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

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since protein kinases have been found to be implicated in many diseases, first of all malignancies, they are considered as promising therapeutic targets. Many protein kinase inhibitors have been designed by now. These molecules have a low molecular weight and most of them bind to protein kinases competing with ATP for the ATP-binding site. Some protein kinase inhibitors currently undergo clinical trials or have already been successfully introduced into treatment as exemplified by Bcr-Abl, c-kit and PDGFR inhibitor imatinib mesylate (Gleevec), flavopiridol and roscovitine, inhibitors of cyclin-dependent kinases, or erlotinib and gefitinib inhibiting EGFR. Discovery of these molecules seems to begin a new era in medicine, especially oncology. Targeting protein kinases represents a promising approach and gives us new hopes of effective non-invasive cancer treatment.
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PMID:Protein kinase inhibitors. 1711 85

Receptor tyrosine kinase (RTK) c-Kit signalling is crucial for the proliferation, survival and differentiation of haematopoietic stem cells (HSCs). To further understand the mechanisms underlying these events we explored how the downstream mediators interact. The present study investigated the function of conventional protein kinase Cs (c-PKC) in c-Kit mediated signalling pathways in HSC-like cell lines. This analysis supported earlier findings, that steel factor (SF) activates c-PKC, extracellular signal-regulated kinase (Erk) and protein kinase B (PKB). The present results were consistent with an important role of c-PKC in the positive activation of Erk and for proliferation. Further, it was observed that c-PKC negatively regulated PKB activity upon SF stimulation, indicating that c-PKC acts as a suppressor of c-Kit signalling. Finally, these observations were extended to show that c-PKC mediated the phosphorylation of the endogenous c-Kit receptor on serine 746, resulting in decreased overall tyrosine phosphorylation of c-Kit upon SF stimulation. This report showed that this specific feedback mechanism of c-PKC mediated phosphorylation of the c-Kit receptor has consequences for both proliferation and survival of HSC-like cell lines.
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PMID:Haematopoietic progenitor cells utilise conventional PKC to suppress PKB/Akt activity in response to c-Kit stimulation. 1715 94

Several studies have suggested that the cyclin-dependent kinase (CDK) inhibitor p21 plays a crucial role in regulating hematopoietic stem and progenitor pool size. To allow assessment of long-term stem cell functioning in vivo, we have backcrossed a p21 null allele to C57BL/6 (B6) mice, the most commonly used mouse strain in hematopoietic stem cell research. In various in vitro assays, the homozygous deletion of the p21 allele did not affect the number of hematopoietic cells in B6 mice. Furthermore, the competitive repopulation ability was not different between p21-deficient and wild-type stem cells from both young and aged (20-month-old) mice. These results show that p21 is not essential for regulation of stem cell number in steady state. When proliferative stress was applied on p21-deficient stem cells by serial transplantation of 1,500 Lin(-)Sca-1(+)c-kit(+) (LSK) cells, again no detrimental effect was observed on cobblestone area-forming cell (CAFC) frequency and competitive repopulating ability. However, when bone marrow cells from mice that received 2 Gy of irradiation were transplanted, p21 deficiency resulted in a more than fourfold reduction in competitive repopulation index. Finally, we did not find major differences in cell cycle status and global gene expression patterns between LSK cells from p21-deficient and wild-type mice. Our findings indicate that the background of mice used for studying the function of a gene by genetic modification may determine the outcome. Cumulatively, our data fail to support the notion that p21 is essential for stem cell function during steady-state hematopoiesis, but may be relatively more important under conditions of cellular stress.
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PMID:A Limited role for p21Cip1/Waf1 in maintaining normal hematopoietic stem cell functioning. 1717 62

Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms).
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PMID:Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. 1717 82

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcoma, such as Ewing/PNET, desmoplastic small round cell sarcoma and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensitive and neoadjuvant protocols regardless of size or overt metastatic disease. A limited number of effective agents available for the treatment of patients with metastatic adult soft-tissue sarcoma exists, which have failed anthracyline and ifosfamide-based chemotherapy. Most other high-grade (grading >I) so-called adult-type soft-tissue sarcomas such as fibro, lipo, pleomorphic and synovial sarcoma are treated with a anthracycline-based regimen with or without ifosfamide as front-line therapy. In this review, the therapeutic activities of drugs currently available as second-line treatment in patients with metastatic soft tissue sarcoma are summarized, providing an overview of contentious or emerging treatment issues. In relapsed 'adult-type' soft-tissue sarcomas trofosfamide, gemcitabine and ecteinascidin (ET-743) appear to be drugs associated with moderate activity and an acceptable toxicity profile. An interesting finding to be noted is that the different drugs have particular effects in distinct subtypes of soft-tissue sarcoma; however, it has to be taken into account that the number of patients included in those phase II trials are limited. The role of the newer agents (e.g. patupilone derivates, brostallicin) is currently not definable. The so-called selective therapy targeting vascular endothelial growth factor (receptor), epidermal growth factor receptor, c-kit, Raf kinase or platelet-derived growth factor receptor and bcl-2 antisensing, proteasome, protein kinase C/B, and mammalian target of rabamycin inhibition will continue to be tested in gastrointestinal stromal tumors patients refractory to imatinib mesylate as well as in selected sarcoma subtypes.
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PMID:Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines. 1726 55

Gab2 is an important adapter molecule for cytokine signaling. Despite its major role in signaling by receptors associated with hematopoiesis, the role of Gab2 in hematopoiesis has not been addressed. We report that despite normal numbers of peripheral blood cells, bone marrow cells, and c-Kit(+)Lin(-)Sca-1(+) (KLS) cells, Gab2-deficient hematopoietic cells are deficient in cytokine responsiveness. Significant reductions in the number of colony-forming units in culture (CFU-C) in the presence of limiting cytokine concentrations were observed, and these defects could be completely corrected by retroviral complementation. In earlier hematopoiesis, Gab2-deficient KLS cells isolated in vitro responded poorly to hematopoietic growth factors, resulting in an up to 11-fold reduction in response to a cocktail of stem cell factor, flt3 ligand, and thrombopoietin. Gab2-deficient c-Kit(+)Lin(-) cells also demonstrate impaired activation of extracellular signal-regulated kinase (ERK) and S6 in response to IL-3, which supports defects in activating the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) signaling cascades. Associated with the early defects in cytokine response, competitive transplantation of Gab2(-/-) bone marrow cells resulted in defective long-term multilineage repopulation. Therefore, we demonstrate that Gab2 adapter function is intrinsically required for hematopoietic cell response to early-acting cytokines, resulting in defective hematopoiesis in Gab2-deficient mice.
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PMID:Abnormal hematopoiesis in Gab2 mutant mice. 1737 39

Using a Transwell chamber as migration assay for mouse primordial germ cells (PGCs), we show here that these cells posses directional migration in the absence of somatic cell and defined matrix support and in response to a Kit ligand (KL) gradient or medium conditioned by Aorta/Gonad/Mesonephros and gonadal ridges. Other putative PGC chemoattractants such as SDF1 and TGFbeta did not exert any attractive action on PGCs. The chemoattractant activity of KL and conditioned medium was also evidenced by their ability to stimulate actin reorganization in PGCs. In the aim to identify downstream signaling pathways governing KL chemoattraction on PGCs, we demonstrated that in such cells KL rapidly (5 min) increased autophosphorylation of its receptor c-Kit and caused phosphorylation of the serine-threonine kinase AKT through the action of PI3K. 740Y-P peptide, a direct activator of PI3 kinase, stimulated PGC migration at levels similar to those elicited by KL. LY294002 (a specific inhibitor of PI3K) abolished KL-dependent PGC migration or the chemoattractant activity of the conditioned medium and inhibited AKT phosphorylation; Src kinase inhibitors PP2 and SU6656, caused significant reduction of the KL-dependent PGC migration and AKT phosphorylation, while U0126, a selective inhibitor of the MEK/ERK protein kinase cascade, reduced PGC migration and AKT phosphorylation at lesser extent. SU6656 completely abolished the chemoattractant activity of the conditioned medium. Finally, SB202190 (a p38 inhibitor) and rapamycin (mTOR inhibitor) did not affect PGC migration. In addition, to demonstrate that somatic cells are not essential for PGC motility and directional migration, we evidenced a novel role for KL as PGC chemoattractant and for PI3K/AKT and Src kinase, as players involved in the activation of the PGC migratory machinery and likely important for their directional movement towards the gonadal ridges.
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PMID:Chemoattractant action and molecular signaling pathways of Kit ligand on mouse primordial germ cells. 1746 86

We previously demonstrated the simultaneous induction of urokinase-type plasminogen activator and interleukin-8, a CXC chemokine, in doxorubicin-treated human NCI-H69 small cell lung cancer cells in which extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase might be involved. NCI-H69 cells expressed one of the receptor tyrosine kinases, c-Kit, and STI571 inhibited the cell growth and stem cell factor-induced phosphorylation of c-Kit. We therefore investigated the effects of STI571 on the expression of urokinase-type plasminogen activator and interleukin-8 in NCI-H69 cells. Microarray analysis revealed the gene induction of not only urokinase-type plasminogen activator and interleukin-8, but also early growth response-1 in STI571-treated cells. Treatment with STI571 resulted in the induction of phosphorylation of all three mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and stress-activated protein kinase/c-jun N-terminal protein kinase. U0126, an inhibitor against extracellular signal-regulated kinase 1/2, however, only inhibited the STI571-induced interleukin-8 accumulation. Urokinase-type plasminogen activator and interleukin-8 are important biological factors in tumor cell regulation; STI571 may therefore influence many aspects of tumor cell biology through inducing urokinase-type plasminogen activator and interleukin-8, in which the induction of early growth response-1 expression and extracellular signal-regulated kinase 1/2 phosphorylation might be involved.
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PMID:Induction of urokinase-type plasminogen activator, interleukin-8 and early growth response-1 by STI571 through activating mitogen activated protein kinase in human small cell lung cancer cells. 1758 16

The sustained differentiation of T cells in the thymus cannot be maintained by resident intrathymic (IT) precursors and requires that progenitors be replenished from the bone marrow (BM). In patients with severe combined immunodeficiency (SCID) treated by hematopoietic stem cell transplantation, late T-cell differentiation defects are thought to be due to an insufficient entry of donor BM progenitors into the thymus. Indeed, we find that the intravenous injection of BM progenitors into nonconditioned zeta-chain-associated protein kinase 70 (ZAP-70)-deficient mice with SCID supports short- but not long-term thymopoiesis. Remarkably, we now show that the IT administration of these progenitors produces a significant level of donor-derived thymopoiesis for more than 6 months after transplantation. In contrast to physiologic thymopoiesis, long-term donor thymopoiesis was not due to the continued recruitment of progenitors from the BM. Rather, IT transplantation resulted in the unique generation of a large population of early c-Kit(high) donor precursors within the thymus. These ZAP-70-deficient mice that received an IT transplant had a significantly increased prothymocyte niche compared with their untreated counterparts; this phenotype was associated with the generation of a medulla. Thus, IT administration of BM progenitors results in the filling of an expanded precursor niche and may represent a strategy for enhancing T-cell differentiation in patients with SCID.
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PMID:Intrathymic transplantation of bone marrow-derived progenitors provides long-term thymopoiesis. 2004 Jul 62

In diabetic patients and animal models of diabetes mellitus (DM), circulating endothelial progenitor cell (EPC) number is lower than in normoglycaemic conditions and EPC angiogenic properties are inhibited. Stromal cell derived factor-1 (SDF-1) plays a key role in bone marrow (BM) c-kit(+) stem cell mobilization into peripheral blood (PB), recruitment from PB into ischemic tissues and differentiation into endothelial cells. The aim of the present study was to examine the effect of DM in vivo and in vitro, on murine BM-derived c-kit(+) cells and on their response to SDF-1. Acute hindlimb ischemia was induced in streptozotocin-treated DM and control mice; circulating c-kit(+) cells exhibited a rapid increase followed by a return to control levels which was significantly faster in DM than in control mice. CXCR4 expression by BM c-kit(+) cells as well as SDF-1 protein levels in the plasma and in the skeletal muscle, both before and after the induction of ischemia, were similar between normoglycaemic and DM mice. However, BM-derived c-kit(+) cells from DM mice exhibited an impaired differentiation towards the endothelial phenotype in response to SDF-1; this effect was associated with diminished protein kinase phosphorylation. Interestingly, SDF-1 ability to induce differentiation of c-kit(+) cells from DM mice was restored when cells were cultured under normoglycaemic conditions whereas c-kit(+) cells from normoglycaemic mice failed to differentiate in response to SDF-1 when they were cultured in hyperglycaemic conditions. These results show that DM diminishes circulating c-kit(+) cell number following hindlimb ischemia and inhibits SDF-1-mediated AKT phosphorylation and differentiation towards the endothelial phenotype of BM-derived c-kit(+) cells.
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PMID:Altered SDF-1-mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus. 2019 80


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