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)

The objective of this study was to investigate the role of calmodulin-dependent protein kinase II (CaMKII) during fertilization in the pig. Since it has been reported that CaMKII is involved in the capacitation and acrosome reaction of spermatozoa, we tested whether supplementation with the CaMKII inhibitor, KN-93, in the fertilization medium affected sperm penetration. The results showed that the addition of KN-93 in the fertilization medium significantly reduced the rate of sperm penetration into oocytes. However, pre-treatment with KN-93 before in vitro fertilization (i.v.f.) did not significantly affect sperm penetration, but it did affect pronuclear formation in a dose-dependent manner. In the oocytes pre-treated with KN-93 before i.v.f. and then co-cultured with spermatozoa without the drug, the decrease in p34cdc2 kinase and the cyclin B1 level were significantly suppressed as compared with those in penetrated oocytes without treatment with KN-93. However, the decrease in MAP kinase activity was not affected by KN-93. Additional treatment with KN-93 after Ca2+ ionophore treatment also inhibited the reduction in p34cdc2 kinase activity and the cyclin B1 level, but not MAP kinase activity. Treatment with KN-92, an inactive KN-93 analogue, did not significantly affect sperm penetration and pronuclear formation. In conclusion, the activation of CaMKII by artificial stimuli or sperm stimulated the disruption of cyclin B1 and the inactivation of p34cdc2 kinase, but did not affect MAP kinase inactivation during oocyte activation in pigs.
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PMID:The role of calcium/calmodulin-dependent protein kinase II on the inactivation of MAP kinase and p34cdc2 kinase during fertilization and activation in pig oocytes. 1545 35

The purpose of this study was to evaluate the expressions and the roles of proteins involved in cell cycle regulation and DNA repair in cis-diamminedichloroplatinum (II) (cisplatin or CDDP)-induced acute renal failure (ARF). Treatment with CDDP (6 mg/kg, iv) induced tubular damage and increased serum creatinine (Scr) and the number of TUNEL-positive cells in the outer stripe of the outer medulla in rats, which reached peak levels at 5 days after CDDP. The expressions of cyclin-dependent kinase inhibitors (p21 and p27), cyclin B1, cyclin D1, PCNA, GADD 45, and GADD 153 were significantly increased in the outer medulla, reaching peak levels at 3 days after CDDP. Increments of p27 and PCNA were observed in the same nuclei. Sodium arsenite (SA), a heavy metal, attenuated tubular damage and increased Scr- and TUNEL-positive cells at 5 days after CDDP. SA augmented CDDP-induced increment of p27 but suppressed the increased expression of cyclin B1 and cyclin D1 at 3 days after CDDP. SA-induced attenuation of nephrotoxicity was associated with enhanced expression of proliferating cell nuclear antigen (PCNA) and growth-arrest and DNA damage (GADD) 153 in damaged tubular cells. Our findings indicated that (1) proteins related to cell cycle regulation and DNA repair are induced in CDDP nephrotoxicity, (2) the SA-induced attenuation of CDDP nephrotoxicity is associated with increased expression of p27 and decreased expression of cyclin B1 and cyclin D1, they all induce cell cycle arrest at G1/S and G2/M, and (3) enhanced expression of DNA repair-related proteins is also associated with attenuation of CDDP-nephrotoxicity.
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PMID:The induction of cell cycle regulatory and DNA repair proteins in cisplatin-induced acute renal failure. 1547 64

In this study, diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS), which are major organosulfur compounds (OSCs) of garlic, were used as experimental materials to investigate their modulation effects on cell viability and cell cycle in human liver tumor cells (J5). According to the results of cell viability assay, 50 or 100 microM DATS significantly decreased the cell viability as compared with the control (P < 0.05) in dose and time dependent relations. Phenomena of cell number loss, shape deformation and lysis were observed after treatment with 100 microM DATS for 24 h. Cell cycle studies showed that J5 cells were significantly arrested in G2/M phase as the cells were treated with 100 microM DADS, 10, 50 or 100 microM DATS for 24 h (P < 0.05). DATS was more effective in arresting cells in G2/M phase than DADS, and the phenomena of arresting J5 cells in G2/M phase increased obviously in dose and time dependent relations. According to the Western blot analysis, DATS decreased cyclin-dependent kinase (Cdks)-Cdk7 (i.e. Cdc2 activate kinase) protein levels in J5 cells but increased cyclin B1 protein level. The modulation potency to cyclin B1 and Cdk7 expressions was in the order of DATS > DADS > DAS. The modulation potency to cyclin B1 and Cdk7 protein levels increased with increasing in DATS concentration and culture time. In conclusion, DATS might affect cell viability and cell morphological changes in J5 cells and lead cells to be arrested in G2/M phase via controlling the expression of cyclin B1 and Cdk7 in J5 cells, and the controlling action might relate to the sulfuric atom numbers in the structures of all these allyl sulfides.
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PMID:Differential effects of allyl sulfides from garlic essential oil on cell cycle regulation in human liver tumor cells. 1550 Sep 31

At the end of oogenesis, Xenopus laevis stage VI oocytes are arrested at the G2/M transition (prophase) waiting for progesterone to release the block and begin maturation. Progesterone triggers a cascade of phosphorylation events such as a decrease of pK(a) and an increase of maturating-promoting factor activity. Progression through meiosis was controlled by the sequential synthesis of several proteins. For instance, the MAPK kinase kinase c-Mos is the very first protein to be produced, whereas cyclin B1 appears only after meiosis I. After the meiotic cycles, the oocyte arrests at metaphase of meiosis II with an elevated c-Mos kinase activity (cytostatic factor). By using a two-hybrid screen, we have identified maskin, a protein involved in the control of mRNA sequential translation, as a binding partner of Aurora-A, a protein kinase necessary for oocyte maturation. Here we showed that, in vitro, Aurora-A directly binds to maskin and that both proteins can be co-immunoprecipitated from oocyte extracts, suggesting that they do associate in vivo. We also demonstrated that Aurora-A phosphorylates maskin on a Ser residue conserved in transforming acidic coiled coil proteins from Drosophila to human. When the phosphorylation of this Ser was inhibited in vivo by microinjection of synthetic peptides that mimic the maskin-phosphorylated sequence, we observed a premature maturation. Under these conditions, proteins such as cyclin B1 and Cdc6, which are normally detected only in meiosis II, were massively produced in meiosis I before the occurrence of the nuclear envelope breakdown. This result strongly suggests that phosphorylation of maskin by Aurora-A prevents meiosis II proteins from being produced during meiosis I.
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PMID:Phosphorylation of maskin by Aurora-A participates in the control of sequential protein synthesis during Xenopus laevis oocyte maturation. 1568 99

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent antiangiogenic factor that has been shown to prevent tumor growth in a xenograph mouse model. In this paper we first demonstrate that 16K hPRL inhibits serum-induced DNA synthesis in adult bovine aortic endothelial cells. This inhibition is associated with cell cycle arrest at both the G(0)-G(1) and the G(2)-M phase. Western blot analysis revealed that 16K hPRL strongly decreases levels of cyclin D1 and cyclin B1, but not cyclin E. The effect on cyclin D1 is at least partially transcriptional, because treatment with 16K hPRL both reduces the cyclin D1 mRNA level and down-regulates cyclin D1 promoter activity. This regulation may be due to inhibition of the MAPK pathway, but it is independent of the glycogen synthase kinase-3beta pathway. Lastly, 16K hPRL induces the expression of negative cell cycle regulators, the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1). In summary, 16K hPRL inhibits serum-induced proliferation of endothelial cells through combined effects on positive and negative regulators of cell cycle progression.
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PMID:The antiangiogenic factor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both the G0-G1 and the G2-M phases. 1574 89

Little is known about the posttranslational control of the cyclin-dependent protein kinase (CDK) inhibitor p21. We describe here a transient phosphorylation of p21 in the G2/M phase. G2/M-phosphorylated p21 is short-lived relative to hypophosphorylated p21. p21 becomes nuclear during S phase, prior to its phosphorylation by CDK2. S126-phosphorylated cyclin B1 binds to T57-phosphorylated p21. Cdc2 kinase activation is delayed in p21-deficient cells due to delayed association between Cdc2 and cyclin B1. Cyclin B1-Cdc2 kinase activity and G2/M progression in p21-/- cells are restored after reexpression of wild-type but not T57A mutant p21. The cyclin B1 S126A mutant exhibits reduced Cdc2 binding and has low kinase activity. Phosphorylated p21 binds to cyclin B1 when Cdc2 is phosphorylated on Y15 and associates poorly with the complex. Dephosphorylation on Y15 and phosphorylation on T161 promotes Cdc2 binding to the p21-cyclin B1 complex, which becomes activated as a kinase. Thus, hyperphosphorylated p21 activates the Cdc2 kinase in the G2/M transition.
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PMID:Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. 1579 20

Retinoid-related molecules are important potential agents for the treatment of cancer. In the present study, we test the effect of a novel retinoid-related ligand, AGN193198 (4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-prophenyl] benzoic acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)- or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR- or RXR receptor-selective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclin-dependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.
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PMID:A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis. 1585 29

It is well known that the cell cycle is controlled by several cyclin/cyclin-dependent kinase (Cdk) complexes whose expression and phosphorylation states vary with orderly periodicity. During the cell cycle, activity of the cyclin/Cdk complexes can be regulated directly or indirectly by a number of molecules, including protein kinases and phosphatases, p53, and Cdk inhibitors. Here, we show that the addition of glial cell line-derived neurotrophic factor (GDNF) induced G2/M cell cycle delay in human SK-N-MC neuroectodermal tumor cells that express RET tyrosine kinase, accompanying actin reorganization. Cell cycle delay at G2/M was characterized by accelerated and prolonged Cdc2 phosphorylation and stabilization of cyclin B1 and Wee1 kinase expression. Interestingly, we found that phosphorylation and/or expression of Cdc2, cyclinB1, and Wee1 was controlled by the Rac1/c-Jun NH2-terminal kinase (JNK) pathway. Immunohistochemical analysis suggested that the G2/M cell cycle delay may be necessary to prevent the mitotic progression of SK-N-MC cells with perturbed actin cytoskeletons.
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PMID:Activation of c-Jun amino-terminal kinase by GDNF induces G2/M cell cycle delay linked with actin reorganization. 1596 97

Two maize (Zea mays) cyclin-dependent kinase (CDK) inhibitors, Zeama;KRP;1 and Zeama;KRP;2, were characterized and shown to be expressed in developing endosperm. Similar to the CDK inhibitors in Arabidopsis (Arabidopsis thaliana) and tobacco (Nicotiana tabacum), the maize proteins contain a carboxy-terminal region related to the inhibitory domain of the mammalian Cip/Kip inhibitors. Zeama;KRP;1 is present in the endosperm between 7 and 21 d after pollination, a period that encompasses the onset of endoreduplication, while the Zeama;KRP;2 protein declines during this time. Nevertheless, Zeama;KRP;1 accounts for only part of the CDK inhibitory activity that peaks coincident with the endoreduplication phase of endosperm development. In vitro assays showed that Zeama;KRP;1 and Zeama;KRP;2 are able to inhibit endosperm Cdc2-related CKD activity that associates with p13(Suc1). They were also shown to specifically inhibit cyclin A1;3- and cyclin D5;1-associated CDK activities, but not cyclin B1;3/CDK. Overexpression of Zeama;KRP;1 in maize embryonic calli that ectopically expressed the wheat dwarf virus RepA protein, which counteracts retinoblastoma-related protein function, led to an additional round of DNA replication without nuclear division.
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PMID:Cyclin-dependent kinase inhibitors in maize endosperm and their potential role in endoreduplication. 1605 80

Mouse eggs arrest at metaphase II following ovulation and are only triggered to complete meiosis when fertilized. Sperm break the cell-cycle arrest by a long-lasting series of Ca2+ spikes that lead to an activation of the anaphase-promoting complex/cyclosome. The signal transduction pathway is not fully resolved but both protein kinase C (PKC) and calmodulin-dependent protein kinase II (CamKII) activities increase at fertilization and previous pharmacological studies have implicated both in cell-cycle resumption. We have used a combination of pharmacological inhibitors and constitutively active cRNA constructs of PKCalpha and CamKIIalpha microinjected into mouse eggs to show that it is CamKII and not PKC that is the sufficient trigger for cell-cycle resumption from metaphase II arrest. Constitutively active PKC constructs had no effect on the resumption of meiosis but caused an immediate and persistent elevation in intracellular Ca2+ when store-operated Ca2+ entry was stimulated. With respect to resumption of meiosis, the effects of constitutively active CamKII on eggs were the same as sperm. Eggs underwent second polar body extrusion and pronucleus formation with normal timings; while both securin and cyclin B1 destruction, visualised by coupling to fluorescent protein tags, were complete by the time of polar body extrusion. Induction of a spindle checkpoint by overexpression of Mad2 or by spindle poisons blocked CamKII-induced resumption of meiosis, but the Ca2+ chelator BAPTA did not. Furthermore direct measurement of Ca2+ levels showed that CamKII did not induce exit from metaphase II arrest by raising Ca2+. Therefore, we conclude that PKCs may play an important role in maintaining Ca2+ spiking at fertilization by promoting store-operated Ca2+ entry, while CamKII transduces cell-cycle resumption, and lies downstream of sperm-induced Ca2+ release but upstream of a spindle checkpoint. These data, combined with the knowledge that CamKII activity increase at fertilization, suggest that mouse eggs undergo cell-cycle resumption through stimulation of CamKII.
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PMID:Calmodulin-dependent protein kinase II, and not protein kinase C, is sufficient for triggering cell-cycle resumption in mammalian eggs. 1609 25


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