Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic fibroblast growth factor (FGF2) is a potent mitogen for medial smooth muscle cells and is necessary for their proliferation after balloon catheter injury; however, intimal smooth muscle cells do not require FGF2 for their proliferation, and they respond only weakly to exogenous FGF2. The present study examined the activation of extracellular signal-regulated kinase (ERK) signaling as well as the expression and activity of cell cycle proteins in FGF2-stimulated intimal smooth muscle cells. FGF2 activates ERKs 1 and 2, and Western blot analysis showed that cyclin D, cyclin E, and cyclin-dependent kinase (CDKs) 2 and 4 were expressed in intimal smooth muscle cells after FGF2 infusion. FGF2 stimulation, however, did not lead to phosphorylation of the retinoblastoma protein (Rb), CDK 2 activation, or expression of cyclin A. Western blot analysis showed that intimal smooth muscle cells express elevated levels of the cell cycle inhibitors p15(INK4b) and p27(Kip1), compared with medial smooth muscle cells, and that FGF2 stimulation does not reduce the level of these inhibitors. These studies suggest that despite activation of ERKs 1 and 2 and expression of the cell cycle activators, cyclin D and cyclin E, high levels of cell cycle inhibitors may inhibit cell cycle transit in FGF2-stimulated intimal smooth muscle cells.
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PMID:Proliferation of intimal smooth muscle cells. Attenuation of basic fibroblast growth factor 2-stimulated proliferation is associated with increased expression of cell cycle inhibitors. 1075 37

Fibroblast growth factor (FGF) and its receptor (FGFR) are thought to be negative regulators of chondrocytic growth, as exemplified by achondroplasia and related chondrodysplasias, which are caused by constitutively active mutations in FGFR3. To understand the growth-inhibitory mechanisms of FGF, we analyzed the effects of FGF2 on cell cycle-regulating molecules in chondrocytes. FGF2 dramatically inhibited proliferation of rat chondrosarcoma (RCS) cells and arrested their cell cycle at the G(1) phase. FGF2 increased p21 expression in RCS cells, which assembled with the cyclin E-Cdk2 complexes, although the expression of neither cyclin E nor Cdk2 increased. In addition, the kinase activity of immunoprecipitated cyclin E or Cdk2, assessed with retinoblastoma protein (pRb) as substrate, was dramatically reduced by FGF-2. Moreover, FGF2 shifted pRb to its underphosphorylated, active form in RCS cells. FGF2 not only induced p21 protein expression in proliferating chondrocytes in mouse fetal limbs cultured in vitro but also decreased their proliferation as assessed by the expression of histone H4 mRNA, a marker for cells in S phase. Furthermore, inhibitory effects of FGF2 on chondrocytic proliferation were partially reduced in p21-null limbs, compared with those in wild-type limbs in vitro. Taken together, FGF's growth inhibitory effects of chondrocytes appear to be mediated at least partially through p21 induction and the subsequent inactivation of cyclin E-Cdk2 and activation of pRb.
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PMID:Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2. 1138 71

Melanoma is the most deadly cutaneous malignancy; its incidence has risen significantly over the last 30 years and there is no effective treatment for advanced melanoma. Autocrine expression of fibroblast growth factors (FGFs) is a common event in malignant melanoma. We therefore sought to inhibit the proliferation and survival of melanoma cells as an approach to melanoma therapy by disrupting FGF signalling via adenoviral-mediated expression of a dominant negative FGF receptor. We tested three melanoma cell lines (A375, IIB and UCD) that express FGF2 and respond to exogenous FGF2 with increased proliferation. In all three cell lines, there was a significant decrease in net proliferation, and in two (A375 and UCD) an increase in cell death, associated with expression of the dominant negative FGF receptor. In these two cell lines, expression of the dominant negative FGF receptor resulted in the accumulation of p21 (WAF1/cip1), decreased cell division cycle-2 (cdc2) kinase activity, an increase in the percentage of cells in the G2 phase of the cell cycle, and inhibition of cytokinesis, with accumulation of binucleated cells. These studies reveal that inhibition of FGF signalling can markedly decrease the net proliferation of melanoma cells by a novel mechanism involving a decrease in cdc2 kinase activity, an increase in p21 expression, inhibition of G2 progression, inhibition of cytokinesis and increased cell death. In contrast, disruption of FGF signalling had only slight effects on normal melanocytes. Disruption of FGF signalling via the expression of the dominant negative FGF receptor is, therefore, a potential therapeutic approach in human melanoma.
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PMID:Inhibition of proliferation and survival of melanoma cells by adenoviral-mediated expression of dominant negative fibroblast growth factor receptor. 1509 Nov 89

Several forms of human dwarfism are due to activating mutations in FGFR3 highlighting the role of FGF signaling in the growth attenuation of cartilage. Here, we studied the effects of FGF2 on RCS chondrocytes. Treatment with FGF2 induced growth arrest in the G1 phase of the cell cycle and partial de-differentiation of cells manifested by changes in cell morphology, loss of the cartilage-like extracellular matrix, and down-regulation of aggrecan expression. FGF2 activated phospholipase Cgamma, protein kinase B, and Erk and p38 MAP kinases. Chemical inhibition of FGFR3 and MEK1/2 antagonized FGF2-mediated growth arrest. Expression of a dominant-negative Ras mutant resulted in a partial reversal of growth inhibition while expression of constitutively activated Ras led to Erk-dependent growth arrest, further demonstrating the role of the Ras/Erk pathway in this phenotype. At the molecular level, FGF2-induced growth arrest was initiated by disintegration of cyclin D3-cdk6 complex followed by increased association of p21(WAF1) and p27(Kip1) with the cyclin-cdk2 and cyclin-cdk4 complexes leading to inhibition of their kinase activities and ultimately to underphosphorylation of the p107 and p130 pocket proteins. Both p21(WAF1) and p27(Kip1) accumulated upon FGF2 treatment, but this accumulation occurred at the protein level at least partially due to interaction with transcriptionally induced cyclin D1.
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PMID:FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells. 1519 33

Huntington's disease is a progressive neurodegenerative disorder characterized by motor disturbances, cognitive decline, and neuropsychiatric symptoms. In this study, we utilized network-based analysis in an attempt to explore and understand the underlying molecular mechanism and to identify critical molecular players of this disease condition. Using human post-mortem microarrays from three brain regions (cerebellum, frontal cortex and caudate nucleus) we selected in a four-step procedure a seed set of highly modulated genes. Several protein-protein interaction networks, as well as microRNA-mRNA networks were constructed for these gene sets with the Elsevier Pathway Studio software and its associated ResNet database. We applied a gene prioritizing procedure based on vital network topological measures, such as high node connectivity and centrality. Adding to these criteria the guilt-by-association rule and exploring their innate biomolecular functions, we propose 19 novel genes from the analyzed microarrays, from which CEBPA, CDK1, CX3CL1, EGR1, E2F1, ERBB2, LRP1, HSP90AA1 and ZNF148 might be of particular interest for experimental validation. A possibility is discussed for dual-level gene regulation by both transcription factors and microRNAs in Huntington's disease mechanism. We propose several possible scenarios for experimental studies initiated via the extra-cellular ligands TGFB1, FGF2 and TNF aiming at restoring the cellular homeostasis in Huntington's disease.
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PMID:Network analysis of human post-mortem microarrays reveals novel genes, microRNAs, and mechanistic scenarios of potential importance in fighting huntington's disease. 2792 90