The role of protein kinase C-δ in PTH stimulation of IGF-binding protein-5 mRNA in UMR-106–01 cells

Erclik, Mary S.; Mitchell, Jane

doi:10.1152/ajpendo.00417.2001

Cited by 25 publications

(19 citation statements)

References 38 publications

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“…PTH rapidly increased the expression of IL-18 in both osteoblastic cell lines and primary osteoblastic cell cultures, and the use of selective signaling activators and inhibitors confirmed that IL-18 gene expression was regulated through the PKA signal transduction pathway. PTH has been reported to activate both the PKA and PKC intracellular signaling pathways in osteoblastic cells, however only IGBP-5 and transforming growth factor-␤ are known to be regulated via the PKC pathway in these cells (29,30). The majority of PTH-regulated genes, for example, osteocalcin (31), c-Fos (32), collagenase-3 (33), IL-6 (34), receptor activator of NF-B ligand, and osteoprotegerin (35), are regulated completely through the PKA signal transduction pathway.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18 Is Regulated by Parathyroid Hormone and Is Required for Its Bone Anabolic Actions

Raggatt¹,

Qin²,

Tamasi

et al. 2008

Journal of Biological Chemistry

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Interleukin-18 (IL-18) can regulate osteoblast and osteoclast function. We have identified, using cDNA microarray technology, that IL-18 expression is increased in UMR 106-01 rat osteoblastic cells in response to parathyroid hormone (PTH) treatment. Confirmation of these data using real-time reverse transcription-PCR showed that steady-state levels of IL-18 mRNA increased by 2 h (3-fold), peaked by 4 h (10-fold), and had diminished after 12 h (4.4-fold) and that this regulation was via the protein kinase A signaling pathway and did not involve activation of the PKC signal cascade. PTH regulation of IL-18 was confirmed at the protein level, and analysis of differentiating primary rat calvarial osteoblasts verified that both IL-18 mRNA and protein are regulated by PTH in primary rat osteoblasts. Promoter reporter assays revealed that PTH regulated the upstream IL-18 promoter and induced the exon 1 containing 1.1-kb IL-18 mRNA transcript in primary osteoblast cells. The in vivo physiological role of IL-18 in the anabolic actions of PTH on bone was then assessed using IL-18 knock-out mice. Female IL-18 null mice and wild-type littermate controls were injected with vehicle or 8 g/100 g of human 1-38 PTH for 4 weeks. In IL-18 knock-out animals the anabolic effect of PTH (determined by bone mineral density changes in the proximal tibia) was abolished in trabecular bone but not in the cortical component. These data characterize the PTH regulation of IL-18 expression in osteoblastic cells and suggest that this cytokine is involved in the anabolic actions of PTH.

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Section: Discussionmentioning

confidence: 99%

Interleukin-18 Is Regulated by Parathyroid Hormone and Is Required for Its Bone Anabolic Actions

Raggatt¹,

Qin²,

Tamasi

et al. 2008

Journal of Biological Chemistry

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“…Binding of the receptor initiates activation of adenylyl cyclase by G s and phospholipase C-(PLC-) by G q/11 (Nissenson & Arnaud 1979, Mitchell & Bansal 1997. Our studies showed that PTH activated both cAMP and PLC-in the UMR106-01 cells and that regulation of protein kinase C-(PKC-) contributed to the increase in IGFBP-5 mRNA levels (Erclik & Mitchell 2002). The present study was undertaken to determine the transcriptional mechanisms by which PTH stimulates IGFBP-5 transcription.…”

Section: Introductionmentioning

confidence: 74%

“…We have previously demonstrated that parathyroid hormone (PTH) induces IGFBP-5 mRNA expression in the osteosarcoma cell line, UMR106-01 cells (Erclik & Mitchell 2002). The effects of PTH in these cells are initiated by the activation of its G protein-coupled PTH/ PTH related peptide receptor (Bringhurst et al 1993).…”

Section: Introductionmentioning

confidence: 99%

Activation of the insulin-like growth factor binding protein-5 promoter by parathyroid hormone in osteosarcoma cells requires activation of an activated protein-2 element

Erclik

Mitchell

2005

Journal of Molecular Endocrinology

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We have previously shown that parathyroid hormone (PTH) stimulates the expression of insulin-like growth factor binding protein-5 (IGFBP-5) transcript levels in the osteosarcoma cell-line, UMR106-01 cells. In the present study we examined the molecular basis for the PTH induction of IGFBP-5 mRNA in these cells. PTH had no effect on the half-life of the IGFBP-5 transcript but did stimulate the transactivation of the proximal 889 base pairs of the rat IGFBP 58 flanking region in a luciferase fusion construct, suggesting that PTH stimulates transcript levels through transcriptional mechanisms. Progressive 58 deletions to -59 base pairs of the proximal promoter region had no effect on PTH induction of transactivation, indicating that an element existed within the first -59 base pairs upstream of the transcription start site that was responsive to PTH. Within the -59 base pairs there are CCAAT/enhancer binding protein (C/EBP), E-box, nuclear factor-1 (NF-1) and activator protein-2 (AP-2) elements. Mutation of the C/EBP, E-box or NF-1 elements had no effect on the ability of PTH to induce the transactivation of the IGFBP-5 promoter. Mutation of the AP-2 element resulted in a 40% reduction of PTH-stimulated luciferase activity. When three tandem repeats of the AP-2 consensus sequence were fused to a luciferase reporter, PTH stimulated a 25% increase in reporter activity. Electrophoretic mobility shift assays using UMR106-01 cell nuclear extracts showed that PTH caused a prominent shifted band in a probe spanning the region containing all four elements. The shifted band was almost completely absent when the probe contained a mutated AP-2 element. These results suggest that the AP-2 element functions in the PTH induction of IGFBP-5 gene expression.

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“…Regulation of cytosolic calcium levels is an important signaling pathway in osteoblasts (46). Many ligands such as PTH, endothelin, and nucleotides bind to G q -coupled receptors to induce release of calcium from intracellular stores and activate protein kinase C, which in turn contribute to the regulation of genes such as insulin-like growth factor-binding protein 5 (47) and transforming growth factor ␤1 in osteoblastic cells (48). Nucleotides act through G q -coupled P2Y receptors on osteoblasts to stimulate proliferation (32).…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

Roy

Nunn

Hong

et al. 2006

Journal of Biological Chemistry

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Regulator of G protein signaling (RGS) proteins limitG protein-coupled receptors (GPCRs) 6 respond to a variety of hormones, paracrine factors, and neurotransmitters by activating heterotrimeric G proteins. Upon activation of the G protein, G␣ is stimulated to exchange bound GDP for cytosolic GTP and is thought to subsequently dissociate from the ␤␥ dimer. Both G␣ and the ␤␥ dimer are then capable of interacting with cellular effectors for a period of time that is limited by the intrinsic GTPase activity of the G␣ subunit. Regulator of G protein signaling (RGS) proteins can reduce the duration of these interactions by increasing the rate of GTP hydrolysis by the G␣ subunits, or by otherwise blocking interactions between G␣ and its target enzymes through a poorly understood process sometimes referred to as "effector antagonism" (1, 2).G protein signaling in osteoblasts is a critical regulator of bone formation. The predominant GPCRs expressed by osteoblasts include the parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (PTH1R), P2Y nucleotide receptors, and prostaglandin receptors (3). Other GPCRs found in osteoblasts include endothelin, adenosine, ␤-adrenergic, angiotensin II, and calcium-sensing receptors (3, 4). Binding of PTH to its specific receptor, PTH1R, predominantly leads to the activation of G s (although under certain conditions the receptor can also couple to G q and G i ) (5, 6). Activated G s stimulates adenylyl cyclase to generate intracellular cAMP, which results in the activation of protein kinase A. Stimulation of G q promotes the activity of phospholipase C-␤ (PLC-␤), resulting in the accumulation of inositol 1,4,5-trisphosphate and diacylglycerol, which lead, respectively, to release of calcium from intracellular stores and activation of protein kinase C. Nucleotide stimulation of P2Y receptors in osteoblasts results in PLC-␤ activation and calcium mobilization, with no effect on adenylyl cyclase (3, 7).

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The role of protein kinase C-δ in PTH stimulation of IGF-binding protein-5 mRNA in UMR-106–01 cells

Cited by 25 publications

References 38 publications

Interleukin-18 Is Regulated by Parathyroid Hormone and Is Required for Its Bone Anabolic Actions

Interleukin-18 Is Regulated by Parathyroid Hormone and Is Required for Its Bone Anabolic Actions

Activation of the insulin-like growth factor binding protein-5 promoter by parathyroid hormone in osteosarcoma cells requires activation of an activated protein-2 element

Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

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