Role of inhibitors of isoprenylation in proliferation, phenotype and apoptosis of human retinal pigment epithelium

Capeáns, C.; Piñeiro, Antonio; Pardo, María Laura; Carneiro, Carmen; Blanco, Marı́a José; Vinuela, Juan M.; Salorio, Manuel Sanchez; Domı́nguez, Fernando

doi:10.1007/s004170000250

Cited by 11 publications

(5 citation statements)

References 40 publications

(46 reference statements)

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“…Thrombin has been shown to activate the classic Ras-dependent MAPK pathway in human [16] and canine [20] tracheal smooth muscle cells. Our results, however, showed that thrombin-induced ERK phosphorylation in RPE cells bypasses Ras, since it was not prevented by the Ras farnesylation inhibitor manumycine, which has been shown to suppress the membrane anchoring of Ras [59] and Ras activation by serum in RPE cells [60].…”

Section: Discussioncontrasting

confidence: 58%

PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation

2008

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Thrombin signalling through PAR (protease-activated receptor)-1 is involved in cellular processes, such as proliferation, differentiation and cell survival. Following traumatic injury to the eye, thrombin signalling may participate in disorders, such as PVR (proliferative vitreoretinopathy), a human eye disease characterized by the uncontrolled proliferation, transdifferentiation and migration of otherwise quiescent RPE (retinal pigment epithelium) cells. PARs activate the Ras/Raf/MEK/ERK MAPK pathway (where ERK is extracellular-signal-regulated kinase, MAPK is mitogen-activated protein kinase and MEK is MAPK/ERK kinase) through the activation of G(alpha) and G(betagamma) heterotrimeric G-proteins, and the downstream stimulation of the PLC (phospholipase C)-beta/PKC (protein kinase C) and PI3K (phosphoinositide 3-kinase) signalling axis. In the present study, we examined the molecular signalling involved in thrombin-induced RPE cell proliferation, using rat RPE cells in culture as a model system for PVR pathogenesis. Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras-independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade. Pharmacological analysis revealed that the activation of 'conventional' PKC isoforms is essential for proliferation, although thrombin-induced phosphorylation of ERK1/2 requires the activation of atypical PKCzeta by PI3K. Consistently, thrombin-induced ERK1/2 activation and RPE cell proliferation were prevented completely by PI3K or PKCzeta inhibition. These results suggest that thrombin induces RPE cell proliferation by joint activation of PLC-dependent and atypical PKC isoforms and the Ras-independent downstream stimulation of the Raf/MEK/ERK1/2 MAPK cascade. The present study is the first report demonstrating directly thrombin-induced ERK phosphorylation in the RPE, and the involvement of atypical PKCzeta in this process.

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Section: Discussioncontrasting

confidence: 58%

PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation

2008

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“…Given the pervasive role of isoprenoids in metabolism, it is not surprising that imbalances in isoprenoid synthesis and utilization can lead to cellular dysfunction and disease. Controlling flux through these pathways is used to prevent and cure human disease; statins, which decrease cellular levels of mevalonate by inhibiting HMG-CoA reductase , , are used widely to control cholesterol levels in humans and may prove useful in the treatment of other diseases − .…”

mentioning

confidence: 99%

Structure of the Ternary Complex of Phosphomevalonate Kinase: The Enzyme and Its Family

et al. 2009

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The Galacto-, Homoserine-, Mevalonate-, Phosphomevalonate-kinase (GHMP) superfamily encompases a wide-range of protein function. Three members of the family (mevalonate kinase, phosphomevalonate kinase and diphosphomevalonate decarboxylase) comprise the mevalonate pathway found in S. pneumoniae and other organisms. We have determined the 1.9 Å crystal structure of phosphomevalonate kinase (PMK) from S. pneumoniae in complex with phosphomevalonate and AMPPNP·Mg2+. Comparison of the apo and ternary PMK structures suggests that ligand binding reverses the side-chain orientations of two anti-parallel lysines residues (100 and 101) with the result that lys101 is “switched” into a position in which its ammonium ion is in direct contact with the β,γ-bridging atom of the nucleotide, where it is expected to stabilize both the ground and transition states of the reaction. Analysis of all available GHMP kinase ternary-complex structures reveals that while their Cα-scaffolds are highly conserved, their substrates bind in one of two conformations, which appear to be either reactive or non-reactive. The active site of PMK seems spacious enough to accommodate interconversion of the reactive and nonreactive conformers. A substantial fraction of the PMK active site is occupied by ordered water, which clusters near the charged regions of substrate. Notably, a water pentamer that interacts extensively with the reactive groups of both substrates was discovered at the active site.

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“…36 Statins affect RPE cell survival and morphology in vitro. 37 The challenge for future laboratory research will be to determine which processes are modulated by statins in vivo and therefore are primarily responsible for the apparent beneficial effects observed in the present study.…”

Section: Discussionmentioning

confidence: 96%

Complex mutations of USH2A gene denote ARRP

Square¹,

London²,

H³

2003

British Journal of Ophthalmology

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Aims: To evaluate the association between age related maculopathy (ARM) and statin use. Methods: A nested case-control study among patients at the Veterans Affairs Medical Center in Birmingham, Alabama, with newly diagnosed ARM (cases) between 1997 to 2001 were selected and age matched to non-ARM controls. Results: 550 incident cases of ARM were identified and matched to 5500 controls. Overall, cases were 70% (OR 0.30, 95% CI 0.21 to 0.45) less likely to have received and filled a statin prescription relative to the controls. This association was present among both current and past (OR 0.34, 95% CI 0.21 to 0.53 and OR 0.26, 95% CI 0.14 to 0.47, respectively) statin users. When considering use of statin and/or non-statin lipid lowering medications, a significant risk reduction was observed for statin only users (OR 0.30, 95% CI 0.20 to 0.45) and combined statin and non-statin users (OR 0.20, 95% CI 0.06 to 0.64); there was no significant association for non-statin only users (OR 0.47, 95% CI 0.20 to 1.13). Conclusions:The results of this study suggest that subjects with ARM were significantly less likely to have filled a statin prescription. Future clinical research initiatives should include a clinical trial to provide direct evidence of the effectiveness of statins in lowering the incidence and progression of ARM.

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Role of inhibitors of isoprenylation in proliferation, phenotype and apoptosis of human retinal pigment epithelium

Cited by 11 publications

References 40 publications

PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation

PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation

Structure of the Ternary Complex of Phosphomevalonate Kinase: The Enzyme and Its Family

Complex mutations of USH2A gene denote ARRP

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