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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin (Epo), along with its receptor EpoR, is the principal regulator of red cell development. Upon Epo addition, the EpoR signaling through the Janus kinase 2 (JAK2) activates multiple pathways including Stat5, phosphoinositide-3 kinase (PI-3K)/Akt, and p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in cytokine receptor signaling. Here, we showed that Lnk-deficient mice have elevated numbers of erythroid progenitors, and that splenic erythroid colony-forming unit (CFU-e) progenitors are hypersensitive to Epo. Lnk(-/-) mice also exhibit superior recovery after erythropoietic stress. In addition, Lnk deficiency resulted in enhanced Epo-induced signaling pathways in splenic erythroid progenitors. Conversely, Lnk overexpression inhibits Epo-induced cell growth in 32D/EpoR cells. In primary culture of fetal liver cells, Lnk overexpression inhibits Epo-dependent erythroblast differentiation and induces apoptosis. Lnk blocks 3 major signaling pathways, Stat5, Akt, and MAPK, induced by Epo in primary erythroblasts. In addition, the Lnk Src homology 2 (SH2) domain is essential for its inhibitory function, whereas the conserved tyrosine near the C-terminus and the pleckstrin homology (PH) domain of Lnk are not critical. Furthermore, wild-type Lnk, but not the Lnk SH2 mutant, becomes tyrosine-phosphorylated following Epo administration and inhibits EpoR phosphorylation and JAK2 activation. Hence, Lnk, through its SH2 domain, negatively modulates EpoR signaling by attenuating JAK2 activation, and regulates Epo-mediated erythropoiesis.
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PMID:Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. 1570 83

Erythropoietin (Epo) plays a central role in erythropoiesis but also has neuroprotective properties. Recently, Epo-related neuroprotective studies used a hypoxic-ischemic neonatal model, which is different from focal stroke, a frequent cause of neonatal brain injury. We report on the effects of Epo treatment given after focal stroke and its potential neuroprotective mechanisms in postnatal day 7 rats with focal cerebral ischemia (FCI) achieved by occlusion of the middle cerebral artery. The experimental groups included sham operation, FCI plus vehicle, and FCI plus Epo. In the Epo-treated group, pups received a single intraperitoneal injection of 1000 U/kg 15 min after FCI or three injections of 100, 1000, or 5000 U/kg, starting at 15 min and repeated at 1 and 2 d after FCI. Epo treatment produced significant reductions in the mean infarct area and volume at 1 and 3 d after FCI, demonstrated by 2,3,5-triphenyltetrazolium chloride staining. Terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining showed a markedly reduced number of TUNEL-positive cells in the Epo-treated group when compared with the vehicle control 3 d after FCI (p<0.01). The most effective dose after FCI was 1000 U/kg for 3 d. Immunoanalyses showed that Epo induced a significant increase in phosphorylated Janus kinase 2 and signal transducer and activator of transcription-5 expressions at 1 and 3 d and up-regulated Bcl-xL expression by 24 h after FCI but did not affect Epo receptor or NF-kappaB expression. In conclusion, Epo given after FCI in neonatal rats provides significant neuroprotection, mediated possibly by activation of the Janus kinase-signal transducer and activator of transcription-Bcl-xL signaling pathways.
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PMID:Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats. 1571 73

Clinical research evidence on outcomes of using epoetin (EPO) to treat or prevent anemia in oncology has recently been systematically synthesized to provide a scientific foundation for developing and implementing clinical practice guidelines. Two groups have distinguished themselves by their meticulous research methods, the Blue Cross and Blue Shield Association Technology Evaluation Center (BCBSA TEC) and the Cochrane Review Group (CRG), and have summarized existing research evidence on the role of EPO in anemia associated with cancer treatment. An ASH/ASCO (American Society of Hematology/American Society of Clinical Oncology) panel has used the BCBSA TEC review to develop practice guidelines on the use of EPO in patients with cancer. The ASH/ASCO guideline panel identified eight important clinical circumstances for which use of EPO in oncology might be considered and used the BCBSA TEC evidence review to formulate evidence-based guidelines that support use of EPO. Both BCBSA TEC and CRG found solid evidence exists to show that EPO improves hemoglobin levels and reduce the risk for transfusion. The ASH/ASCO panel concluded that best empirical evidence exists to support the use of EPO to correct anemia due to chemotherapy if Hgb</=10g/dl. In other clinical circumstances the ASH/ASCO panel made recommendations either by extrapolating evidence from similar settings or relied on expert opinion since sufficient evidence was lacking. Both BCBSA TEC and CRG also concluded that limited evidence exists that EPO improves symptoms, fatigue, or quality of life, particularly when anemia is less severe. The finding from these systematic reviews are also reflected in the opinion of the ASH/ASCO guidelines panel, which also concluded that better evidence is needed to support use of EPO in oncology under these circumstances. In this paper, the findings from the guidelines set by ASH/ASCO that were culled from systematic reviews by BCBSA TEC and the Cochrane Review are compared and contrasted.
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PMID:Erythropoietin use in oncology: a summary of the evidence and practice guidelines comparing efforts of the Cochrane Review group and Blue Cross/Blue Shield to set up the ASCO/ASH guidelines. 1579 20

Erythropoietin (Epo) is used for managing anemia in cancer patients. However, recent studies have raised concerns for this practice. We investigated the expression and function of Epo and the erythropoietin receptor (EpoR) in tumor biopsies and cell lines from human head and neck cancer. Epo responsiveness of the cell lines was assessed by Epoetin-alpha-induced tyrosine phosphorylation of the Janus kinase 2 (JAK2) protein kinase. Transmigration assays across Matrigel-coated filters were used to examine the effects of Epoetin-alpha on cell invasiveness. In 32 biopsies, we observed a significant association between disease progression and expression of Epo and its receptor, EpoR. Expression was highest in malignant cells, particularly within hypoxic and infiltrating tumor regions. Although both Epo and EpoR were expressed in human head and neck carcinoma cell lines, only EpoR was upregulated by hypoxia. Epoetin-alpha treatment induced prominent JAK2 phosphorylation and enhanced cell invasion. Inhibition of JAK2 phosphorylation reduced both basal and Epo-induced invasiveness. Our findings support a role for autocrine or paracrine Epo signaling in the malignant progression and local invasiveness of head and neck cancer. This mechanism may also be activated by recombinant Epo therapy and could potentially produce detrimental effects in rhEpo-treated cancer patients.
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PMID:Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. 1596 6

Erythropoietin (EPO) is the major regulator of erythropoiesis. EPO's actions have been shown to be antiapoptotic and dependent on JAK2 signaling and Akt phosphorylation. These effects serve as link between EPO and heme oxygenase-1 (HO-1). HO-1 is an inducible enzyme with potent antioxidant and antiapoptotic activities which are regulated by Akt signaling. EPO's ability to alter cellular systems that involve apoptosis and oxidants suggests that EPO treatments are likely to have multiple and different effects which may start a good news/bad news story. Recombinant human EPO is the recognized treatment of choice to address anemia and to stimulate erythropoiesis in chronic renal failure patients, through its antiapoptotic action which likely involves HO-1. On the other hand, EPO treatment to address anemia in cancer patients, while providing significant improvements in cancer patients' quality of life, its effects on survival are equivocal, likely due to its linkage with HO-1. Two clinical trials of EPO in patients with solid tumors have, in fact, shown specific negative effects on survival. However, EPO's effect on tumor growth and survival is not uniformily pro growth and pro survival, as EPO may act synergistically with chemotherapy to induce apoptosis. Finally, compounds have been synthesized that do not trigger EPO receptor and thus may allow experimental distinction and, therefore, at least potentially affect at the clinical level the tissue-protective effects of EPO (e.g., antiapoptosis) without provoking its other potentially detrimental effects.
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PMID:A role for heme oxygenase-1 in the antioxidant and antiapoptotic effects of erythropoietin: the start of a good news/bad news story? 1655 68

The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.
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PMID:Characterization of murine JAK2V617F-positive myeloproliferative disease. 1714 59

Progressive ankylosis (Ank and the human homolog, ANKH) is a transmembrane protein which regulates transport of inorganic pyrophosphate (PPi). ank/ank mice with a mutated ank gene, have calcification and bone ankylosis of the affected joints. In the course of studying these mutant mice, we found that they have microcytosis. These mutant mice have lower mean red blood cell volume (MCV) and lower hemoglobin content in red cells (mean corpuscular hemoglobin, MCH) than normal mice. Using quantitative real-time PCR analysis, we showed that Ank was expressed in the E/Meg bipotent precursor, BFU-E, CFU-E, but there was no Ank expression in the hemoglobinizing erythroblasts. Stable ANKH transfectants in K562 cells highly expressed two immature erythroid cell markers, E-cadherin and endoglin. Enhanced Erythropoietin (Epo) expression and downregulation of SHP-1 were detected in these transfectants. Consequently, the autocrine Epo-EpoR signaling pathway was activated, as evidenced by higher p-Tyr JAK2, p-Tyr EpoR and p-Tyr STAT5B in the ANKH transfectants. Our results revealed a novel function of ANKH in the promotion of early erythroid differentiation in K562 cells. We also showed that ank/ank mice have lower serum levels of Epo than the normal littermates, and this is the likely cause of microcytosis in these mutant mice.
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PMID:Microcytosis in ank/ank mice and the role of ANKH in promoting erythroid differentiation. 1795 Jul 26

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.
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PMID:Asialoerythropoietin prevents contrast-induced nephropathy. 1818 58

Erythropoietin (Epo) induces erythrocytosis by suppressing erythroid progenitor cell apoptosis through the Janus-activated kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Since apoptosis contributes to cisplatin (CP)-induced nephrotoxicity and Epo receptors (EpoR) are expressed in the kidney, we examined the role of antiapoptosis in recombinant human erythropoietin (rHuEpo)-mediated renal protection. In human renal proximal tubular epithelial (RPTE) cells in culture, rHuEpo, but not inactive rHuEpo (I-rHuEpo), the receptor-binding sites of which are mutated, caused a significant reduction in CP-induced apoptosis at > or = 100 U/ml. rHuEpo, but not I-rHuEpo, increased STAT5 and Akt/PKB phosphorylation, demonstrating functional EpoR expression on RPTE cells. Furthermore, the JAK2 inhibitor tyrphostin AG-490 attenuated rHuEpo protection, suggesting a role of the JAK-STAT pathway in rHuEpo-mediated antiapoptosis. In rats, intravenous administration of 5,000 U/kg rHuEpo, but not an equivalent peptide mass of I-rHuEpo, before a single 5.5 mg/kg iv injection of CP, significantly increased hematocrit (Hct) and reduced the CP-induced increase in serum creatinine. Serum creatinine on day 4 was 3.4 +/- 0.3, 1.9 +/- 0.3, and 3.5 +/- 0.4 mg/dl in the CP, CP + rHuEpo, and CP + I-rHuEpo groups, respectively. Similarly, darbepoietin-alpha (DA), a hyperglycosylated analog of rHuEpo with prolonged in vivo activity when injected at 25 microg/kg iv before CP, significantly increased Hct and reduced serum creatinine. Renal clearance studies based on glomerular filtration rate and renal blood flow confirmed the significant renal protection by DA against CP. Tubular apoptosis and necrosis were significantly reduced in the kidneys of the CP + DA vs. the CP + saline group. Moreover, the equalization of Hct by venesection did not abrogate the DA-mediated renal protection. Administration of DA 48 h after CP injection also conferred significant renal protection. Thus our experiments confirm a role for erythropoiesis-stimulating proteins, including the new analog DA, in limiting CP-induced nephrotoxicity and suggest that antiapoptosis via the Epo-EpoR interaction is an important mechanism for renal protection.
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PMID:Antiapoptotic properties of erythropoiesis-stimulating proteins in models of cisplatin-induced acute kidney injury. 1838 71

Recombinant human erythropoietin is widely used to treat anemia associated with cancer and with the myelosuppressive effects of chemotherapy, particularly platinum-based regimens. Erythropoietin is the principal regulator of erythroid cell proliferation, differentiation, and apoptosis. Recently, the antiapoptotic and proliferative effects of erythropoietin on nonhematopoietic cells were also established. We now show the effect of erythropoietin treatment on the response of A2780 and SKOV3 ovarian carcinoma cell lines to photodynamic therapy (PDT) using hypericin. SKOV3 exhibited an increased resistance to hypericin when cells were treated with erythropoietin. This resistance was reversed by treatment of SKOV3 cells with the specific Janus kinase 2 kinase inhibitor AG490 or the tyrosine kinase inhibitor genistein. These results support a role for the specific erythropoietin-induced Janus kinase 2/STAT signal transduction pathway in PDT resistance. Evidence of erythropoietin signaling was obtained by the demonstration of Akt phosphorylation in both A2780 and SKOV3 cells. Erythropoietin-treated SKOV3 cells exhibited decreased apoptosis induced by hypericin, an effect that was blocked by the phosphoinositide 3-kinase/Akt inhibitor wortmannin. These results may have important implications for ovarian cancer patients undergoing PDT and receiving erythropoietin.
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PMID:Erythropoietin inhibits apoptosis induced by photodynamic therapy in ovarian cancer cells. 2037 27


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