Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells

Sugimoto, Naotoshi; Miwa, Shinji; Ohno‐Shosaku, Takako; Tsuchiya, Hiroyuki; Hitomi, Yoshiaki; Nakamura, Hiroyuki; Tomita, Katsuro; Yachie, Akihiro; Koizumi, Satoshi

doi:10.1016/j.neulet.2011.04.028

Cited by 17 publications

(18 citation statements)

References 24 publications

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“…Moreover, in this study, we showed that Epac plays a key role in cAMP-induced inhibition of cell proliferation (Figure 6). In our recent study, cAMP was shown to inhibit the activity of Akt through Epac-PTEN pathway activation and in turn inhibit cell proliferation in glial cells and osteosarcoma cells [17, 22]. In this study, theophylline and IBMX fully inhibited cell proliferation (Figures 2(b) and 3(b)) and Akt activation (data not shown).…”

Section: Discussionsupporting

confidence: 45%

“…8-CPT-cAMP is a nonhydrolyzable cAMP analog that activates Epac with greater potency than PKA [16]. Previous studies have shown that concentrations of 8-CPT-cAMP as low as 3 μ M effectively activate Epac in studies using cultured cells [17]. In our experiments, we observed that pretreating NIH3T3 cells with 3 μ M of 8-CPT-cAMP appreciably inhibited LCWE-induced phosphorylation of NF- κ B (Figures 5(e) and 5(f)).…”

Section: Resultsmentioning

confidence: 99%

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Phosphodiesterase Inhibitors SuppressLactobacillus caseiCell-Wall-Induced NF-κB and MAPK Activations and Cell Proliferation through Protein Kinase A—or Exchange Protein Activated by cAMP-Dependent Signal Pathway

Saito

Sugimoto

Ohta

et al. 2012

The Scientific World Journal

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Specific strains of Lactobacillus have been found to be beneficial in treating some types of diarrhea and vaginosis. However, a high mortality rate results from underlying immunosuppressive conditions in patients with Lactobacillus casei bacteremia. Cyclic AMP (cAMP) is a small second messenger molecule that mediates signal transduction. The onset and progression of inflammatory responses are sensitive to changes in steady-state cAMP levels. L. casei cell wall extract (LCWE) develops arteritis in mice through Toll-like receptor-2 signaling. The purpose of this study was to investigate whether intracellular cAMP affects LCWE-induced pathological signaling. LCWE was shown to induce phosphorylation of the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways and cell proliferation in mice fibroblast cells. Theophylline and phosphodiesterase inhibitor increased intracellular cAMP and inhibited LCWE-induced cell proliferation as well as phosphorylation of NF-κB and MAPK. Protein kinase A inhibitor H89 prevented cAMP-induced MAPK inhibition, but not cAMP-induced NF-κB inhibition. An exchange protein activated by cAMP (Epac) agonist inhibited NF-κB activation but not MAPK activation. These results indicate that an increase in intracellular cAMP prevents LCWE induction of pathological signaling pathways dependent on PKA and Epac signaling.

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Section: Discussionsupporting

confidence: 45%

Section: Resultsmentioning

confidence: 99%

Phosphodiesterase Inhibitors SuppressLactobacillus caseiCell-Wall-Induced NF-κB and MAPK Activations and Cell Proliferation through Protein Kinase A—or Exchange Protein Activated by cAMP-Dependent Signal Pathway

Saito

Sugimoto

Ohta

et al. 2012

The Scientific World Journal

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“…A possible explanation for the reversal of insulin resistance and reduction in apoptosis induced by BPV and metformin may be that it is a result of reducing PTEN and activating the PI3K/AKT pathway. A previous study showed that overexpression of PTEN inhibits AKT activity and induces apoptosis through the PI3K/AKT pathway (21).…”

Section: Discussionmentioning

confidence: 99%

Suppression of phosphatase and tensin homolog protects insulin-resistant cells from apoptosis

Wang

Yang

et al. 2015

Molecular Medicine Reports

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In the present study, a glucosamine-induced model of insulin-resistant skeletal muscle cells was established in order to investigate the effect of inhibition of phosphatase and tensin homolog (PTEN)/5'-adenosine monophosphate-activated protein kinase (AMPK) on these cells. The glucosamine-induced insulin-resistant skeletal muscle cells were produced and the rate of glucose uptake was measured using the glucose oxidase-peroxidase method. The expression levels of PTEN and phosphorylated PTEN (p-PTEN) were assessed using western blotting. Glucose transporter 4 (GLUT4) translocation was detected by immunofluorescence. Cell apoptosis was evaluated using flow cytometry. Following insulin stimulation, the rate of glucose uptake was significantly reduced in the cells with glucosamine-induced insulin-resistance in comparison with those in the control group. The expression and translocation of GLUT4 were reduced in the insulin-resistant muscle cells. By contrast, the expression of PTEN and p-PTEN as well as apoptosis were significantly increased. Following treatment with bisperoxopicolinatooxovanadate (BPV) or metformin in the insulin-resistant skeletal muscle cells, there was an increase in the rate of glucose uptake, an increase in GLUT4 expression and its translocation, a reduction in the expression of PTEN and p-PTEN, and a decrease in cell apoptosis compared with untreated insulin-resistant cells. Glucosamine may be used to produce an effective model of insulin-resistant skeletal muscle cells. Cells with glucosamine-induced insulin-resistance exhibited a reduced expression of GLUT4 and dysfunction in GLUT4 translocation, as well as increased activation of PTEN and increased cell apoptosis. Inhibition of PTEN or its upstream regulator, AMPK, protects glucosamine-induced insulin-resistant skeletal muscle cells from apoptosis.

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“…Previous work has demonstrated that bisphosphonates inhibit osteoclast differentiation and function by inhibition of Rap1A (effector of the cAMP-binding EPAC protein) isoprenylation and function (34). In the prior literature, there was no direct demonstration that EPAC1/2 played a role in osteoclast differentiation; however, Granholm (19) reported that an EPAC-selective cAMP analog mimics the inhibitory effects of calcitonin and other compounds that activate cAMP in osteoclast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Activation of EPAC1/2 is essential for osteoclast formation by modulating NFκB nuclear translocation and actin cytoskeleton rearrangements

Mediero¹,

Pérez-Aso²,

Cronstein³

2014

FASEB j.

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Bisphosphonates inhibit osteoclast differentiation/function via inhibition of Rap1A isoprenylation. As Rap1 is the effector of exchange protein directly activated by cAMP (EPAC) proteins, we determined the role of EPAC in osteoclast differentiation. We examined osteoclast differentiation as the number of primary murine/human bone-marrow precursors that differentiated into multinucleated TRAP-positive cells in the presence of EPAC-selective stimulus (8-pCTP-2=-O-Me-cAMP, 100 M; 8-pCTP-2=-O-Me-cAMP-AM, 1 M) or inhibitor brefeldin A (BFA), ESI-05, and ESI-09 (10 M each). Rap1 activity was assessed, and signaling events, as well as differentiation in EPAC1/2-knockdown RAW264.7 cells, were studied. Direct EPAC1/2 stimulation significantly increased osteoclast differentiation, whereas EPAC1/2 inhibition diminished differentiation (113؎6%, P<0.05, and 42؎10%, P<0.001, of basal, respectively). Rap1 activation was maximal 15 min after RANKL stimulation (147؎9% of basal, P<0.001), whereas silencing of EPAC1/2 diminished activated Rap1 (43؎13 and 20؎15% of control, P<0.001) and NFkB nuclear translocation. TRAP-staining revealed no osteoclast differentiation in EPAC1/ 2-KO cells. Cathepsin K, NFATc1, and osteopontin mRNA expression decreased in EPAC1/2-KO cells when compared to control. RhoA, cdc42, Rac1, and FAK were activated in an EPAC1/2-dependent manner, and there was diminished cytoskeletal assembly in EPAC1/2-KO cells. In summary, EPAC1 and EPAC2 are critical signaling intermediates in osteoclast differentiation that permit RANKL-stimulated NFkB nuclear translocation and actin rearrangements. Targeting Osteoclasts, multinucleated giant cells derived from myeloid precursors belonging to the monocyte/ macrophage family (1, 2), resorb bone during normal bone remodeling and, by increasing in number and resorptive capacity, mediate pathological bone loss, as well. Osteoclasts adhere to bone and form a sealing zone into which they secrete HCl and proteases, such as collagenases, cathepsin K, and tartrate-resistant acid phosphatase (TRAP), which dissolve the mineral and matrix components of bone (3). Myeloid precursors differentiate into osteoclasts after stimulation by macrophage colony-stimulating factor 1 (M-CSF), which acts via its receptor CSF-1R. After interaction with M-CSF, differentiation and activation of osteoclasts is mediated by a complex network of regulatory factors (systemic hormones and locally produced cytokines) and cell-cell and cell-matrix interactions that are required for transition of the osteoclast precursor into a multinucleated and fully activated osteoclast (4, 5). Among these factors, receptor activator of nuclear factor -B ligand (RANKL) is a critical extracellular regulator of osteoclast differentiation and activation (6 -10). RANKL binds to its receptor, RANK, on the surface of osteoclast precursors (OCPs), resulting in the recruitment of TNF receptor associated factors (TRAFs), which activate nuclear factor B (NFB), c-Fos, phospholipase C␥ (PLC␥), and nuclear factor of

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Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells

Cited by 17 publications

References 24 publications

Phosphodiesterase Inhibitors SuppressLactobacillus caseiCell-Wall-Induced NF-κB and MAPK Activations and Cell Proliferation through Protein Kinase A—or Exchange Protein Activated by cAMP-Dependent Signal Pathway

Phosphodiesterase Inhibitors SuppressLactobacillus caseiCell-Wall-Induced NF-κB and MAPK Activations and Cell Proliferation through Protein Kinase A—or Exchange Protein Activated by cAMP-Dependent Signal Pathway

Suppression of phosphatase and tensin homolog protects insulin-resistant cells from apoptosis

Activation of EPAC1/2 is essential for osteoclast formation by modulating NFκB nuclear translocation and actin cytoskeleton rearrangements

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