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

The RAS-activated RAF-->MEK-->extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3'-kinase)-->PDK1-->AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells. To explore the mechanisms that underlie such cooperation, we have derived cells harboring conditionally active, steroid hormone-regulated forms of RAF and AKT. These cells permit the assessment of the biological and biochemical effects of activation of these protein kinases either alone or in combination with one another. Under conditions where activation of neither RAF nor AKT alone promoted S-phase progression, coactivation of both kinases elicited a robust proliferative response. Moreover, under conditions where high-level activation of RAF induced G(1) cell cycle arrest, activation of AKT bypassed the arrest and promoted S-phase progression. At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27(Kip1) expression. Repression of p27(Kip1) was accompanied by a dramatic reduction in KIP1 mRNA and was observed in primary mouse embryo fibroblasts derived from mice either lacking SKP2 or expressing a T187A mutated form of p27(Kip1). Consistent with these observations, pharmacological inhibition of MEK or PI3'-kinase inhibited the effects of activated RAS on the expression of p27(Kip1) in NIH 3T3 fibroblasts and in a panel of bona fide human pancreatic cancer cell lines. Furthermore, we demonstrated that AKT activation led to sustained activation of cyclin/cdk2 complexes that occurred concomitantly with the removal of RAF-induced p21(Cip1) from cyclin E/cdk2 complexes. Cumulatively, these data strongly suggest that the RAF-->MEK-->ERK and PI3'K-->PDK-->AKT signaling pathways can cooperate to promote G(0)-->G(1)-->S-phase cell cycle progression in both normal and cancer cells.
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PMID:Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. 1557 89

The abilities of mutated active K-RAS and H-RAS proteins, in an isogenic human carcinoma cell system, to modulate the activity of signaling pathways and cell cycle progression following exposure to ionizing radiation is largely unknown. Loss of K-RAS D13 expression in parental HCT116 colorectal carcinoma cells blunted basal ERK1/2, AKT and JNK1/2 activity by -70%. P38 activity was not detected. Deletion of the allele to express activated K-RAS nearly abolished radiation-induced activation of all signaling pathways. Expression of H-RAS V12 in HCT116 cells lacking an activated RAS molecule (H-RAS V12 cells) restored basal ERK1/2 and AKT activity to that observed in parental cells, but did not restore or alter basal JNK1/2 and p38 activity. In parental cells radiation (1 Gy) caused stronger ERK1/2 pathway activation compared to that of the PI3K/AKT pathway. In H-RAS V12 cells radiation caused stronger PI3K/AKT pathway activation compared to that of the ERK1/2 pathway. Radiation (1 Gy) promoted S phase entry in parental HCT116 cells within 24h, but not in either HCT116 cells lacking K-RAS D13 expression or in H-RAS V12 cells. In parental cells radiation-stimulated S phase entry correlated with ERK1/2-, JNK1/2- and PI3K-dependent increased expression of cyclin D1 and cyclin A, and to a lesser extent cyclin E, 6-24 h after exposure. Cyclin A and cyclin D1 expression were not increased by radiation in cells lacking K-RAS D13 expression or in H-RAS V12 cells. Radiation (1 Gy) modestly enhanced expression of p53, hMDM2 and p21 in parental cells 2-6 h after exposure, which was abolished in cells lacking K-RAS D13 expression. Introduction of H-RAS V12 into cells lacking mutant active RAS partially restored radiation-induced expression of p21 and p53, and enhanced the induction of hMDM2 beyond that observed in parental cells. Collectively, our findings argue that the coordinated activation of multiple signaling pathways, in particular ERK1/2 and JNK1/2, by radiation is required to elevate the expression of G1 and S phase cyclin proteins and to promote S phase entry in human colon carcinoma cells expressing wild type p53. In HCT116 cells H-RAS V12 promotes hMDM2 expression after radiation exposure which correlates with reduced p53 expression and increased cell survival.
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PMID:Radiation-stimulated ERK1/2 and JNK1/2 signaling can promote cell cycle progression in human colon cancer cells. 1565 48

The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor with well-characterized ability to inhibit trypsin and chymotrypsin activities, has been shown to be an effective suppressor of carcinogenesis and treated in human phase IIa clinical trial. However, the precise mechanisms by which BBI suppresses carcinogenesis are unknown. In this study, we demonstrated that BBI specifically and potently inhibits the proteasomal chymotrypsin-like activity in vitro and in vivo in MCF7 breast cancer cells. Proteasome inhibition by BBI is associated with accumulation of ubiquitinated proteins and the proteasome substrates, p21Cip1/WAF1 and p27Kip1, accompanied with downregulation of cyclin D1 and cyclin E which could arrest cell cycle at G1/S phase. Moreover, BBI suppressed MCF7 cell growth and had a novel effect on the decrease of phosphorylated extracellular signal-related kinases (ERK1/2). However, BBI was unable to inactivate ERK1/2 in the presence of a phosphatase inhibitor or a transcription inhibitor suggesting the involvement of a specific phosphatase. We found an induction of MAP kinase phosphatase-1 (MKP-1) in dose- and time-dependent manner correlated with dephosphorylation of ERK1/2 in BBI-treated MCF7 cells. In addition, BBI exhibited no inhibitory effects on EGF-stimulated activation of ERK1/2 and Akt. Together, we suggested that BBI abates proteasome function and results in upregulation of MKP-1, which in turn suppresses ERK1/2 activity. Our results support the notion that proteasome inhibition by BBI is a novel mechanism that contributes to prevention of cancer and further provides evidence that soybean products have the potential to advance as chemopreventive agents.
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PMID:Bowman-Birk inhibitor abates proteasome function and suppresses the proliferation of MCF7 breast cancer cells through accumulation of MAP kinase phosphatase-1. 1574 61

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

Cyclin-dependent kinases (CDKs) are a family of evolutionarily conserved serine/threonine kinases. CDK2 acts as a checkpoint for the G(1)/S transition in the cell cycle. Despite a down-regulation of CDK2 activity in postmitotic cells, many cell types, including muscle cells, maintain abundant levels of CDK2 protein. This led us to hypothesize that CDK2 may have a function in postmitotic cells. We show here for the first time that CDK2 can be activated by neuregulin (NRG) in differentiated C2C12 myotubes. In addition, this activity is required for expression of the acetylcholine receptor (AChR) epsilon subunit. The switch from the fetal AChRgamma subunit to the adult-type AChRepsilon is required for synapse maturation and the neuromuscular junction. Inhibition of CDK2 activity with either the specific CDK2 inhibitory peptide Tat-LFG or by RNA interference abolished neuregulin-induced AChRepsilon expression. Neuregulin-induced activation of CDK2 also depended on the ErbB receptor, MAPK, and PI3K, all of which have previously been shown to be required for AChRepsilon expression. Neuregulin regulated CDK2 activity through coordinating phosphorylation of CDK2 on Thr-160, accumulation of CDK2 in the nucleus, and down-regulation of the CDK2 inhibitory protein p27 in the nucleus. In addition, we also observed a novel mechanism of regulation of CDK2 activity by a low molecular weight variant of cyclin E in response to NRG. These findings establish CDK2 as an intermediate molecule that integrates NRG-activated signals from both the MAPK and PI3K pathways to AChRepsilon expression and reveal an undiscovered physiological role for CDK2 in postmitotic cells.
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PMID:Novel role for cyclin-dependent kinase 2 in neuregulin-induced acetylcholine receptor epsilon subunit expression in differentiated myotubes. 1582 6

Bovine type I collagen (BIC), which is widely used as a fibrous extracellular matrix component in cell culture models, inhibits the progression of melanoma cell cycle via p27 up-regulation. BIC also induces nitric oxide synthase in macrophages through JunB/AP-1 and NF-kappaB activation. Given the previous observations, this study investigates the effect of BIC on the cell cycle progression and regulatory function of Raw264.7 macrophage cells and the responsible signaling pathways. Cell cycle analysis revealed that BIC completely suppressed proliferation of Raw264.7 cells with inhibition of the percentage of cells in the S phase and the reciprocal decrease in the G0/G1 phase. DNA synthesis was also inhibited by BIC, as evidenced by a decrease in the cellular incorporation of [3H]thymidine. The G1/S arrest induced by BIC was reversed by chemical inhibition of phosphatidylinositol 3-kinase (PI3-kinase) or overexpression of the p85 subunit of PI3-kinase. Either PD98059 or stable transfection with mitogen-activated protein kinase kinase-1 [MKK1(-)] or c-Jun N-terminal kinase 1 [JNK1(-)] also released the cell cycle arrest. Immunoblot analyses revealed that the levels of cyclins D1, A and B1 were partly or completely down-regulated by BIC, but cyclin E, p21 and p27 were minimally changed. Chemical inhibition and dominant negative mutant overexpression experiments revealed that either PI3-kinase inhibition or JNK1(-) transfection prevented the decreases in cyclin D1, A and B1 by BIC, indicating that the PI3-kinase and JNK1 pathways were associated with disruption of the cyclins. The pathway involving MKK1-extracellular signal-regulated kinase-1/2 (ERK1/2) was responsible for the suppression of cyclin A and B1, but not that of cyclin D1. The present study showed that BIC inhibited proliferation of Raw264.7 cells and that the pathways involving PI3-kinase and mitogen-activated protein kinases regulate the cell cycle arrest.
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PMID:Bovine type I collagen inhibits Raw264.7 cell proliferation through phosphoinositide 3-kinase- and mitogen-activated protein kinase-dependent down-regulation of cyclins D1, A and B1. 1587 97

The Skp1-Cullin1 F-box protein-Fbw7 ubiquitin ligase regulates phosphorylation-dependent cyclin E degradation, and disruption of this pathway is associated with genetic instability and tumorigenesis. Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechanisms other than mutation of Fbw7 may also disrupt cyclin E proteolysis in cancers. We show that oncogenic Ha-Ras activity regulates cyclin E degradation by the Fbw7 pathway. Activated Ras impairs Fbw7-driven cyclin E degradation, and, conversely, inhibition of normal Ras activity decreases cyclin E abundance. Moreover, activation of the mitogen-activated protein kinase pathway is the essential Ras function that inhibits cyclin E turnover, and activated Ha-Ras expression inhibits both the binding of cyclin E to Fbw7 and cyclin E ubiquitination. Last, we found that oncogenic Ras activity potentiates cyclin E-induced genetic instability but only when cyclin E is susceptible to degradation by Fbw7. Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis.
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PMID:Ras activity regulates cyclin E degradation by the Fbw7 pathway. 1598 Jan 50

We recently reported that the ginseng saponin metabolite, compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, IH901), inhibits the growth of U937 cells through caspase-dependent apoptosis pathway. In this study, we further characterized the effects of compound K on U937 cells and found that, in addition to apoptosis, compound K induced the arrest of the G1 phase. The compound K treated U937 cells showed increased p21 expression; an inhibitory protein of cyclin-cdk complex. The up-regulation of p21 was followed by the inactivation of cyclin D and the cdk4 protein, which act at the early G1 phase, and cyclin E, which acts at the late G1 phase. Furthermore, compound K induced the activation of JNK and the transcription factor AP-1, which is a downstream target of JNK. These findings suggest that the up-regulation of p21 and activation of JNK in the compound K treated cells contribute to the arrest of the G1 phase.
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PMID:G1 phase arrest of the cell cycle by a ginseng metabolite, compound K, in U937 human monocytic leukamia cells. 1604 78

We examined the effect of EGF on the proliferation of mouse embryonic stem (ES) cells and their related signal pathways. EGF increased [3H]thymidine and 5-bromo-2'-deoxyuridine incorporation in a time- and dose-dependent manner. EGF stimulated the phosphorylation of EGF receptor (EGFR). Inhibition of EGFR tyrosine kinase with AG-1478 or herbimycin A, inhibition of PLC with neomycin or U-73122, inhibition of PKC with bisindolylmaleimide I or staurosporine, and inhibition of L-type Ca2+ channels with nifedipine or methoxyverapamil prevented EGF-induced [3H]thymidine incorporation. PKC-alpha, -betaI, -gamma, -delta, and -zeta were translocated to the membrane and intracellular Ca2+ concentration ([Ca2+]i) was increased in response to EGF. Moreover, inhibition of EGFR tyrosine kinase, PLC, and PKC completely prevented EGF-induced increases in [Ca2+]i. EGF also increased inositol phosphate levels, which were blocked by EGFR tyrosine kinase inhibitors. Furthermore, EGF rapidly increased formation of H2O2, and pretreatment with antioxidant (N-acetyl-L-cysteine) inhibited EGF-induced increase of [Ca2+]i. In addition, we observed that p44/42 MAPK phosphorylation by EGF and inhibition of EGFR tyrosine kinase, PLC, PKC, or Ca2+ channels blocked EGF-induced phosphorylation of p44/42 MAPKs. Inhibition of p44/42 MAPKs with PD-98059 (MEK inhibitor) attenuated EGF-induced increase of [3H]thymidine incorporation. Finally, inhibition of EGFR tyrosine kinase, PKC, Ca2+ channels, or p44/42 MAPKs attenuated EGF-stimulated cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, and CDK4, respectively. In conclusion, EGF partially stimulates proliferation of mouse ES cells via PLC/PKC, Ca2+ influx, and p44/42 MAPK signal pathways through EGFR tyrosine kinase phosphorylation.
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PMID:EGF stimulates proliferation of mouse embryonic stem cells: involvement of Ca2+ influx and p44/42 MAPKs. 1610 8

Coptisine, an isoquinoline alkaloid isolated from rhizome of Coptis japonica, inhibits proliferation of vascular smooth muscle cells (VSMCs). The aim of this study was to evaluate the action of coptisine, along with berberine (a structurally similar isoquinoline alkaloid), on progression of the cell cycle in VSMCs. Coptisine displayed antiproliferative action against VSMCs by blocking the cell cycle at G(1) and G(2)/M phases. The G(1) block was shown by inhibition of [(3)H]thymidine incorporation into VSMCs at coptisine concentrations higher than 15 microM. The mechanism underlying the G(1) arrest involved a decrease in cyclin D1 protein, although cyclin E, A, and B were not affected by coptisine treatment. The selective reduction in cyclin D1 protein was mainly attributable to accelerated proteolysis via proteasome-dependent pathway, since it was inhibited by a proteasome inhibitor, N-carbobenzoxy-L-leucinyl-L-leucinyl-L-norleucinal (MG132) and further the mRNA level of cyclin D1, protein synthesis, and mitogen-activated protein kinase (MAPK) activity remained unaltered. The mechanism underlying the G(2)/M arrest involved partial inhibition of tubulin polymerization, which was apparent at coptisine concentration of 3 microM. Berberine arrested the cell cycle at G(1) phase via a mechanism identical with coptisine, but did not cause block at G(2)/M phase. The results demonstrate that a small difference in the structure between isoquinoline alkaloids produces a big difference in activity, and that coptisine has a unique double action in arresting the cell cycle of VSMCs.
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PMID:Double blockade of cell cycle progression by coptisine in vascular smooth muscle cells. 1614 Feb 75


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