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)

Parathyroid hormone (PTH)-related protein (PTHrP) is the main factor responsible for humoral hypercalcemia of malignancy. Both PTH and PTHrP bind to the common type I PTH/PTHrP receptor (PTHR), thereby activating phospholipase C and adenylate cyclase through various G proteins, in bone and renal cells. However, various normal and transformed cell types, including hypercalcemic Walker 256 (W256) tumor cells, do not produce cAMP after PTHrP stimulation. We characterized the PTHrP receptor and the signaling mechanism upon its activation in the latter cells. Scatchard analysis of PTHrP-binding data in W256 tumor cells revealed the presence of high affinity binding sites with an apparent K(d) of 17 nM, and a density of 90 000 sites/cell. In addition, W256 tumor cells immunostained with an anti-PTHR antibody, recognizing its extracellular domain. Furthermore, reverse transcription followed by PCR, using primers amplifying two different regions in the PTHR cDNA corresponding to the N- and C-terminal domains, yielded products from W256 tumor cell RNA which were identical to the corresponding products obtained from rat kidney RNA. Consistent with our previous findings on cAMP production, 1 microM PTHrP(1-34), in contrast to 10 microg/ml cholera toxin or 1 microM isoproterenol, failed to affect protein kinase A activity in W256 tumor cells. However, in these cells we found a functional PTHR coupling to G(alpha)(q/11), whose presence was demonstrated in these tumor cell membranes by Western blot analysis. Our findings indicate that W256 tumor cells express the PTHR, which seems to be coupled to G(alpha)(q/11). Taken together with previous data, these results support the hypothesis that a switch from the cAMP pathway to the phospholipase C-intracellular calcium pathway, associated with PTHR activation, occurs in malignant cells.
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PMID:Characterization of parathyroid hormone/parathyroid hormone-related protein receptor and signaling in hypercalcemic Walker 256 tumor cells. 1085 78

Parathyroid hormone (PTH)-related peptide (PTHrP) can modulate the proliferation and differentiation of a number of cell types including osteoblasts. PTHrP can activate a G protein-coupled PTH/PTHrP receptor, which can interface with several second-messenger systems. In the current study, we have examined the signaling pathways involved in stimulated type I collagen and alkaline phosphatase expression in the human osteoblast-derived osteosarcoma cells, MG-63. By use of Northern blotting and histochemical analysis, maximum induction of these two markers of osteoblast differentiation occurred after 8 h of treatment with 100 nM PTHrP-(1-34). Chemical inhibitors of adenylate cyclase (H-89) or of protein kinase C (chelerythrine chloride) each diminished PTHrP-mediated type I collagen and alkaline phosphatase stimulation in a dose-dependent manner. These effects of PTHrP could also be blocked by inhibiting the Ras-mitogen-activated protein kinase (MAPK) pathway with a Ras farnesylation inhibitor, B1086, or with a MAPK inhibitor, PD-98059. Transient transfection of MG-63 cells with a mutant form of Galpha, which can sequester betagamma-subunits, showed significant downregulation of PTHrP-stimulated type I collagen expression, as did inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) by wortmannin. Consequently, the betagamma-PI 3-kinase pathway may be involved in PTHrP stimulation of Ras. Collectively, these results demonstrate that, acting via its G protein-coupled receptor, PTHrP can induce indexes of osteoblast differentiation by utilizing multiple, perhaps parallel, signaling pathways.
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PMID:Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. 1150 Mar 4

The PTH/PTHrP receptor, a G protein coupled receptor, mediates the actions of PTH and PTHrP. Homozygous inactivating mutations in this receptor cause a rare disorder called Blomstrand chondrodystrophy. Since this disease is lethal in utero or perinatal period, the existence of PTH resistance has not been verified. Inactivating mutations in PTH/PTHrP receptor have not been found in the patients with pseudohypoparathyroidism (PsH), a group of disorders characterized by biochemical hypoparathyroidism and unresponsiveness to PTH. In patients with PsH type Ia, numerous heterozygous inactivating mutations have been identified in the gene (GNAS1) encoding the alpha-subunit of Gs protein (Gs alpha) which couples multiple receptors to the stimulation of adenylate cyclase. It is suggested that some abnormality in GNAS1 outside the coding exons may lead to PsH type Ib. To explain the heredity and phenotypic variation of PsH, tissue- or cell-specific imprinting of Gs alpha has been implicated.
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PMID:[PTH/PTHrP receptor and pseudohypoparathyroidism]. 1185 23

Regulator of G-protein signaling-2 (RGS-2) belongs to a novel family of GTPase-activating proteins that rapidly turn-off G-protein coupled receptor signaling. RGS proteins contain a characteristic RGS domain by which they interact with the alpha-subunit of G-proteins and drive them into their inactive GDP-bound forms. Previously, we have reported that RGS-2 mRNA is rapidly and transiently increased by PTH in rat bone and in osteoblast cultures in vitro. In this study, we further explored the molecular basis for the regulation of RGS-2 by cloning and functionally characterizing the RGS-2 gene promoter. We cloned 2.3- and 2.8-kb fragments of the 5'-flanking regions of the rat and mouse RGS-2 genes, respectively, and generated a stable clone of UMR106 osteoblastic cells containing the rat RGS-2 promoter driving the beta-gal reporter gene (p2.3RGS-2-beta-gal). Treatment of the stable clone with PTH resulted in a maximal 2.2- to 3.6-fold increase in promoter activity at 8 h, reminiscent of the early response observed with endogenous RGS-2 mRNA regulation. Further, PTH (1-38), (1-31), PTHrP (1-34), and forskolin, which elevate cAMP levels, stimulated the promoter, while PTH (3-34) and (7-34), which do not readily stimulate cAMP accumulation, and PMA that directly activates protein kinase C, had no effect on promoter activity. Taken together, these results implicate the involvement of the Galpha(s)-adenylate cyclase-protein kinase A pathway in stimulating RGS-2 expression. Maintenance of a hyperphosphorylated state via the inhibition of type 2A protein phosphatases by okadaic acid, resulted in a strong dose-dependent increase in transcriptional activity of the RGS-2 promoter as well as that of the endogenous RGS-2 gene. Furthermore, overexpression of the osteoblast-specific transcription factor Runx2 also led to a stimulation of RGS-2 promoter activity. Functional analysis using RGS-2 overexpression suggests the potential negative regulatory effects of RGS-2 on PTH- and forskolin-induced cAMP production in osteoblastic cells. In summary, our data suggest that PTH treatment results in a direct transcriptional stimulation of RGS-2 that in turn may play a role in modulating the duration/intensity of PTH receptor signaling.
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PMID:Analysis of regulator of G-protein signaling-2 (RGS-2) expression and function in osteoblastic cells. 1196 23

PTH and PTHrP have been shown to inhibit maturation of growth plate chondrocytes and the expression of type X collagen. In order to examine the regulatory mechanisms involved, fetal bovine growth plate chondrocytes were incubated for 24-48 h under serum-free conditions with PTH and PTHrP and various aminoterminal, midregional, and carboxyterminal fragments of these hormones. Analysis of type X collagen mRNA levels by Northern hybridization showed a significant suppression by PTH (1-84), PTH (1-34), and PTHrP (1-40), but not by PTH (28-48) or PTH (53-84). PTH fragment (3-34) did not reduce alpha1(X) mRNA levels, while bis-indolylmaleimide, an inhibitor of the protein-kinase C pathway, did not affect alpha1(X) mRNA suppression by PTH, supporting the notion that the inhibition of type X collagen expression by PTH involves predominantly the adenylate cyclase pathway of the PTH/PTHrP-receptor. Since PTH and PTHrP have been shown to induce c-fos in osteoblasts and chondrocytes, the possibility was tested that c-fos mediated the suppressive effect of PTH/PTHrP on collagen X expression. In fetal bovine hypertrophic chondrocytes PTH (1-34), but not PTH (3-34) nor the midregional or C-terminal PTH fragments induced c-fos expression. In order to identify cis- and trans-acting elements in the COL10A1 gene involved in c-fos-mediated inhibition of collagen X expression by PTH/PTHrP, reporter gene constructs carrying various fragments of the human COL10A1 promoter coupled to the luciferase gene were transfected into hypertrophic chondrocytes. A tissue-specific, strong enhancer region, which we had previously located in the promoter of the human type X collagen gene COL10A1, was further narrowed down to a 530-bp sequence, located between - 1,870- and - 2,407 bp upstream of the transcription start site. The transcriptional activity of this enhancer element in transfected hypertrophic chondrocytes was significantly reduced after incubation with PTH (1-34) or PTHrP (1-40). Transcription of these reporter genes was also inhibited when chondrocytes were cotransfected with a c-fos expression vector. These results indicate the presence of a PTH/PTHrP responsive element in the human COL10A1 enhancer, which may be represented by multiple putative AP-1 sites located in this region.
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PMID:Role of c-fos in the regulation of type X collagen gene expression by PTH and PTHrP: localization of a PTH/PTHrP-responsive region in the human COL10A1 enhancer. 1221 Jul 35

Parathyroid hormone-related protein (PTHrP) has been implicated as being important in the growth of tumor cells responsive to the peptide. We utilized a rat osteoblastic osteosarcoma cell line, UMR 106-01, which has PTHrP receptors and a PTHrP-responsive adenylate cyclase/cAMP messenger system, to produce a modified cell line that overexpresses PTHrP. The human PTHrP cDNA sequence was transfected by electroporation into UMR 106-01 cells and the stable cell lines UMR-36 and UMR-34 were established. The modified cell line, UMR-36, had increased levels of PTHrP mRNA compared with control cell lines and secreted PTHrP into the culture medium at levels of 0.01-0.1 pmol/10(7) cells in 12 h. The secreted peptide was biologically active as indicated by its ability to activate adenylate cyclase. The number of UMR-36 cells following 9 days in culture was reduced by up to 80% compared with control lines, which was associated with decreased (3)H-thymidine incorporation into genomic DNA. Addition of 1000-fold excess of the PTHrP antagonist, PTHrP(7-34), to UMR-36 cells resulted in the escape of growth inhibition and increased rate of growth. In vivo, tumors derived from UMR-36 cells were smaller in size compared with tumors derived from control cells. In conclusion, increased autocrine secretion of, and responsiveness to, PTHrP results in inhibited growth kinetics of an osteoblast-like bone tumor cell line in vitro and in vivo.
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PMID:Local secretion of parathyroid hormone-related protein by an osteoblastic osteosarcoma (UMR 106-01) cell line results in growth inhibition. 1247 74

Since its discovery in 1923, the parathyroid hormone (PTH), was thought to be the sole hormone capable of stimulating bone resorption, renal tubular calcium reabsorption, calcitriol synthesis, and urinary excretion of phosphate. However, in 1987, the PTHrP (PTH-related peptide), was demonstrated to share most of the biological actions of PTH through the activation of the same receptor. This receptor was cloned in 1992 and named PTH/PTHrP receptor or PTH-R1. Both, PTH and PTHrP bind with great affinity to PTH-R1 and stimulate a signal transduction system involving different G-proteins, phospholipase C, and adenylate cyclase. A third member of the PTH family, the TIP-39 (tuberoinfundibular peptide), binds and activates another PTH receptor (PTH-R2). There is evidence for other PTH receptors, a PTH-R3, probably specific for PTHrP in keratinocytes, kidney, placenta and a PTH-R4 specific for C-terminal PTH fragments. Activating mutations in the PTH-R1 gene cause Jansen type metaphyseal chondrodysplasia, whereas inactivating mutations are responsible for Blomstrand type rare chondrodysplasia and enchondromatosis. The renal and bone PTH-R1 expression is upregulated in vitamin D deficient rats and by endotoxin, interleukin-2, dexamethasone, T3, and TGF beta. On the contrary, PTH, PTHrP, angiotensin-II, IGF-1, PGE2, vitamin D, and chronic renal failure decrease its expression. In conclusions, the biological implications of the identification and cloning of different PTH receptors are at their beginning. The almost ubiquitous distribution of PTHrP and PTH-R1, the numerous PTHrP and PTH fragments, let us suppose the existence of other PTH-related receptors, and a great complexity of the bone and mineral metabolism.
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PMID:[The PTH/PTHrP receptor: biological implications]. 1277 47

Phex (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome) is expressed predominantly in bone in which it has been implicated in the mineralization process. Multiple factors and hormones, including PTHrP, regulate formation, development, and/or homeostasis of bone. The purpose of the present study was to determine whether PTHrP(1-34) regulates Phex expression and identify the signaling pathway used. Phex mRNA and protein levels were analyzed by RT-PCR and immunoblotting, respectively. In UMR-106 cells, PTHrP(1-34) caused a time- and concentration-dependent decrease in Phex expression. Forskolin, an adenylate cyclase activator, had the same effect. Dibutiryl cAMP also decreased Phex expression, and its effect was blocked by H89, a protein kinase A (PKA) inhibitor. In contrast, 12-O-tetradecanoyl phorbol-13-acetate, a protein kinase C (PKC) activator, increased Phex expression in a time- and dose-dependent manner. This effect was reversed by bisindolylmaleimide Iota, a PKC inhibitor. Bovine PTH(3-34), which activates PKC but not PKA, had no effect. On the contrary, human PTH(1-31), which activates PKA but not PKC, decreased Phex expression. H89 but not bisindolylmaleimide Iota blocked the effect of PTHrP(1-34). PTHrP(1-34) also decreased Phex expression in cultures of fetal rat calvaria cells at d 7 of culture but not at later stages. These data demonstrate that PTHrP(1-34), through PKA, down-regulates Phex expression in osteoblasts.
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PMID:Parathyroid hormone-related protein(1-34) regulates Phex expression in osteoblasts through the protein kinase A pathway. 1296 44

Humoral hypercalcemia of malignancy is widely associated with tumor production of parathyroid hormone related protein (PTH-rP). This peptide functions in endocrine, autocrine and paracrine mechanisms in a manner similar to PTH; increasing renal uptake of calcium, decreasing retention of phosphorous, and stimulating adenylate cyclase and phospholipase C. Although PTH-rP production has been well documented in neoplasms of the exocrine pancreas, we present here two cases of endocrine pancreatic neoplasms elaborating PTH-rP. We then review the literature of previous cases and delve into the pathophysiology of this peptide.
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PMID:Hypercalcemia and pancreatic endocrine neoplasia with elevated PTH-rP: report of two new cases and subject review. 1569 24

Adrenocortical tumors (ACT) are rare and heterogeneous, but their pathogenesis is unclear. The oncoprotein parathyroid hormone-related protein (PTHrP), found in many common tumors, can regulate their growth in an autocrine/paracrine fashion through the PTH-R1 receptor. Little is known about the role of PTHrP in ACT. We monitored the synthesis of PTHrP and PTH-R1 in a series of 25 ACT: 12 adrenocortical carcinomas (ACC) and 13 adrenocortical adenomas (ACA), and investigated the effects of PTHrP(1-34) on H295R cells derived from an ACC. PTH-R1 mRNA and proteins were detected by real-time PCR and Western blotting in all the ACT samples and in H295R cells. Their concentrations did not differ significantly from one ACT to another. PTHrP mRNA was assayed by quantitative real-time PCR. It was detected in 90% of ACC, and in 10% of ACA. There was a positive correlation with the prognostic factors, McFarlane stage and Weiss score. Tissue-specific PTHrP protein processing was shown by Western blotting. Immunohistochemical staining revealed numerous, dense foci of PTHrP-containing cells in ACC, but few positive cells in ACA or normal tissue. PTHrP stimulated the growth of H295R cells, whereas a specific anti-PTHrP antibody and a PTHrP-R1 antagonist both enhanced their apoptosis. PTHrP activated both adenylate cyclase/protein kinase A and the intracellular calcium/protein kinase C pathways via PTHrP-R1. The active synthesis of PTHrP is linked to poor prognosis in ACC, in which it may act as an autocrine/paracrine factor in tumor growth and malignancy.
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PMID:Differential expression of parathyroid hormone-related protein in adrenocortical tumors: autocrine/paracrine effects on the growth and signaling pathways in H295R cells. 1876 93


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