Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic adenosine monophosphate (cAMP) keeps oocytes in meiotic arrest, thereby preventing activation of the key regulators of meiosis, p34cdc2/cyclin B1, (known as maturation-promoting factor (MPF)) and Erk 1 and 2, members of the mitogen-activated protein kinase (MAPK) family. The activity of MAPK in oocytes is upregulated by Mos. We previously demonstrated that Mos translation in rat oocytes is negatively regulated by a PKA-mediated cAMP action, which inhibits c-mos mRNA polyadenylation and is associated with the suppression of p34 cdc2 kinase. The goal of the present study was to provide definitive evidence that Mos translation is subjected to MPF regulation. In order to inhibit MPF activity, we employed the double-stranded (ds) RNA interference (RNAi) of gene expression. We demonstrated that the introduction of cyclin B1 dsRNA into rat oocytes selectively depleted the corresponding mRNA, further ablating its protein product. These oocytes, which exhibit low MPF activity, failed to elongate the c-mos mRNA poly(A) tail, did not accumulate Mos and were unable to activate MAPK. We conclude that an active MPF in rat oocytes is necessary for c-mos mRNA polyadenylation and Mos translation.
 ...
PMID:Selective degradation of cyclin B1 mRNA in rat oocytes by RNA interference (RNAi). 1529 44

Recent studies have shown that selective cyclooxygenase-2 (COX-2) inhibitors induce growth inhibition and cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism by which COX-2 inhibitors regulate the cell cycle and whether or not growth signal pathways are involved in the growth inhibition remain unclear. In this study, we investigated the mechanisms of growth inhibition and cell cycle arrest by etodolac, a selective COX-2 inhibitor, in HCC cell lines, HepG2 and PLC/PRF/5, by studying cell cycle regulatory proteins, and the MAP kinase and PDK1-PKB/AKT signaling pathways. Etodolac inhibited growth and PCNA expression and induced cell cycle arrest in both HCC cell lines. Etodolac induced p21WAF1/Cip1 and p27Kip1 expression and inhibited CDK2, CDK4, CDC2, cyclin A and cyclin B1 expression, but did not affect cyclin D1 or cyclin E. HGF and 10% FBS induced ERK phosphorylation, but phosphorylation of p38, JNK and AKT was down-regulated by etodolac. PD98059, a selective inhibitor of ERK phosphorylation, induced growth inhibition, the expression of p27Kip1 and cell cycle arrest. In conclusion, p21WAF1/Cip1, p27Kip1, CDK2, CDK4, CDC2, cyclin A, cyclin B1 and the MAP kinase signaling pathway are involved in growth inhibition and cell cycle arrest by a selective COX-2 inhibitor in HCC cell lines.
 ...
PMID:Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines. 1529 30

Extracts of Artemisia asiatica Nakai (Asteraceae) possess anti-inflammatory and anti-oxidative activities. Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone), one of the pharmacologically active ingredients derived from A. asiatica, was shown to induce apoptosis in human promyelocytic leukemia (HL-60) cells [Mutat Res 496 (2001) 191]. In the present study, we examined the cytostatic effects of eupatilin in H-ras-transformed human breast epithelial (MCF10A-ras) cells. Eupatilin inhibited the growth of MCF10A-ras cells in a concentration-dependent and time-related manner. To explore whether the anti-proliferative effects of eupatilin could be mediated through modulation of the cell cycle in MCF10A-ras, DNA contents were analyzed by the flow cytometry. Eupatilin inhibited the expression of cyclin D1, cyclin B1, Cdk2 and Cdc2 that are key regulators of the cell cycle. In addition, eupatilin treatment led to elevated expression of p53 and p27Kip1 that act as Cdk inhibitors. It has been known that the Ras-signaling pathway plays integral roles in the induction of cyclin D1. Eupatilin inhibited the activation of ERK1/2 as well as expression of Raf-1 and Ras in MCF10A-ras cells. Thus, the inhibitory effect of eupatilin on cyclin D1 expression appears to be mediated by targeting the Raf/MEK/ERK signaling cascades. Eupatilin did not change activation of Akt, an important component of cell-survival pathways. In conclusion, the anti-proliferative effect of eupatilin in MCF10A-ras cells is associated with its blockade of cell cycle progression which appears to be attributable in part to inhibition of ERK1/2 activation.
 ...
PMID:Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces cell cycle arrest in ras-transformed human mammary epithelial cells. 1531 4

Degradation of proteins mediated by ubiquitin-proteasome pathway (UPP) plays important roles in the regulation of eukaryotic cell cycle. In this study, the functional roles and regulatory mechanisms of UPP in mouse oocyte meiotic maturation, fertilization, and early embryonic cleavage were studied by drug-treatment, Western blot, antibody microinjection, and confocal microscopy. The meiotic resumption of both cumulus-enclosed oocytes and denuded oocytes was stimulated by two potent, reversible, and cell-permeable proteasome inhibitors, ALLN and MG-132. The metaphase I spindle assembly was prevented, and the distribution of ubiquitin, cyclin B1, and polo-like kinase 1 (Plk1) was also distorted. When UPP was inhibited, mitogen-activated protein kinase (MAPK)/p90rsk phosphorylation was not affected, but the cyclin B1 degradation that occurs during normal metaphase-anaphase transition was not observed. During oocyte activation, the emission of second polar body (PB2) and the pronuclear formation were inhibited by ALLN or MG-132. In oocytes microinjected with ubiquitin antibodies, PB2 emission and pronuclear formation were also inhibited after in vitro fertilization. The expression of cyclin B1 and the phosphorylation of MAPK/p90rsk could still be detected in ALLN or MG-132-treated oocytes even at 8 h after parthenogenetic activation or insemination, which may account for the inhibition of PB2 emission and pronuclear formation. We also for the first time investigated the subcellular localization of ubiquitin protein at different stages of oocyte and early embryo development. Ubiquitin protein was accumulated in the germinal vesicle (GV), the region between the separating homologous chromosomes, the midbody, the pronuclei, and the region between the separating sister chromatids. In conclusion, our results suggest that the UPP plays important roles in oocyte meiosis resumption, spindle assembly, polar body emission, and pronuclear formation, probably by regulating cyclin B1 degradation and MAPK/p90rsk phosphorylation.
 ...
PMID:Ubiquitin-proteasome pathway modulates mouse oocyte meiotic maturation and fertilization via regulation of MAPK cascade and cyclin B1 degradation. 1532 87

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.
 ...
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

Roscovitine, a specific inhibitor of MPF kinase activity, has been shown to block efficiently and reversibly the meiotic resumption of oocytes from different species, including cattle. In view to verify that oocytes maintain germinal vesicle like molecular activities under roscovitine treatment, we compared in the present study the M-phase Promoting Factor (MPF) and Mitogen Activated Protein (MAP) kinase activities; protein synthesis and phosphorylation patterns in oocytes and cumulus cells; and CDK1 and Cyclin B messengers storage under control culture and under roscovitine inhibition. We observed that roscovitine induced a full and reversible inhibition of MPF kinase activity and of the activating phosphorylation of both ERK1/2 MAPK. During in vivo maturation, there was a highly significant increase in the relative mRNA level of both cyclin B1 and CDK1 whereas during in vitro culture, the relative amount of CDK1 messenger was reduced. These messengers may be used as markers for the optimization of in vitro maturation treatment. Roscovitine reversibly prevented this drop in relative quantities of CDK1 messenger. Oocytes cultured in the presence of roscovitine maintained a GV like profile of protein synthesis except that two proteins of 48 and 64 kDa specific of matured oocytes also appeared under roscovitine treatment. However, roscovitine did not prevent most of the modifications of protein phosphorylation pattern observed during maturation. In conclusion, results of this study revealed that the use of roscovitine did not prevent all the events related to maturation of bovine oocytes.
 ...
PMID:Protein synthesis and mRNA storage in cattle oocytes maintained under meiotic block by roscovitine inhibition of MPF activity. 1545 12

The proteasome plays a pivotal role in controlling cell proliferation, apoptosis, and differentiation in a variety of normal and tumor cells. PS-341, a novel boronic acid dipeptide that inhibits 26S proteasome activity, has prominent effects in vitro and in vivo against several solid tumors. We examined its antiproliferation, proapoptotic effects using three human glioblastoma multiforme (GBM) cell lines and five primary GBM explants. PS-341 markedly inhibited proliferation of GBM cell lines and explants in liquid and soft agar culture. These cells developed a G2/M cell cycle arrest with a concomitant decreased percentage of cells in S phase ( approximately 2-fold), associated with an increased expression of p21(WAF1), p27(KIP1), as well as cyclin B1 and decreased levels of CDK2, CDK4, and E2F4. About 35-40% of the cells became apoptotic when exposed to PS-341 (10(-7) M, 24-48 h) as shown by Annexin V analysis; in concert with these findings, immunobloting showed a C-terminal 85 kDa apoptotic fragment of poly ADP-ribose polymerase (PARP), and a decreased level of Bcl2 and Bcl-xl. PS-341 downregulated the expression of Bcl-2 and Bcl-xl in protein levels at an early time of treatment. These changes occurred irrespective of the p53 mutational status of the cells. PS-341 activated JNK/c-Jun signaling in GBM cells, and the JNK inhibitor SP600125 blocked the JNK signaling to reverse partially the PS-341 growth inhibition. PS-341 (10(-7) M, 24 h) decreased nuclear NF-kappaB levels as shown by Western blot, and reduced transcriptional activity of NF-kappaB as measured by reporter assays in these transformed cells. Also, PS-341 enhanced TRAIL (TNF-related apoptosis-inducing ligand) and TNFalpha (tumor necrosis factor alpha) induced cell death and apoptosis (two- to five-fold) in GBM cells. In summary, PS-341 has profound effects on growth and apoptosis of GBM cells, suggesting that PS-341 may be an effective therapy for patients with gliomas.
 ...
PMID:Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). 1553 18

Activation of the complement system plays an important role in innate and acquired immunity. Activation of complement and subsequent formation of C5b-9 channels on the surface of cellular membranes leads to cell lysis. When the number of channels assembled on the surface of nucleated cells is limited, C5b-9 does not cause lysis, but instead can induce cell-cycle progression by activating signal transduction pathways, transcription factors, and key components of the cell-cycle machinery. Cell-cycle induction by C5b-9 is dependent on the activation of phosphatidylinositol 3-kinase and the ERK1 pathway in a Gi protein-dependent manner. Cell-cycle activation is regulated, in part, by activation of proto-oncogene c-jun and AP1 DNA binding activity. C5b-9 induces sequential activation of CDK4 and CDK2, leading to G1/S-phase transition and cellular proliferation. RGC-32 is a novel gene whose expression is induced by C5b-9. RGC-32 may play a key role in cell-cycle activation by increasing cyclin B1-CDC2 activity. C5b-9-mediated cell-cycle activation plays an important role in cellular proliferation and protection from apoptosis.
 ...
PMID:The role of c5b-9 terminal complement complex in activation of the cell cycle and transcription. 1559 21

The forkhead box (FOX) transcription factor FOXM1 is ubiquitously expressed in proliferating cells. FOXM1 expression peaks at the G2/M phase of the cell cycle and its functional deficiency in mice leads to defects in mitosis. To investigate the role of FOXM1 in the cell cycle, we used synchronized hTERT-BJ1 fibroblasts to examine the cell cycle-dependent regulation of FOXM1 function. We observed that FOXM1 is localized mainly in the cytoplasm in cells at late-G1 and S phases. Nuclear translocation occurs just before entry into the G2/M phase and is associated with phosphorylation of FOXM1. Consistent with the dependency of FOXM1 function on mitogenic signals, nuclear translocation of FOXM1 requires activity of the Raf/MEK/MAPK signaling pathway and is enhanced by the MAPK activator aurintricarboxylic acid. This activating effect was suppressed by the MEK1/2 inhibitor U0126. In transient reporter assays, constitutively active MEK1 enhances the transactivating effect of FOXM1c, but not FOXM1b, on the cyclin B1 promoter. RT-PCR analysis confirmed that different cell lines and tissues predominantly express the FOXM1c transcript. Mutations of two ERK1/2 target sequences within FOXM1c completely abolish the MEK1 enhancing effect, suggesting a direct link between Raf/MEK/MAPK signaling and FOXM1 function. Importantly, inhibition of Raf/MEK/MAPK signaling by U0126 led to suppression of FOXM1 target gene expression and delayed progression through G2/M, verifying the functional relevance of FOXM1 activation by MEK1. In summary, we provide the first evidence that Raf/MEK/MAPK signaling exerts its G2/M regulatory effect via FOXM1c.
 ...
PMID:Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c. 1567 Oct 63

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.
 ...
PMID:Phosphorylation of maskin by Aurora-A participates in the control of sequential protein synthesis during Xenopus laevis oocyte maturation. 1568 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>