Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cGMP-cGMP-dependent protein kinase (protein kinase G) system plays an important role in the pathogenesis of mesangial proliferative glomerulonephritis. However, the molecular mechanisms of the inhibitory effects of the cGMP-protein kinase G system in the cell cycle progression of mesangial cells are not well known. To determine the inhibitory pathway of cGMP-protein kinase G in cultured mesangial cells, we investigated the effects of cGMP- and adenovirus-mediated overexpression of protein kinase G on the promoter activities of cyclin E, cyclin D1, and cyclin A. 8-Bromo-cGMP (8-BrcGMP) and overexpression of protein kinase G reduced [(3)H]thymidine uptake, reduced the numbers of cells in S and G(2)/M phases, and decreased the phosphorylation of retinoblastoma (Rb) protein. 8-BrcGMP (10(-3) M), protein kinase G adenovirus (Ad-cGKIbeta; 10(10) plaque-forming units/ml), atrial natriuretic peptide (ANP), and C-type natriuretic peptide (CNP) inhibited the promoter activity of cyclin E to 49, 57, 77, and 78%, respectively. On the other hand, the promoter activities of cyclin D1 and cyclin A were not changed significantly. In Western blot analysis, 8-BrcGMP, Ad-cGKIbeta, ANP, and CNP also inhibited cyclin E protein expression dose and time dependently. The p44/p42 mitogen-activated protein kinase (MAPK) kinase 1-p44/p42 MAPK had no effect on cyclin E promoter activities, and the cGMP-protein kinase G pathway did not change MAPK activity. In conclusion, our findings suggest that the reduction of the cyclin E promoter activity that downregulates G(1)/S transition plays a dominant role in the cGMP- and protein kinase G-induced inhibition of mesangial cell proliferation.
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PMID:Overexpression of protein kinase G using adenovirus inhibits cyclin E transcription and mesangial cell cycle. 1129 28

Previously, we have demonstrated that cGMP-dependent protein kinase (PKG) activity is downregulated in vessels from diabetic animals or in vascular smooth muscle cells (VSMCs) exposed to high-glucose conditions, contributing to diabetes-associated vessel dysfunction. However, whether decreased PKG activity plays a role in hyperglycemia-induced proliferation of VSMCs is unknown. In this report, high-glucose-mediated decreased PKG activity in VSMCs was restored by transfection of cells with expression vector for the catalytic domain of PKG-I (PKG-CD, constitutive active PKG). The effect of glucose on cell proliferation was determined. Our data demonstrated that high glucose exposure stimulated VSMC proliferation and G1 to S phase progression of the cell cycle, which was inhibited by restoration of PKG activity. Expression of constitutively active PKG inhibited G1 phase exit in VSMCs under high glucose conditions, which was accompanied by an inhibition of retinoblastoma protein (Rb) phosphorylation (a key switch for G1 to S phase cell cycle progression). Glucose-induced cyclin E expression and cyclin E-cyclin-dependent kinase 2 activity was also reduced by expression of PKG-CD in VSMCs. Moreover, expression of PKG-CD suppressed glucose-induced p27 degradation. These data demonstrate that restoring the high-glucose-mediated decrease in PKG activity in VSMCs inhibits glucose-induced abnormal VSMC proliferation occurring upstream of Rb phosphorylation. Our work provides the first direct evidence linking decreased PKG activity to high glucose-induced proliferation and cell cycle progression in VSMCs, suggesting that strategies to increase PKG activity might be useful in preventing abnormal VSMC proliferation in diabetic patients and might provide treatments for diabetes-associated proliferative vascular diseases.
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PMID:Expression of constitutively active cGMP-dependent protein kinase inhibits glucose-induced vascular smooth muscle cell proliferation. 1971 28

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase (NOS). ADMA is eliminated largely by the action of dimethylarginine dimethylaminohydrolase1 (DDAH1). Decreased DDAH activity is found in several pathological conditions and is associated with increased risk of vascular disease. Overexpression of DDAH1 has been shown to augment endothelial proliferation and angiogenesis. To better understand the mechanism by which DDAH1 influences endothelial proliferation, this study examined the effect of DDAH1 deficiency on cell cycle progression and the expression of some cell cycle master regulatory proteins. DDAH1 KO decreased in vivo Matrigel angiogenesis and depressed endothelial repair in a mouse model of carotid artery wire injury. DDAH1 deficiency decreased VEGF expression in HUVEC and increased NF1 expression in both HUVEC and DDAH1 KO mice. The expression of active Ras could overcome the decreased VEGF expression caused by the DDAH1 depletion. The addition of VEGF and knockdown NF1 could both restore proliferation in cells with DDAH1 depletion. Flow cytometry analysis revealed that DDAH1 sRNAi knockdown in HUVEC caused G1 and G2/M arrest that was associated with decreased expression of CDC2, CDC25C, cyclin D1 and cyclin E. MEF cells from DDAH1 KO mice also demonstrated G2/M arrest that was associated with decreased cyclin D1 expression and Akt activity. Our findings indicate that DDAH1 exerts effects on cyclin D1 and cyclin E expression through multiple mechanisms, including VEGF, the NO/cGMP/PKG pathway, the Ras/PI3K/Akt pathway, and NF1 expression. Loss of DDAH1 effects on these pathways results in impaired endothelial cell proliferation and decreased angiogenesis. The findings provide background information that may be useful in the development of therapeutic strategies to manipulate DDAH1 expression in cardiovascular diseases or tumor angiogenesis.
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PMID:DDAH1 deficiency attenuates endothelial cell cycle progression and angiogenesis. 2426 Feb 21

Despite advances in chemotherapy, ovarian cancer (OC) is still the most lethal gynecologic malignancy. So, it is imperative to explore its mechanism and find novel targets to improve the outcome. Type II cyclic guanosine 3',5'-monophosphate (cGMP)-dependent protein kinase (PKG II) has been recently reported to inhibit proliferation and metastasis in several tumors. The present study is to clarify the effect of PKG II combined with l-arginine (l-Arg) on OC cells. SKOV3 and A2780 cells were infected with adenovirus coding cDNA of PKG II to increase PKG II expression and l-Arg was applied to activate this kinase. CCK8 assay, Transwell migration and TUNEL assay were applied to detect the proliferation, migration and apoptosis of the OC cells, respectively. Western blotting was used to detect the level of total and phosphorylated proteins. Our results showed that co-treatment with PKG II and l-Arg inhibited EGF-induced proliferation and the expression of Proliferating Cell Nuclear Antigen (PCNA), Cyclin E and N-Cadherin, whereas up-regulated the expression of E-Cadherin, abolished the anti-apoptotic effect of EGF, prevented the process of epithelial-to-mesenchymal transition (EMT) as well as blocked EGF-triggered Raf-MEK and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. Our results suggested that PKG II activated by l-Arg could inhibit proliferation and migration and promote the apoptosis of OC cells. Based on the above results and our previous data, it is speculated that PKG II is an inhibitor of cancer with extensive effects.
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PMID:Active PKG II inhibited the growth and migration of ovarian cancer cells through blocking Raf/MEK and PI3K/Akt signaling pathways. 3135 Mar 42