Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.22 (cdc2)
8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G(1)/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.
...
PMID:Chk2 drives late G1/early S phase arrest of clonal myeloid progenitors expressing the p210 BCR-ABL tyrosine kinase in response to STI571. 1504 68

Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB-453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells.
...
PMID:Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. 1511 89

Cell cycle aberrations occurring at the G(1)/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1beta inhibits insulin-like growth factor (IGF)-I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this juxtamembrane cross-talk between cytokine and growth factor receptors to downstream cell cycle machinery. IL-1beta reduces the ability of IGF-I to activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not the mammalian target of rapamycin or mitogen-activated protein kinase pathways, is required for IGF-I to hyperphosphorylate retinoblastoma and to cause accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt activation and cell cycle progression, IL-1beta has no effect. IL-1beta induces p21(Cip1/Waf1), which may contribute to its inhibition of IGF-I-activated Cdk2. Collectively, these data establish a novel mechanism by which prolonged Akt phosphorylation serves as a convergent target for both IGF-I and IL-1beta; stimulation by growth factors such as IGF-I promotes G(1)-S phase progression, whereas IL-1beta antagonizes IGF-I-induced Akt phosphorylation to induce cytostasis. In this manner, Akt serves as a critical bridge that links proximal receptor signaling events to more distal cell cycle machinery.
...
PMID:IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells. 1518 2

Tyrosine kinases play crucial roles in cell differentiation and proliferation. Using degenerative primed PCR followed by differential display, we analyzed the tyrosine kinase expression profiles of cultured rat follicular papilla (FP) cells versus dermal fibroblasts. We showed that c-met, cdc2, and tec were preferentially expressed in cultured FP cells, whereas alpha-platelet-derived growth factor receptor (alpha-PDGFR) was preferentially expressed in cultured fibroblasts. The cell type specificity of these tyrosine kinases was confirmed by semi-quantitative RT-PCR using both rat and human cultured cells. Consistent with these results, hepatocyte growth factor preferentially stimulated the growth of rat FP cells, whereas PDGF-AA preferentially stimulated rat fibroblasts. High concentrations of some these kinases are also found in the follicular matrix keratinocytes as revealed by in situ hybridization. The expression of specific tyrosine kinases in FP and matrix cells may play roles in regulating hair growth and cycling.
...
PMID:Expression profiles of tyrosine kinases in cultured follicular papilla cells versus dermal fibroblasts. 1524 26

Cancer genes exert their greatest influence on the cell cycle by targeting regulators of a critical checkpoint in late G(1). Once cells pass this checkpoint, they are fated to replicate DNA and divide. Cancer cells subvert controls at work at this restriction point and remain in cycle. Previously, we showed that RACK1 inhibits the oncogenic Src tyrosine kinase and NIH 3T3 cell growth. RACK1 inhibits cell growth, in part, by prolonging G(0)/G(1). Here we show that RACK1 overexpression induces a partial G(1) arrest by suppressing Src activity at the G(1) checkpoint. RACK1 works through Src to inhibit Vav2, Rho GTPases, Stat3, and Myc. Consequently, cyclin D1 and cyclin-dependent kinases 4 and 2 (CDK4 and CDK2, respectively) are suppressed, CDK inhibitor p27 and retinoblastoma protein are activated, E2F1 is sequestered, and G(1)/S progression is delayed. Conversely, downregulation of RACK1 by short interference RNA activates Src-mediated signaling, induces Myc and cyclin D1, and accelerates G(1)/S progression. RACK1 suppresses Src- but not mitogen-activated protein kinase-dependent platelet-derived growth factor signaling. We also show that Stat3 is required for Rac1 induction of Myc. Our results reveal a novel mechanism of cell cycle control in late G(1) that works via an endogenous inhibitor of the Src kinase.
...
PMID:RACK1 regulates G1/S progression by suppressing Src kinase activity. 1525 45

The epidermal growth factor (EGF) plays a role in the development of prostate cancer, which becomes essential after androgen resistance has emerged. The EGF receptor (EGFR) is therefore a potential target for anticancer therapy. We evaluated the effects of ZD1839 ('Iressa'), an orally active EGFR-tyrosine kinase inhibitor, on prostate cancer cell lines. The effects of ZD1839 were evaluated on the anchorage dependent and independent growth of androgen-responsive (LNCaP) and androgen-independent (DU145 and PC3) cells by a cell proliferation assay, cell counting, and soft agar analysis. Flow cytometric analysis and Western blotting were used to assess the effects on the cell-cycle and on protein expression levels, respectively. ZD1839 caused a dose- and time-dependent growth inhibition in all three cell lines. A dose-dependent supra-additive increase in growth inhibition was observed when ZD1839 was combined with the antiandrogen flutamide or ionizing radiation (IR). The antiproliferative effect of ZD1839 was mainly cytostatic and associated with a block in the G(0)/G(1) phase of the cell-cycle, evident after about 12 h of treatment. In the DU145 cells this block was associated with an increase in expression of the CDK inhibitor p27(Kip1), both in the cytoplasmic and nuclear fractions. The increase in p27(Kip1) was not evident in the LNCaP and PC3 cells. No changes were observed in the expression of cyclin D1 protein. These results demonstrate the antiproliferative effects of ZD1839 on the growth of prostate cancer cells and suggest that inhibition of EGFR-associated signal transduction pathway might represent a promising novel therapeutic strategy for the treatment of prostate cancer.
...
PMID:Targeted inhibition of the epidermal growth factor receptor-tyrosine kinase by ZD1839 ('Iressa') induces cell-cycle arrest and inhibits proliferation in prostate cancer cells. 1528 Oct 92

Epithelial growth factor receptor (EGFR) has been proposed as a target for anticancer therapy. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is under clinical use in cancer patients. However, the molecular mechanisms involved in ZD1839-mediated anticancer effects remain largely uncharacterized. In this study, exposure of human lung adenocarcinoma A549 cells to ZD1839 caused G1 arrest, and subsequently induced apoptosis. Moreover, ZD1839 increased the protein levels of p27(KIP1) and retinoblastoma-related Rb2/p130 while decreased the expression of cyclin-dependent kinase-2 (CDK2), CDK4, CDK6 and cyclin-D1, cyclin-D3. In vitro kinase assay showed that ZD1839 decreased these CDKs expression in A549 cells, leading to significantly reduce their kinase activities. In addition, ZD1839-induced death of A549 cells with characteristics of apoptosis including apoptotic morphological changes, DNA fragmentation and enhancement of TUNEL-positive cell. These events were accompanied by a marked increase of Fas protein expression, and activation of caspase-2, -3, -8. Co-treatment of cells with Fas antagonist antibody significantly blocked ZD1839-induced apoptosis. Caspase-8 and caspase-3 inhibitors, but not a caspase-9 inhibitor, were also capable of restoring cell viability. Our results indicate that downregulation of the expression and function of CDK2, CDK4, CDK6, cyclin-D1 and cyclin-D3, as well as upregulation of p27(KIP1) and pRb2/p130, are strong candidates for the cell cycle regulator that arrests ZD1839-treated A549 cells at G1 phase. Furthermore, upregulation of Fas appears to play a major role in the initiation of ZD1839-induced apoptosis, activation of caspase-8/caspase-3 cascade is involved in the execution phase of this death program.
...
PMID:Molecular mechanisms of ZD1839-induced G1-cell cycle arrest and apoptosis in human lung adenocarcinoma A549 cells. 1534 35

Previous studies have shown that cerebral hypoxia results in increased tyrosine phosphorylation of cerebral cortical cell membrane proteins as well as nuclear membrane anti-apoptotic protein, Bcl-2. The present study tests the hypothesis that hypoxia results in increased protein tyrosine kinase activity in cortical cell membranes of newborn piglets and that the inhibition of neuronal NOS by administration of 7-nitroindazole sodium salt (7-NINA), a selective inhibitor of nitric oxide synthase (NOS), will prevent the hypoxia-induced increase in protein tyrosine kinase activity. To test this hypothesis, protein tyrosine kinase activity was determined in cerebral cortical membranes of 2- to 4-day-old newborn piglets divided into normoxic (n=6), hypoxic (n=5) and 7-NINA-treated hypoxic (n=5) (7-NINA, 1mg/kg, i.p., prior to hypoxia) groups. Tissue hypoxia was achieved by exposing the animals to an FiO(2) of 0.07 for 60 min and was documented biochemically by determining tissue ATP and phosphocreatine (PCr) levels. Cortical P(2) membranes were isolated and protein tyrosine kinase activity determined by (33)P incorporation into a specific peptide substrate for 15 min at 37 degrees C in a medium containing 100 mM HEPES, pH 7.0, 1mM EDTA, 125 mM MgCl(2), 25 mM MnCl(2), 2mM DTT, 0.2 mM sodium orthovanadate, 2mM EGTA, 150 microM tyrosine kinase peptide substrate [Lys 19] cdc2(6-20)-NH(2), (33)P-ATP, and 10 microg of membrane protein. Protein tyrosine kinase activity was determined by the difference between (33)P incorporation in the presence and absence of specific peptide substrate and expressed as pmol/mg protein/h. The ATP values in the normoxic, hypoxic and 7-NINA-treated hypoxic animals were ATP: 4.57+/-0.45 micromol/g, 1.29+/-0.23 micromol/g (p<0.05 versus normoxic) and 1.50+/-0.14 micromol/g brain (p<0.05 versus normoxic), respectively. The PCr values in the normoxic, hypoxic and 7-NINA-treated hypoxic animals were: 3.77+/-0.36 micromol/g, 0.77+/-0.13 micromol/g (p<0.05 versus normoxic) and 1.02+/-0.24 micromol/g brain (p<0.05 versus normoxic), respectively. Protein tyrosine kinase activity in the normoxic, hypoxic and the 7-NINA-treated groups was 378+/-77 pmol/mg protein/h, 854+/-169 pmol/mg protein/h (p<0.05 versus normoxic) and 464+/-129 pmol/mg protein/h (p<0.05 versus hypoxic), respectively. The data show that cerebral tissue hypoxia results in increased protein tyrosin kinase activity in cortical membranes of newborn piglets and pretreatment with 7-NINA prevents the hypoxia-induced increase in protein tyrosine kinase activity. We conclude that the hypoxia-induced increase in protein tyrosine kinase activity is NO-mediated. We propose that the hypoxia-induced increase in protein tyrosine kinase activity leading to increased phosphorylation of Bcl-2 is a critical link to hypoxic neuronal injury pathway.
...
PMID:Effect of hypoxia on protein tyrosine kinase activity in cortical membranes of newborn piglets--the role of nitric oxide. 1553 Oct 99

Chronic B cell malignancies are often chemoresistant and the development of new therapeutic modalities is a high priority. Many B cell malignancies have autocrine production of IL-10, which regulates B cell growth and differentiation. Here we demonstrate that the soy isoflavone genistein, a tyrosine kinase inhibitor, rapidly decreased IL-10 secretion followed by upregulation of IFNgamma and inhibition of cell proliferation with pre-dominantly G2 arrest. The antiproliferative effects of genistein were reversed by the addition of exogenous IL-10. Genistein downregulated cdc25C and cdk1 as well as anti-apoptotic proteins survivin and Ian-5. After genistein withdrawal, the G2M arrested cells reentered the cell cycle and underwent apoptosis, which was significantly augmented by fludarabine. We conclude that genistein can sensitize malignant B cells to the action of other chemotherapeutic agents by modulating the cytokine profile and controlling cell cycle progression.
...
PMID:Genistein induces G2 arrest in malignant B cells by decreasing IL-10 secretion. 1561 48

Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G(1) cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27(Kip1) and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27(Kip1) at the level of transcription. We further show that BCR-ABL also regulates p27(Kip1) protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27(Kip1) by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27(Kip1). We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27(Kip1) mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27(Kip1) contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27(Kip1) and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.
...
PMID:BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells. 1583 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---