cAMP inhibits the proliferation of retinal pigmented epithelial cells through the inhibition of ERK1/2 in a PKA-independent manner

Hecquet, Christiane; Lefèvre, G.; Valtink, Monika; Engelmann, Katrin; Mascarelli, Frédéric

doi:10.1038/sj.onc.1205765

Cited by 56 publications

(42 citation statements)

References 25 publications

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“…In corneal epithelial cells, Ras is proposed to be involved in the signal transduction pathways induced by the glial cell-derived neurotrophic factor, suggesting that Ras is involved in corneal wound healing (44). In addition, Ras and Raf-1 are considered to be the key components in signaling for retinal pigment epithelial cell proliferation (45). The data are presented here showing that, in diabetes, retinal H-Ras and Raf-1 expressions are increased and can be inhibited by antioxidants.…”

Section: Discussionmentioning

confidence: 57%

Potential Contributory Role of H-Ras, a Small G-Protein, in the Development of Retinopathy in Diabetic Rats

Kowluru

Chakrabarti

et al. 2004

Diabetes

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Hyperglycemia is thought to be the underlying factor in the development of diabetic retinopathy, but the mechanisms involved remain partially understood. Diabetes increases oxidative stress, and reactive oxygen species affect the interactions between a small-molecularweight G-protein, H-Ras, and several of its effector proteins. The purpose of this study was to examine the regulatory role of H-Ras in glucose-induced apoptosis of retinal endothelial cells. The expressions of H-Ras and its effector protein (Raf-1) were compared in the retina obtained from diabetic rats (2-8 months' duration) and age-matched normal rats and in retinal endothelial cells exposed to high-glucose medium. The effect of inhibition of H-Ras function on glucose-induced capillary cell death and the potential involvement of oxidative stress in diabetes-induced activation of H-Ras were also determined. The expressions of H-Ras and Raf-1 were increased in the retina in diabetes, and antioxidant therapy prevented diabetes-induced increased protein and mRNA expressions. The inhibitors of Ras farnesylation inhibited glucose-induced nitric oxides and apoptosis in isolated retinal endothelial cells. Thus, the results suggest that functional activation of H-Ras might be one of the signaling steps involved in glucoseinduced capillary cell apoptosis and supports the role of H-Ras in the development of retinopathy in diabetes.

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Section: Discussionmentioning

confidence: 57%

Potential Contributory Role of H-Ras, a Small G-Protein, in the Development of Retinopathy in Diabetic Rats

Kowluru

Chakrabarti

et al. 2004

Diabetes

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“…However, there have been many cases in which cellular processes are modulated by elevated cAMP levels via PKA-independent pathways. [24][25][26][27] Further experiments are needed to confirm whether nefiracetam potentiation is due to the G as membrane-delimited pathway or to a cAMP-depen- 2) dent process other than the PKA pathway.…”

Section: Roles Of Protein Kinases and G Proteins In Nefiracetam Potenmentioning

confidence: 99%

Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

Narahashi

Moriguchi

Zhao

et al. 2004

Biological & Pharmaceutical Bulletin

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No strategies for curing Alzheimer's disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer's disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients' cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer's disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer's patients. Nefiracetam has been shown to potentiate ACh currents in the a a4b b2 receptor of rat cortical neurons with a bell-shaped dose-response relationship and the maximum effect at 1 nM. This effect was exerted via G s proteins. The a a7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the a a4b b2 receptor and potentiated NMDA currents with the maximum effect at 1 m mM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1-10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients' learning, cognition, and memory.

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“…p38 MAPK and JNK are usually related to cell growth inhibition or apoptosis, whereas ERK promotes cell proliferation (23), and cAMP signal can intervene during these processes. In many instances, cAMP can inhibit cellular proliferation by blocking ERK signaling stimulated by growth factors (13,(24)(25)(26). The activity of p38 MAPK can also be regulated by cAMP signals; for example, cAMPincreasing signals induce p38 MAPK activation and this activation is blocked by PKA catalytic inhibitor in NG108-15 neuroblastoma Â glioma hybrid cells (27), SK-N-MC human neuroblastoma cells (28), and Chinese hamster ovary cells stably transfected with the human thyroid-stimulating hormone (TSH) receptor (29).…”

Section: Introductionmentioning

confidence: 99%

8-Chloro-Cyclic AMP–Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells

2005

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8-Chloro-cyclic AMP (8-Cl-cAMP), which is known to induce growth inhibition, apoptosis, and differentiation in various cancer cell lines, has been studied as a putative anticancer drug. However, the mechanism of anticancer activities of 8-ClcAMP has not been fully understood. Previously, we reported that the 8-Cl-cAMP-induced growth inhibition is mediated by protein kinase C (PKC) activation. In this study, we found that p38 mitogen-activated protein kinase (MAPK) also plays important roles during the 8-Cl-cAMP-induced growth inhibition and apoptosis. SB203580 (a p38-specific inhibitor) recovered the 8-Cl-cAMP-induced growth inhibition and apoptosis, whereas other MAPK inhibitors, such as PD98059 (an extracellular signal-regulated kinase-specific inhibitor) and SP600125 (a c-Jun NH 2 -terminal kinase-specific inhibitor), had no effect. The phosphorylation (activation) of p38 MAPK was increased in a time-dependent manner after 8-ClcAMP treatment. Furthermore, SB203580 was able to block PKC activation induced by 8-Cl-cAMP. However, PKC inhibitor (GF109203x) could not attenuate p38 activation, indicating that p38 MAPK activation is upstream of PKC activation during the 8-Cl-cAMP-induced growth inhibition. 8-Chloroadenosine, a metabolite of 8-Cl-cAMP, also activated p38 MAPK and this activation was blocked by adenosine kinase inhibitor. These results suggest that 8-Cl-cAMP exerts its anticancer activity through p38 MAPK activation and the metabolite(s) of 8-Cl-cAMP mediates this process. (Cancer Res 2005; 65(11): 4896-901)

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cAMP inhibits the proliferation of retinal pigmented epithelial cells through the inhibition of ERK1/2 in a PKA-independent manner

Cited by 56 publications

References 25 publications

Potential Contributory Role of H-Ras, a Small G-Protein, in the Development of Retinopathy in Diabetic Rats

Potential Contributory Role of H-Ras, a Small G-Protein, in the Development of Retinopathy in Diabetic Rats

Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

8-Chloro-Cyclic AMP–Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells

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