Cyclooxygenase 2 Promotes Cell Survival by Stimulation of Dynein Light Chain Expression and Inhibition of Neuronal Nitric Oxide Synthase Activity

Chang, Yu-Wen E.; Jakobi, Rolf; McGinty, Ann; Foschi, Marco; Dünn, Michael J.; Sorokin, Andrey

doi:10.1128/mcb.20.22.8571-8579.2000

Cited by 78 publications

(56 citation statements)

References 57 publications

(66 reference statements)

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“…This was not unexpected, since p21 cip-1 protects against p53-mediated apoptosis (30). Moreover, COX-2 is a survival factor by suppressing caspase-3 activity (31) or inhibiting NO-and superoxide-mediated apoptosis (32). Thus, COX-2 might exclusively influence the growth suppressing properties of p53 in our cell system.…”

Section: Discussionmentioning

confidence: 94%

Cyclooxygenase-2 Overexpression Inhibits Platelet-derived Growth Factor-induced Mesangial Cell Proliferation through Induction of the Tumor Suppressor Gene p53 and the Cyclin-dependent Kinase Inhibitors p21waf-1/cip-1 and p27kip-1

Zahner¹,

Wolf²,

Ayoub³

et al. 2002

Journal of Biological Chemistry

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Cyclooxygenase-2 (COX-2) is an inducible enzyme and serves as a source of paracrine prostaglandin E2 (PGE2) formation in many tissues. In glomerular immune injury COX-2 formation is up-regulated in association with increased mesangial cell growth. To examine whether COX-2 exerts growth modulating effects on glomerular cells, we established two separate COX-2-overexpressing mesangial cell lines (COX-2؉) and assessed their proliferative response to the potent mesangial cell growth-promoting factor, platelet-derived growth factor (PDGF). PDGF increased proliferation in mocktransfected cells. In contrast, PDGF did not induce proliferation in COX-2؉ cells. Our results also showed that the tumor suppressor protein p53 and the cyclindependent kinase inhibitors p21 cip-1 and p27 kip-1 were up-regulated in COX-2؉ cells de novo as well as under PDGF-stimulated conditions. To study whether COX-2 products are required for these effects, COX-2؉ cells were treated with indomethacin (1 g/ml) or NS-398 (3 M). Unexpectedly, both COX inhibitors had no significant effect on cell proliferation, not on the protein levels of p53, p21 cip-1 , or p27 kip-1 . To evaluate the role of p21 cip-1 and p27 kip-1 , COX-2 was overexpressed in mesangial cells derived from p21 cip-1 (p21؊/؊ COX-2؉) and p27 kip-1 (p27؊/؊ COX-2؉) null mice. In contrast to the wild type COX-2؉ cells, p21؊/؊ COX-2؉ and p27؊/؊ COX-2؉ cells proliferated in response to PDGF. These data suggest that COX-2 inhibits mesangial cell proliferation by a novel mechanism that is independent of prostaglandin synthesis, but involves p53, p21 cip-1 , and p27 kip-1 .

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Section: Discussionmentioning

confidence: 94%

Cyclooxygenase-2 Overexpression Inhibits Platelet-derived Growth Factor-induced Mesangial Cell Proliferation through Induction of the Tumor Suppressor Gene p53 and the Cyclin-dependent Kinase Inhibitors p21waf-1/cip-1 and p27kip-1

Zahner¹,

Wolf²,

Ayoub³

et al. 2002

Journal of Biological Chemistry

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“…One function is the modulation of nNOS catalytic activity to prevent deleterious overproduction of NO. Indeed, it has been reported that a cyclooxygenase-induced increase of PIN expression is, through an inhibition of the production of superoxide and NO by nNOS, able to prevent nerve growth factor-deprived PC12 cells from apoptosis (37). Concerning pancreatic ␤-cells, PIN overexpression resulted in a clear increase in insulin secretion, bearing evidence that this highly conserved protein plays a role in the stimulus-secretion coupling of the ␤-cell.…”

Section: Discussionmentioning

confidence: 99%

Protein Inhibitor of Neuronal Nitric Oxide Synthase (PIN) Is a New Regulator of Glucose-Induced Insulin Secretion

et al. 2006

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We previously showed that pancreatic ␤-cells express neuronal nitric oxide synthase (nNOS) that controls insulin secretion through two catalytic activities: nitric oxide (NO) production and cytochrome c reductase activity. We now provide evidence that the endogenous protein inhibitor of nNOS (PIN) is expressed in rat pancreatic islets and INS-1 cells. Double-immunofluorescence studies showed a colocalization of PIN with both nNOS and myosin Va in insulin-secreting ␤-cells. Electron microscopy studies confirmed that PIN is mainly associated with insulin secretory granules and colocated with nNOS in the latter. In addition, PIN overexpression in INS-1 cells enhanced glucoseinduced insulin secretion, which is only partly reversed by addition of an NO donor, sodium nitroprusside (SNP), and unaffected by the inhibitor of cytochrome c reductase activity, miconazole. In contrast, the pharmacological inhibitor of nNOS, N-nitro-L-arginine methyl ester, amplified glucose-induced insulin secretion, an effect insensitive to SNP but completely normalized by the addition of miconazole. Thus, PIN insulinotropic effect could be related to its colocalization with the actin-based molecular motor myosin Va and as such be implicated in the physiological regulation of glucose-induced insulin secretion at the level of the exocytotic machinery. Diabetes 55: 3279 -3288, 2006 T he second messenger nitric oxide (NO) is synthesized from L-arginine by a family of enzymes known as NO synthases (NOSs). Three NOS isoforms have been identified, including the constitutive neuronal NO synthase (nNOS), endothelial NOS (eNOS), and the cytokine-inducible NOS (iNOS) (1). Constitutive NOSs produce small amounts of NO, implicated in physiological functions such as synaptic transmission (2) and vascular tone (3), whereas iNOS produces high amounts of NO, acting as a cytotoxic mediator in immune response (4). In addition to these beneficial roles, NO exerts deleterious effects as a result of its overproduction, leading to neuronal death during brain ischemia and certain neurodegenerative pathologies (5) and to autoimmune diseases (6). For these reasons, a tight regulation of NOS catalytic activity is essential for its physiological function. Modulation of iNOS expression by cytokines is believed to be the most important component of iNOS regulation, but posttranscriptional mechanisms also operate (7,8). As for the constitutive isoforms, catalytic activity is closely modulated by different mechanisms. The enzyme's activity is first controlled by the reversible binding of Ca 2ϩ -calmodulin (9), which allows the transfer of NADPH-derived electrons from the reductase to the oxygenase domain of the enzyme (10). It is also positively or negatively regulated through phosphorylation by various protein kinases such as cAMP-dependent protein kinase and protein kinase C (11,12). In addition to the role of intracellular Ca 2ϩ levels and protein kinases, constitutive NOSs are also regulated via protein-protein interactions. Thus, eNOS-associated protein-1 (ENAP-1...

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“…COX-2 has been reported to inhibit nerve growth factor withdrawal apoptosis in differentiated PC12 cells (28). A different study found that an apoptosisrelated gene, dynein light chain (DLC), was up-regulated in PC12 cells by COX-2 expression or PGE 2 treatment (29). DLC expression prevented apoptosis of PC12 cells by reducing neuron nitric-oxide synthase activity.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 Inducing Mcl-1-dependent Survival Mechanism in Human Lung Adenocarcinoma CL1.0 Cells

Lin¹,

Lee²,

Yang³

et al. 2001

Journal of Biological Chemistry

174

111

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Cyclooxygenase 2 Promotes Cell Survival by Stimulation of Dynein Light Chain Expression and Inhibition of Neuronal Nitric Oxide Synthase Activity

Cited by 78 publications

References 57 publications

Cyclooxygenase-2 Overexpression Inhibits Platelet-derived Growth Factor-induced Mesangial Cell Proliferation through Induction of the Tumor Suppressor Gene p53 and the Cyclin-dependent Kinase Inhibitors p21waf-1/cip-1 and p27kip-1

Cyclooxygenase-2 Overexpression Inhibits Platelet-derived Growth Factor-induced Mesangial Cell Proliferation through Induction of the Tumor Suppressor Gene p53 and the Cyclin-dependent Kinase Inhibitors p21waf-1/cip-1 and p27kip-1

Protein Inhibitor of Neuronal Nitric Oxide Synthase (PIN) Is a New Regulator of Glucose-Induced Insulin Secretion

Cyclooxygenase-2 Inducing Mcl-1-dependent Survival Mechanism in Human Lung Adenocarcinoma CL1.0 Cells

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