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)

Intracellular kinases play important roles in signal transduction and are involved in the surface receptor-mediated regulation of cellular functions, including mitogenesis. In the present study, we examined the possible involvement of various protein kinases in the passage of a mitogenic signal from the cell surface to the nucleus of Nb2 cells, a rat nodal lymphoma cell line in which prolactin is a mitogen. Following a prolactin challenge, various kinase activities were monitored at short intervals in different cellular fractions over a 60 min period. Protein kinase C (PKC) activity in the cytosolic fraction rapidly declined to 50% of its original activity within the first 30 min, while PKC activity in the nuclear fractions increased sharply, reaching its highest level by 30 min following a prolactin challenge. There were also increases in both casein kinase and protein tyrosine kinase (PTK) activities in the nuclear fractions during the first 30 min following a prolactin challenge that paralleled PKC activity. The activities of all three kinases declined thereafter, reaching levels close to their respective basal values by 60 min following initiation of prolactin treatment. These observations suggest the possibility that multiple protein kinases may be involved in mitogenic signal transduction for prolactin in Nb2 cells.
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PMID:Nuclear accumulation of multiple protein kinases during prolactin-induced proliferation of Nb2 rat lymphoma cells. 861 65

Effects of acetylcholine (ACh) on the L-type calcium current were examined in isolated atrioventricular nodal cells that exhibited spontaneous contractions. ACh (0.1 to 10 microM) inhibited basal calcium current dose-dependently. This inhibition was eliminated by dialysis with 8Br cAMP or cAMP-dependent kinase inhibitory peptide. Both extracellular N-ethylmaleimide 50 microM and intracellular GDPssS 0.2 mM abolished the ACh effect. Dialysis with cGMP or NG-monomethyl-L-arginine did not significantly affect ACh inhibition of basal calcium current. Similarly, cGMP-dependent protein kinase inhibitor KT5823 (1 microM) and the type II phosphodiesterase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (30 microM) did not attenuate the ACh effect. Therefore, ACh inhibits the basal calcium current in the atrioventricular node mainly by suppressing cAMP synthesis through the inhibitory GTP-binding protein.
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PMID:Muscarinic inhibition of basal L-type calcium current in pacemaker cells from the rabbit atrioventricular node. 944 1

Cell cycle deregulation can occur at different levels in cancer. In human breast cancer it includes overexpression of cyclins D1 and E, down-regulation of cyclin-dependent kinase inhibitors and inactivation of the retinoblastoma and p53 tumor suppressor proteins. Telomerase activity is strongly associated with an immortal phenotype and expression of telomerase is linked to the cell cycle. We have recently demonstrated a connection between specific cell cycle defects within the pRB pathway and levels of telomerase activity in breast cancer. In the present study, 106 tumors were investigated for p53 gene and protein status. By single strand conformation polymorphism (SSCP) analysis, 15% showed mutations within exons 5-8 and by immunohistochemistry (IHC), 29% were p53 positive. Tumors with a telomerase activity above median (i.e., telomerase(high)) were significantly associated with p53 protein accumulation (p = 0.004), but not with p53 gene mutations. The strongest telomerase expression was found in tumors with p53 protein accumulation. Morphologic grade, estrogen and progesterone receptor expression differed significantly between the telomerase(high) and telomerase(low) groups (p < 0.0001, p = 0.016 and p = 0.046, respectively), but no difference was observed for stage or nodal status. Telomerase(high) tumors were significantly associated with a poor prognosis for node-negative (N0) patients (p = 0.008), but not for node-positive (N+) patients, whereas the opposite was demonstrated for tumors with p53 accumulation. The survival data indicated that telomerase expression has biological importance particularly for N0 tumors, suggesting that telomerase(low) tumors constitute a group of "pre-immortalized" tumors with a good prognosis.
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PMID:Telomerase activity in relation to p53 status and clinico-pathological parameters in breast cancer. 969 24

In the USA, the incidence of kidney cancer has increased 43% since 1973. The risk of the disorder is higher in men than in women and increases with age. The von Hippel-Lindau tumour-suppressor gene is inactivated in over 75% of sporadic cases. Metastatic disease is present in 20-30% of patients at diagnosis. Early-stage kidney cancer is treated with a radical nephrectomy, but under certain circumstances a partial nephrectomy may be done. Tumour thrombus into the vena cava or right atrium requires thoracotomy and hypothermic circulatory arrest for successful removal of the tumour, but should not be done if extensive nodal or frank metastatic disease is present. Interleukin-2 is the systemic therapy of choice for metastatic disease at present, with long-term relapse-free survival of 5-8%. Several treatments including anti-angiogenesis drugs, cyclin-dependent kinase inhibitors, and differentiating agents are being actively investigated. Fluorouracil has a 10-15% response rate, and surgical excision of isolated metastases should always be considered. Therapy for metastatic renal cancer remains inadequate, but recent developments in basic and clinical research suggest future improvement.
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PMID:Kidney cancer. 1002 13

Various types of Cl- currents have been recorded in cardiac myocytes from different regions of the heart and in different species. With few exceptions, most of these currents are not active under basal conditions, but are activated under the influence of various agonists and by physical stress. These channels are distributed nonuniformly, depending on the cell type, tissue and region of the heart. Therefore, Cl- current activation may influence membrane potential and impulse formation differently in different cells, and may play a role in arrhythmogenesis. Among these Cl- currents, the protein kinase A-activated Cl- current (I Cl.PKA), the stretch- or swelling-activated Cl- current (I Cl.SWELL) and the Ca(2+)-activated Cl current (I Cl.Ca) comprise the major anion currents that modify cardiac electrical activity. These currents exhibit outward-going rectification, or are predominantly activated at depolarized voltages and, thus, contribute significantly to shortening of the action potential duration but little to diastolic depolarization. The action potential shortening by Cl- current activation may not only perpetuate reentry by shortening the refractory period in a reentry pathway, but may also prevent the development of early afterdepolarization and triggered activity caused by the prolongation of action potentials. I Cl.Ca contributes to delayed afterdepolarization at diastolic potentials in Ca(2+)-overloaded cells. Another factor limiting the influence of Cl- currents on diastolic potentials is the presence of a predominantly opposing background K+ current, except at the nodal regions that lack these K+ channels, or under conditions of decreased K+ conductance. Therefore, the contribution of Cl- currents to the genesis of arrhythmias may depend on their association with the conductance of other ions, especially that of K+.
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PMID:Role of cardiac chloride currents in changes in action potential characteristics and arrhythmias. 987 14

Lymphatic mapping with selective sentinel lymphadenectomy allows accurate pathologic examination of the nodes most likely to contain macro- or micrometastastic disease for staging and proper adjuvant chemotherapy. The hypothesis of SLN biopsies was histopathologically validated by Turner et al that if the node is tumor free by H&E and immunohistochemistry, the probability of non-SLN involvement is less than 0.1%. Giuliano et al and Veronesi et al reported that detection of metastases in SLNs by frozen section technique is 89% and 64%, respectively. At MCC, frozen section evaluation of SLN is not performed because of its potential loss of micrometastasis in the cryostat, freezing artifacts, sampling error, and perhaps radioactive contamination. Intraoperative detection of macro- or micrometastasis is critical because it enables conversion of patients with positive SLN to CLND in one surgical setting more cost-effectively. IIC of the lymph nodes has been used routinely in the diagnosis of hematologic malignancies and also in breast cancer as a useful method in many series. In the author's experience, IIC by Diff-Quik stain converted 100% of grossly positive and suspicious SLNs and 22% of grossly negative SLNs. The significance of detecting micrometastases in axillary lymph nodes using immunohistochemical techniques has been reported in many series. At the MCC, routine use of CKI on paraffin sections of grossly negative SLNs enabled the upstaging of 10.6% of patients from N0 to N1. Recent addition of intraoperative rapid CKI as an adjunct to complement Diff-Quik stain has proven to be more sensitive in detecting micrometastases than using Diff-Quik stain alone. IIC technique using either Diff-Quik stain or CKI requires intensive training and experience to avoid potential pitfalls and errors in interpretation. Evaluation of SLN should use methods that enhance the ability to detect micrometastasis, however, in a cost-effective manner. The cost-effectiveness of IIC by Diff-Quik stain is incomparable with frozen section evaluation. The added cost of routine immunohistochemical stain and perhaps multiple levels of H&E stain should be offset by the decreased costs of IIC and clinically by treating most patients in the outpatient settings. In summary, IIC by Diff-Quik stain is simple, rapid, and has excellent diagnostic accuracy in grossly positive and suspicious SLNs allowing cost-effective, immediate CLND. IIC by CKI is an extremely useful ancillary technique that complements Diff-Quik stain in detecting micrometastases particularly in low grade ductal or lobular carcinoma and low tumor cell volume. Appropriate combined use of both stains may lead to intraoperative nodal staging and cost-effective CLND. SLN mapping technology at MCC using IIC in conjunction with serial sections, entire tissue submission, routine use of CKI, and multiple levels of the SLN have led us to uncover micrometastasis in high-risk, traditionally node-negative patients. These results have encouraged investigators to pursue even more sensitive techniques to detect micrometastases, including molecular biology techniques such as RT-PCR. Experienced cytopathologists and active cytopathology services are required to avoid potential pitfalls in performing and interpreting IIC. More long-term follow-up and prospective trials are needed to determine the prognostic significance of upstaging by ancillary techniques, which may lead to a revision of the current TNM staging system.
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PMID:Pathologic examination of sentinel lymph nodes in breast cancer. 1044 90

We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A-H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 microm), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 microm). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A-H interval shortening were studied. Adenosine (3 microm) inhibited isoproterenol-stimulated (0.1 microm) I(Ca,L)(beta -I(Ca,L)) by 46+/-6% (P<0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 microm) and L-NNA (500 microm) attenuated the effect of adenosine on beta -I(Ca,L)by 69+/-8% (P<0.001, n=16) and 69+/-7% (P<0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 microm) reduced the inhibitory effect of adenosine on beta -I(Ca,L)by 97+/-6% (P=0.004, n=15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 microm) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 microm) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 microm) diminished beta -I(Ca,L), but to a significantly smaller degree (16+/-4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.
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PMID:Antagonism of the positive dromotropic effect of isoproterenol by adenosine: role of nitric oxide, cGMP-dependent cAMP-phosphodiesterase and protein kinase G. 1096 24

Protein kinase inhibitor (PKI) is an endogenous inhibitor of cAMP-dependent protein kinase A (PKA). We have found that the alpha-isoform of PKI (PKIalpha) is asymmetrically expressed along the left-right (L-R) axis in chick embryos. At stage 6, PKIalpha is expressed on the right side of the node, and this asymmetric expression continues until stage 7+. After stage 8, PKIalpha expression returns symmetric. Treatment of embryos with antisense PKIalpha oligonucleotides increased the incidence of reversed heart looping. Antisense oligonucleotides also induced ectopic expression of the left-specific genes Nodal and Pitx2, and suppressed the expression of the right-specific gene SnR in the right lateral plate mesoderm. Similarly, treatment with PKA activators forskolin and Sp-cAMPs resulted in both reversed heart looping and bilateral expression of NODAL: Ectopic activin induced PKIalpha on the left side of the node, while ectopic Shh and anti-Shh antibody had no effect on PKIalpha expression. Taken together, these data suggest that PKIalpha induced by an activin-like molecule, through the inhibition of PKA activity, suppresses the Nodal-Pitx2 pathway on the right side of the body.
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PMID:The role of an endogenous PKA inhibitor, PKIalpha, in organizing left-right axis formation. 1149 67

Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin beta 1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged <50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin beta 1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin beta 1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.
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PMID:Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. 1187 May 34

Glycogen synthase kinase-3beta (GSK3beta) plays important roles in metabolism, embryonic development, and tumorigenesis. Here we investigated the role of GSK3beta signaling in vascular biology by examining its function in endothelial cells (ECs). In EC, the regulatory phosphorylation of GSK3beta was found to be under the control of phosphoinositide 3-kinase-, MAPK-, and protein kinase A-dependent signaling pathways. The transduction of a nonphosphorylatable constitutively active mutant of GSKbeta promoted apoptosis under the conditions of prolonged serum deprivation or the disruption of cell-matrix attachments. Conversely, the transduction of catalytically inactive GSK3beta promoted EC survival under the conditions of cellular stress. Under normal cell culture conditions, the activation of GSK3beta signaling inhibited the migration of EC to vascular endothelial growth factor or basic fibroblast growth factor. Angiogenesis was inhibited by GSK3beta activation in an in vivo Matrigel plug assay, whereas the inhibition of GSK3beta signaling enhanced capillary formation. These data suggest that GSK3beta functions at the nodal point of converging signaling pathways in EC to regulate vessel growth through its control of vascular cell migration and survival.
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PMID:Regulation of angiogenesis by glycogen synthase kinase-3beta. 1216 28


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