after 6 weeks of the dietary intervention. Renal function was normal in all groups of animals. Blood levels of PTH were significantly (p < 0.01) lower in PD and PD-V after 1 week of PD than in PW and PW-V rats, and they remained low throughout the study. The basal levels of [Ca2+]i in the renal proximal tubular cells were normal after 1 week of PD but rose by the third week of the study and remained elevated by the end of the sixth week. These values were significantly (p < 0.01) higher than those in PD-V, PW and PW-V rats. The concentrations of mRNA of the PTH-PTHrP receptor relative to that of the housekeeping gene G3DPH were significantly (p < 0.01) lower in PD rats after 3 and 6 weeks than in the other three groups of rats. The phosphaturic response to PTH or cAMP was significantly (p < 0.01) greater in PD-V rats than in PD animals. The data show that PD is associated with a rise in [Ca2+]i of renal proximal tubular cells and with down-regulation of PTH-PTHrP receptor in the kidney despite low levels of PTH and normal renal function; normalization of the concentration of [Ca2+]i in PD-V rats was associated with normal expression of mRNA of the receptor. These results provide strong support for the proposal that elevated [Ca2+]i down-regulates the mRNA of the PTH-PTHrP receptor even in the absence of CRF and elevated blood PTH levels. The improvement in the phosphaturic response to PTH and cAMP in PD-V rats is consistent with the notion that the elevated [Ca2+]i of the renal cell in PD rats may interfere with the coupling of PTH receptor-adenylate cyclase system and/or with the postreceptor events responsible for the inhibition of phosphate reabsorption by these agonists.
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PMID:Renal mRNA of PTH-PTHrP receptor, [Ca2+]i and phosphaturic response to PTH in phosphate depletion. 905 70

Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin-6 (IL-6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL-6 promoter fused (-1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast-like osteosarcoma SaOS-2 cells. We compared the effects of PTH on IL-6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, interleukin-1 alpha (IL-1 alpha), prostaglandin E-2 (PGE-2), RS-66271 (a parathyroid hormone-related peptide analog), and platelet-derived growth factor-BB (PDGF-BB). Analyses of cell clones showed that IL-6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001-100 nM) for 12 h stimulated CAT expression in a dose-dependent manner (200-500% of control). Treatment with IL-1 alpha was more potent than PTH in inducing transcription of the IL-6 promoter (900-1,000%). Activation of the cAMP-PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS-66271, previously shown to have PTH-like effects, induced a comparable level of IL-6 promoter expression. When examined together, PTH+RS-66271 effects were comparable to PTH effects alone. Exposure to PGE-2, PMA, PDGF-BB, or A23187 for 12 h did not significantly alter IL-6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS-66271, and IL-1 alpha stimulate IL-6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL-6 expression.
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PMID:Parathyroid hormone (1-34)-mediated interleukin-6 induction. 932 32

The present study was performed to characterize the possible involvement of cAMP synthesis and protein kinase C (PKC) activation in the DNA synthesis-stimulating effect of parathyroid hormone-related protein (PTHrP) in proximal tubule cells. We found that DNA synthesis was stimulated by 10 microM 8BrcAMP, and 1 microM Sp-cDBIMPS, two cAMP analogs, and also by 1 microM phorbol 12-myristate 13-acetate (PMA) and 100 microM 1,2-dioctanoyl-sn-glycerol, two PKC activators, and 10 nM [Cys23] human (h)PTHrP (24-35) amide in rabbit proximal tubule cells (PTC). Both Sp-cDBIMPS and PMA, at 1 microM, also increased DNA synthesis in SV40-immortalized mouse proximal tubule cells MCT. Human PTHrP (7-34) amide [PTHrP (7-34)] dose dependently stimulated DNA synthesis in a similar manner as [34Tyr]PTHrP (1-34) amide [PTHrP (1-34)], in PTC. PMA pre-treatment for 20 h, which downregulates PKC, completely blocked the effect induced by PTHrP (7-34), but not that of PTHrP (1-34), in the latter cells. In contrast, the same PMA pre-treatment abolished the DNA synthesis stimulation by PTHrP (1-34) and PTHrP (7-34) in MCT cells, which appear to have PTH receptors mainly coupled to phospholipase C and not adenylate cyclase. Our results indicate that the stimulatory effect of PTHrP on DNA synthesis in proximal tubule cells is mediated by a cAMP- and PKC-dependent mechanism.
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PMID:Parathyroid hormone-related protein increases DNA synthesis in proximal tubule cells by cyclic AMP- and protein kinase C-dependent pathways. 965 Nov 15

Parathyroid hormone-related protein (PTHrP) is a key factor behind humoral hypercalcemia of malignancy (HHM). It is produced in most breast tumors and may be an important local mediator of skeletal metastases due to breast cancer. PTHrP may mediate local bone destruction in the absence of increased circulating PTHrP. Calcitonin (CT) is used for treatment of HHM, but there are data showing that CT can increase PTHrP expression and secretion in vitro. We have therefore studied the effect of CT on PTHrP gene expression and secretion in MCF-7 breast cancer cells. PTHrP mRNA decreased significantly after 4, 8, and 16 h incubation with 10 nM salmon calcitonin (sCT) when compared with the respective controls. PTHrP mRNA also decreased significantly and dose-dependently after incubation with sCT at 0.1 to 10 nM for 16 h. The PTHrP levels in the conditioned medium also decreased in a similar dose-dependent manner. The adenylate cyclase agonist forskolin lowered the PTHrP mRNA dose-dependently. In cells exposed to varying concentrations of sCT for 15 min, the cAMP levels increased dose-dependently. In conclusion, sCT can suppress PTHrP gene expression in MCF-7 breast cancer cells. The suppressive effect is probably exerted mainly via the cAMP-protein kinase A pathways.
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PMID:Calcitonin-suppressed expression of parathyroid hormone-related protein in breast cancer cells. 1054 24

Parathyroid hormone (PTH)-related protein (PTHrP) is present in the pancreatic islet. Recent data in transgenic mice suggest that PTHrP might modulate islet mass and insulin secretion. In the present study, we assessed the effect of the N-terminal PTH-like region of PTHrP on DNA synthesis in isolated rat islets. PTHrP (1-34), between 1 pM and 10 nM, for 48 h stimulated []thymidine incorporation into rat islets. This effect was maximally induced, about 2.5-fold over control, by 10 pM of this peptide, decreasing thereafter. In contrast, PTHrP (38-64) amide or PTHrP (107-139) were ineffective in increasing DNA synthesis in islets. Using reverse transcription followed by PCR, we confirmed that rat islets express PTHrP and the type I PTH/PTHrP receptor. Addition of a neutralizing anti-PTHrP antibody to the incubation medium of proliferating islets decreased islet DNA synthesis by 30%. The effect of a submaximal dose (30 pM) of PTHrP (1-34) on DNA synthesis in rat islets was abolished by 25 nM bisindolylmaleimide I, a protein kinase C (PKC) inhibitor, but not by 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, a protein kinase A inhibitor. Moreover, 100 nM phorbol-12-myristate-13-acetate for 48 h also increased DNA synthesis 2-fold over controls in islets. PTHrP (1-34), at 100 nM, in contrast to 50 microM forskolin or 10 mM NaF, failed to affect adenylate cyclase activity in islet membranes. PTHrP, at 30 pM, was also found to increase 2-fold insulin released into the islet-conditioned medium within 24-48 h. Our results suggest that PTHrP is a modulator of pancreatic islet growth and/or function by a PKC-mediated mechanism.
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PMID:Parathyroid hormone-related peptide stimulates DNA synthesis and insulin secretion in pancreatic islets. 1058 13

Secretin, glucagon, gastric inhibitory polypeptide (GIP), and parathyroid hormone (PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP-secretin-glucagon family), which also includes growth hormone-releasing hormone and exendins. All the members of this peptide family possess a remarkable amino-acid sequence homology, and bind to G-protein-coupled receptors, whose signaling mechanism primarily involves AC/protein kinase A and phospholipase C/protein kinase C cascades. VIP and pituitary AC-activating polypeptide play a role in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and in this review we survey findings that also other members of the VIP-secretin-glucagon family may have the same function. Secretin and secretin receptors are expressed in the hypothalamus and pituitary gland, and secretin inhibits adrenocorticotropic hormone (ACTH) release. No evidence is available for the presence of secretin receptors in adrenal glands, but secretin selectively depresses the glucocorticoid response to ACTH of dispersed zona fasciculata-reticularis (ZF/R) cells. Glucagon and glucagon-like peptide-1 are contained in the hypothalamus, and all the components of the HPA axis are provided with glucagon and glucagons-like-1 receptors. These peptides exert a short-term inhibitory effect on stress-induced pituitary ACTH release and depress the ZF/R cell response to ACTH by inhibiting the AC/protein kinase A cascade; they also stimulate hypothalamic arginine-vasopressin release. GIP receptors are present in the ZF/R of the normal adrenals, and are particularly abundant in some types of adrenocortical adenomas and hyperplasias. GIP, through the activation of the AC/protein kinase A cascade, evokes a sizeable glucocorticoid secretagogue effect, leading to the identification of a food/GIP-dependent Cushing's syndrome. PTH and PTH-related protein are expressed in the hypothalamus and pituitary gland, and PTH and PTH-related protein receptors in all the components of the HPA axis. Both peptides enhance ACTH and arginine-vasopressin release, as well as stimulate aldosterone and glucocorticoid secretion of dispersed zona glomerulosa and ZF/R cells, respectively. The involvement of growth hormone-releasing hormone and exendins in the functional regulation of the HPA axis has not yet been extensively investigated.
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PMID:Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis. 1076 61


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