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)

Most spontaneously developing hyperplastic and neoplastic lesions of the pituitary occur in the anterior pituitary. Targeted disruption of various cell-cycle proteins, including Rb, p27(kip1) (p27), and p18(INK4c) (p18), is associated with intermediate lobe pituitary hyperplasia. To develop a model of anterior pituitary proliferation to study the pathogenesis of pituitary tumors, we crossed the glycoprotein hormone alpha-subunit (alphaSU)-null mice that develop thyroid-stimulating hormone (TSH) cell hyperplasia with p18-null mice. The resulting offsprings developed accelerated enlargement of the anterior lobe with predominantly TSH cell hyperplasia. Immunohistochemical and histological analyses of these mice along with p27/p18 double-null mice, p18-null mice, and p27-null mice showed evidence of TSH, adrenocorticotropic hormone, prolactin, and luteinizing hormone hyperplasia. To determine whether there were alterations of p27 and the target proteins implicated in the ubiquitin degradation of p27 and other cyclin-dependent kinase inhibitors, we examined expression of SKP 2, Grb 2, and Jab 1 in the pituitaries of null mice. In the alphaSU-null mice there were decreased levels of SKP 2 and elevated levels of Grb 2 expression by Western blot analysis. Immunohistochemical analysis of the pituitary showed elevated Grb 2 in alphaSU-null and p18/alphaSU double-null mice. Jab 1 levels were not different from controls in the pituitary. These results show that 1) the p18/alphaSU double-null mice represent a good model to study the rapid development of anterior pituitary hyperplasia, and 2) various proteins important in p27 and other cyclin-dependent kinase inhibitor protein degradation are altered in the pituitary of alphaSU-null and p18/alphaSU double-null mouse models.
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PMID:Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation. 1189 Dec 12

Cyclooxygenase-2 is the rate-limiting enzyme in synthesis of prostaglandins and other eicosanoids. Prior reports have shown that inhibition of cyclooxygenase-2 activity, either by selective inhibitors or by antisense oligonucleotide, results in suppression of growth of squamous cell carcinoma cell lines which express high cyclooxygenase-2 levels, such as NA, a cell line established from a squamous cell carcinoma of the tongue. To investigate the mechanisms by which cyclooxygenase-2 inhibitors suppressed growth of these cells, the effects of NS-398, the selective cyclooxygenase-2 inhibitor, on cell-cycle distribution were examined. NS-398 induced G0/G1 cell-cycle arrest in NA cells which expressed cyclooxygenase-2. G0/G1 arrest induced by NS-398 was accompanied by up-regulation of cyclin-dependent kinase inhibitor p21, but not by up-regulation of the other cyclin-dependent kinase inhibitors. Transfection with p21 antisense oligonucleotide inhibited cell-cycle arrest induced by NS-398. Accumulation in G0/G1 was also observed in NA cells transfected with cyclooxygenase-2 antisense oligonucleotide. On the other hand, NS-398-treated NA cells showed a loss of plasma membrane asymmetry, a marker of early events in apoptosis. However, NS-398 did not induce other morphological and biochemical changes related to apoptotic cell death. These results suggest that cyclooxygenase-2 inhibitor induces G0/G1 cell-cycle arrest in NA cells by up-regulation of p21. Our results also suggest that NS-398 is not sufficient to complete the whole process of apoptosis in NA cells, although it induces an early event in apoptosis.
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PMID:Inhibitor of cyclooxygenase-2 induces cell-cycle arrest in the epithelial cancer cell line via up-regulation of cyclin dependent kinase inhibitor p21. 1195 64

Many dramatic alterations in various cellular processes during the cell cycle are known to involve ion channels. In ascidian embryos and Caenorhabditis elegans oocytes, for example, the activity of inwardly rectifying Cl(-) channels is enhanced during the M phase of the cell cycle, but the mechanism underlying this change remains to be established. We show here that the volume-sensitive Cl(-) channel, ClC-2 is regulated by the M-phase-specific cyclin-dependent kinase, p34(cdc2)/cyclin B. ClC-2 channels were phosphorylated by p34(cdc2)/cyclin B in both in vitro and cell-free phosphorylation assays. ClC-2 phosphorylation was inhibited by olomoucine and abolished by a (632)Ser-to-Ala (S632A) mutation in the C-terminus, indicating that (632)Ser is a target of phosphorylation by p34(cdc2)/cyclin B. Injection of activated p34(cdc2)/cyclin B attenuated the ClC-2 currents but not the S632A mutant channel currents expressed in Xenopus oocytes. ClC-2 currents attenuated by p34(cdc2)/cyclin B were increased by application of the cyclin-dependent kinase inhibitor, olomoucine (100 microM), an effect that was inhibited by calyculin A (5 nM) but not by okadaic acid (5 nM). A yeast two-hybrid system revealed a direct interaction between the ClC-2 C-terminus and protein phosphatase 1. These data suggest that the ClC-2 channel is also counter-regulated by protein phosphatase 1. In addition, p34(cdc2)/cyclin B decreased the magnitude of ClC-2 channel activation caused by cell swelling. As the activities of both p34(cdc2)/cyclin B and protein phosphatase 1 vary during the cell cycle, as does cell volume, the ClC-2 channel could be regulated physiologically by these factors.
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PMID:Phosphorylation and functional regulation of ClC-2 chloride channels expressed in Xenopus oocytes by M cyclin-dependent protein kinase. 1198 77

The molecular mechanisms mediating death receptor-induced caspase-independent necrotic cell death are still largely unknown. We have previously reported that NIH3T3 cells are sensitized by caspase inhibition to death receptor-induced cytotoxicity leading to a necrosis-like cell death. In addition, we have identified an important role of cell cycle progression for this sensitization effect. Here, we report that tumor necrosis factor-induced necrotic death is preceded by an upregulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Increased expression of p21(WAF1/Cip1) occurs prior to cell death in the nucleus, where it binds to a cyclin-dependent kinase indicating its functionality. The use of specific pharmacological inhibitors revealed a partial involvement of p38 mitogen-activated protein kinase in the upregulation of p21(WAF1/Cip1). Inhibition of p21(WAF1/Cip1) upregulation prevents a previously observed delay of the cells in the G2/M phase of the cell cycle thereby augmenting, not inhibiting cell death.
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PMID:Upregulation of p21(WAF1/Cip1) precedes tumor necrosis factor-induced necrosis-like cell death. 1205 22

Gap junctions are known to play a role in the control of cell proliferation, and connexins (Cx) are considered to be tumor suppressors. However, the effects of Cx on cell proliferation are dependent on the Cx which is expressed and on the cell type under consideration. We previously found that restoration of cell-to-cell communication by stable transfection of two independent thyroid-derived cell lines, FRTL-5 and FRT cells, with the Cx32 gene induced a marked reduction of their proliferation rate. This study aimed i) at determining whether Cx43, which is coexpressed with Cx32 by thyroid epithelial cells, exerts the same action as Cx32 on cell proliferation and ii) at identifying alterations of the cell cycle control system that might account for the Cx32-induced proliferation slowdown in thyrocytes. In contrast with previous data on different epithelial cell types, we report that restoration of intercellular communication in FRTL-5 and FRT cells by stable expression of Cx43 did not modify their proliferation properties. Cell cycle analyses revealed that the Cx32-induced proliferation slow-down was related to a lengthening of the G1 phase. The level of expression of two regulatory proteins of the Cip/Kip cyclin-dependent kinase inhibitor family, p27kip1 and p2cip1, was increased in the two cell lines expressing Cx32. In conclusion, Cx32 and Cx43, physiologically coexpressed by thyrocytes, have a differential impact on thyroid cell proliferation in vitro. The cyclin-dependent kinase inhibitors, p27kip1 and p21cip1 might represent cell cycle effectors relaying the down-regulatory effect of Cx32 on the proliferation of thyroid epithelial cells.
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PMID:Thyroid cell proliferation in response to forced expression of gap junction proteins. 1206 60

p27 is regarded as a cyclin-dependent kinase inhibitor of the G1-to-S cell cycle progression by suppressing the kinase activity of cyclin/cyclin-dependent kinase complex. This study aimed to investigate p27 expression in the normal endometrium and endometrioid adenocarcinoma of the uterine corpus and the correlation of its expression with cell proliferation and clinicopathological parameters. Tissue samples of 127 endometrioid adenocarcinomas and 15 normal endometria were used in the study. Immunohistochemical staining for detecting p27 and Ki-67 was performed by the labelled streptavidin-biotin method on formalin-fixed and paraffin-embedded tissue samples. The expression was given as the labelling index, which indicates the percentage of positive nuclei. p27 staining was observed in the nuclei of the glandular cells in the functional layer of the secretory phase endometrium, whereas it was negative in those of the proliferative phase. In endometrioid adenocarcinomas, the labelling index of p27 expression paradoxically increased more significantly in the higher histological grades and was correlated with that of Ki-67. The high level of p27 expression was associated with clinicopathological parameters such as FIGO stage, lymph node metastasis, lymphovascular space involvement and myometrial invasion. High p27 expression was linked to higher grades of endometrioid adenocarcinoma, cell proliferation and some clinical prognostic factors. These results indicate that p27 might be an indicator of poor prognosis.
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PMID:Paradoxical expression of cell cycle inhibitor p27 in endometrioid adenocarcinoma of the uterine corpus - correlation with proliferation and clinicopathological parameters. 1208 61

The therapeutic promise of hematopoietic stem cells in medicine has been expanded as broader differentiation potential of the cells has gained experimental support. However, hurdles for stem cell manipulation in vitro and tissue regeneration in vivo remain because of lack of the molecular biology of the stem cells. In particular, elucidating the molecular control of cell cycle entry is necessary for rational stem cell expansion strategies. Understanding how the stem and progenitor cell populations are controlled by negative regulators of cell cycle entry may provide one basis for manipulating these cells. In this mini-review, we focus on the rationale of targeting the cyclin-dependent kinase inhibitors (CKIs) in stem cell biology. Two CKI members, p21(Cip1/Waf1) (p21) and p27kip1 (p27), have been shown to govern the pool sizes of hematopoietic stem and progenitor cells, respectively. Of note, their inhibitory roles in primitive hematopoietic cells are distinct from the action of the inhibitory cytokine, transforming growth factor-beta1 (TGF-beta1). Therefore, the distinct roles of p21, p27, and TGF-beta1 in hematopoietic cells offer attractive targets for specific manipulation of the stem or progenitor cell populations in therapeutic strategies.
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PMID:Cell cycle entry of hematopoietic stem and progenitor cells controlled by distinct cyclin-dependent kinase inhibitors. 1209 44

Using an estrogen-inducible retroviral system, we demonstrate that oncogenic Raf-1 induces growth arrest and morphological changes in finite lifespan human mammary epithelial cells (HMEC). This arrest does not rely on expression of the cyclin-dependent kinase inhibitor (CKI) p16(INK4a), nor on changes in expression of the CKIs p21(Cip1), p14(ARF), p27(Kip1) or p57(Kip2). The Raf-induced arrest is independent of viral oncogene mediated inactivation of p53 and pRB, or c-myc overexpression. Flow cytometric analysis demonstrates that cells arrest in both G1 and G2. The Raf-induced arrest is mitigated or eliminated in some immortally transformed HMEC. Immortal HMEC that have both overcome replicative senescence and undergone the recently described conversion process maintain growth in the presence of transduced oncogenic Raf-1; they also gain EGF-independent growth and a low frequency of anchorage-independent growth. However, HMEC that have overcome replicative senescence but have not undergone conversion and HMEC immortalized by transduction with the catalytic subunit of telomerase, hTERT, remain severely growth arrested. These results indicate that the molecular mechanisms responsible for the Raf-1-induced growth arrest may vary among different finite lifespan cell types, and that in HMEC, this mechanism is altered during the conversion process, rather than as a direct consequence of overcoming senescence or expressing hTERT.
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PMID:Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion. 1221 73

The human Ink4a/Arf tumor suppressor locus encodes two distinct products: p16(Ink4a) which prevents phosphorylation and inactivation of the retinoblastoma protein and, p14(Arf), a nucleolar protein which activates the function of the tumor suppressor p53 protein in the nucleoplasm in response to oncogenic stimulation through an as yet ill-defined mechanism. Here we show that the level of endogenous p14(Arf) and its balance between the nucleolus and the nucleoplasm in HeLa cells are exquisitely sensitive to changes in cell morphology and to short-lived perturbations in cell cycle and in nucleolar function such as those induced by the cyclin-dependent kinase inhibitor, roscovitine, and the casein kinase II and RNA synthesis inhibitor, DRB. Most remarkably, whereas p14(Arf) predominantly concentrates in the nucleolus of interphase cells and transiently disappears between metaphase and early G1 under normal growth conditions, it massively and reversibly accumulates in the nucleoplasm of postmitotic and S-phase cells upon short-term treatment with roscovitine and, at a lesser extent, DRB. In line with the fact that the nuclear level of p53 reaches a peak between mid-G1 and the G1/S border in p53-expressor cells which lack Arf expression, these results provide a clue that, in p53+/Arf+ cells, Arf proteins might serve both to speed and to amplify p53-mediated responses in conditions and cell cycle periods in which the mechanisms involved in p53 stabilization and activation are not fully operational. They further suggest that human endogenous p14(Arf) might activate p53 pathways in physiologic situations by acting inside the nucleoplasm, especially when normal cell cycle progression and nucleolar function are compromised.
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PMID:Human p14(Arf): an exquisite sensor of morphological changes and of short-lived perturbations in cell cycle and in nucleolar function. 1236 Apr 4

The mammalian target of rapamycin (mTOR) modulates key signaling pathways that promote uncontrolled proliferation of glioblastoma multiforme (GBM). Because rapid tumor proliferation may contribute to the clinical radioresistance of GBM tumors, the combination of rapamycin, a selective mTOR inhibitor, and radiation was studied in vitro and in vivo in a GBM model. In monolayer cultures of U87 and SKMG-3 cells, rapamycin had no impact on radiation sensitivity. In contrast, rapamycin significantly enhanced the efficacy of fractionated radiation of established U87 xenografts in nude mice. Similar effects were seen in U87 spheroids treated with rapamycin and radiation, which suggests that the sensitizing effects of this drug are dependent on disruption of mTOR signaling pathways specifically within tumor cells. Inhibition of these signaling pathways can lead to inhibition of G(1)-specific cyclin-dependent kinase activities, and this could contribute to the sensitizing effects of rapamycin. Consistent with this idea, roscovitine, a specific cyclin-dependent kinase inhibitor, also enhanced the efficacy of fractionated radiation in U87 spheroids. These data demonstrate that inhibition of tumor proliferation does not diminish the efficacy of fractionated radiation and suggest that disruption of key signal transduction pathways may significantly enhance the effectiveness of radiation therapy in malignant gliomas.
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PMID:Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. 1249 72


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