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:2.7.12.2 (MEK)
18,161 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

Histone deacetylase inhibitors such as TSA, SAHA, and NaBu etc. are prospective cancer therapeutics of growing interest. Here, we demonstrated that oncogenic ras-transformed rat liver epithelial (WB-ras) cells were specifically undergone apoptosis by 48 h treatment of NaBu. During this, inhibition of ras proteins, especially farnesylated form of ras, and down-regulation of ERK1/2 were observed, which suggest ras/raf/MEK/ERK down-regulation, while p38 MAP kinase was maintained up-regulated. In addition, up-regulation of pro-apoptotic proteins such as p53 and p21CIP1/WAF1, and down-regulation of cell cycle regulator/anti-apoptotic proteins such as cdk2, -4 and phosphorylated Akt were observed concurrently with an increase in apoptotic cell portion. A phosphatase inhibitor, sodium orthovanadate (SOV), efficiently blocked apoptosis and restored responsible proteins for each phenomenon including ERK1/2 while SB203580, a specific p38 MAP kinase inhibitor, showed minor effect on them. Thus, ras/ERK signaling pathway can be considered in chemotherapeutic strategies of NaBu regardless of its inhibitory action on histone deacetylase.
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PMID:Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate. 1597 24

We reported previously that KG-1, a human acute leukemia cell line, has mutational loss of 8-oxoguanine (8-hydroxyguanine; oh8Gua) glycosylase 1 (OGG1) activity and undergoes apoptotic death after treatment with 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodeoxyguanosine, 8-hydroxydeoxyguanosine; oh8dG). In our present study, we further characterized the effects of oh8dG in KG-1 cells and found that, in addition to apoptosis, oh8dG induced the arrest of KG-1 at the G1 phase. Simultaneously, oh8dG-treated KG-1 showed an increase in the oh8Gua content of DNA, upregulation of p21 (an inhibitor of cdk), and Ras inactivation. Moreover, the upregulation of p21 was followed by the inactivations of cdk4 and cdk2, the hypophosphorylation of Rb, and a marked decline in the expression of c-myc (a gene regulated by E2F that is a transcription factor whose activity is suppressed when it is bound to hypophosphorylated Rb). Ras inactivation was also followed by the inactivation of ERK kinase (MEK) and the inactivation of AP-1, a downstream target of the Ras signaling pathway. The specific MEK inhibitors, PD98059 and U0126, also induced G1 arrest. These findings suggest that p21 upregulation and Ras inactivation contribute to G1 arrest. An increase of oh8Gua content in DNA does not seem to be a principal contributor to G1 arrest, however, because the kinetics of increases of oh8Gua content in DNA and of G1 cell number did not coincide. We report that oh8dG induces the arrest of KG-1 growth at the G1 phase mainly by upregulating p21 and inactivating Ras.
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PMID:Oh8dG induces G1 arrest in a human acute leukemia cell line by upregulating P21 and blocking the RAS to ERK signaling pathway. 1605 17

MEK1/2 inhibitors like U0126 can potentiate or antagonize the antitumor activity of cytotoxic agents such as cisplatin, paclitaxel or vinblastine, depending on the drug or the target cells. We now investigated whether U0126, differentially regulates melanoma signaling in response to UV radiation or betulinic acid, a drug lethal against melanoma. This report shows that U0126 inhibits early response (ERK) kinase activation and cyclin A expression in wt p53 C8161 melanoma exposed to either UV radiation or betulinic acid. However, U0126 does not protect from UV damage, but counteracts betulinic acid-mediated apoptosis in the same cells. Protection from the latter drug by joint treatment with U0126 was also evident in wt p53 MelJuso melanoma and mutant p53 WM164 melanoma. The latter cells were the most responsive to betulinic acid, showing a selective decline in the cdk4 protein, without a comparable change in other key cell cycle proteins like cdc2, cdk2, cdk7 or cyclin A, prior to apoptosis-associated PARP fragmentation. Laser scanning cytometry also showed that betulinic acid induced a significant increase in chromatin condensation in WM164 melanoma irrespective of whether they were in adherent form or as multicellular spheroids. All these betulinic acid-induced changes were counteracted by U0126. Our data show for the first time that (a) cdk4 protein is an early target of betulinic acid-induced apoptosis and (b) unrestricted ERK signaling favours betulinic acid-induced apoptosis, but this is counteracted by U0126, partly through counteracting chromatin condensation and restoring Akt activation decreased by betulinic acid treatment.
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PMID:Signalling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status. 1615 20

Cyclin D1 overexpression is a frequent change in hepatocellular carcinomas (HCCs). Our present study demonstrated that cyclin D1 overexpression with abundant cyclin E, cdk4, cdk2, and p27Kip1 (p27) occurred in neoplastic hepatocytes from the early stage of mouse hepatocarcinogenesis. While cyclin D1 expression was mainly found in the cytoplasm of the tumor cells, it shifted to the nucleus in association with cell proliferation after the animals were subjected to a partial hepatectomy (PH), and then returned once more to the cytoplasm when the cells became quiescent. Inhibition of PI3 kinase (PI3K) by Ly294002 in mouse HCC cells in vitro suppressed the nuclear shift of cyclin D1 as well as cell proliferation, while PI3K activation by PTEN suppression failed to induce nuclear shift of cyclin D1, suggesting that PI3K activation is essential but not sufficient for the cyclin D1 nuclear shift. While MEK-ERK1/2 inhibition by PD98059 and mTOR inhibition by rapamycin affected the cyclin D1 nuclear shift and cell proliferation to a lesser extent, both these inhibitors reduced cyclin D1 levels. Finally, although p27, cdk4 and calmodulin (CaM) were detected in the cyclin D1 immunoprecipitates from both quiescent and proliferating HCC cells, Hsc70 and SSeCKS were detected only in the immunoprecipitate from quiescent cells, and p21Waf1/Cip1 (p21) was detected only in that from proliferating cells, suggesting that the cyclin D1 complex is different in quiescent and proliferating cells. These observations indicate that the nuclear/cytoplasmic localization of cyclin D1 plays an important role in the proliferation/quiescence of neoplastic hepatocytes.
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PMID:Neoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesis. 1701 36

The differentiation capacity of mesenchymal stem cells has been extensively studied, but little is known on cell cycle-related events in the proliferation and differentiation phases of these cells. Here, we demonstrate that exposure to cAMP-increasing agents inhibits proliferation of adipose stem cells (ASCs). This antiproliferative effect is associated with both reduced cdk2 activity and pRB phosphorylation. Concomitantly, however, the level of cyclin E markedly increases upon cAMP induction, indicating that cyclin E may have cdk2-independent functions in these cells besides its role as a cdk2 activator. Indeed, we found indications of a cdk2-independent role of cyclin E in DNA damage-induced apoptosis. 8-CPT-cAMP sensitizes ASCs to gamma-irradiation-induced apoptosis, an effect abolished by knockdown of cyclin E. Moreover, cAMP induces early activation of ERK, leading to reduced degradation of cyclin E. The cAMP-mediated up-regulation of cyclin E was blocked by knockdown of ERK or by an inhibitor of the ERK kinase MEK. We conclude that cAMP inhibits cdk2 activity and pRB phosphorylation, leading to reduced ASC proliferation. Concomitant with this growth inhibition, however, cyclin E levels are increased in a MEK/ERK-dependent manner. Our results suggest that cyclin E plays an important, cdk2-independent role in genotoxic stress-induced apoptosis in mesenchymal stem cells.
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PMID:cAMP-mediated induction of cyclin E sensitizes growth-arrested adipose stem cells to DNA damage-induced apoptosis. 1879 28

Expression of p21(Sdi1) downstream of p53 is essential for induction of cellular senescence, although cancer cell senescence can also occur in the p53 null condition. We report herein that senescence-associated phosphorylated extracellular signal-regulated protein kinases 1 and 2 (SA-pErk1/2) enhanced p21(Sdi1) transcription by phosphorylating Sp1 on Ser(59) downstream of protein kinase C (PKC) alpha. Reactive oxygen species (ROS), which was increased in cellular senescence, significantly activated both PKCalpha and PKCbetaI. However, PKCalpha, but not PKCbetaI, regulated ROS generation and cell proliferation in senescent cells along with activation of cdk2, proven by siRNAs. PKCalpha-siRNA also reduced SA-pErk1/2 expression in old human diploid fibroblast cells, accompanied with changes of senescence phenotypes to young cell-like. Regulation of SA-pErk1/2 was also confirmed by using catalytically active PKCalpha and its DN-mutant construct. These findings strongly suggest a new pathway to regulate senescence phenotypes by ROS via Sp1 phosphorylation between PKCalpha and SA-pErk1/2: employing GST-Sp1 mutants and MEK inhibitor analyses, we found that SA-pErk1/2 regulated Sp1 phosphorylation on the Ser(59) residue in vivo, but not threonine, in cellular senescence, which regulated transcription of p21(Sdi1) expression. In summary, PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells.
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PMID:Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate Sp1 on serine 59 and regulate cellular senescence via transcription of p21Sdi1/Cip1/Waf1. 1931 49

Sea urchins provide an excellent model for studying cell cycle control mechanisms governing DNA replication in vivo. Fertilization and cell cycle progression are tightly coordinated by Ca(2+) signals, but the mechanisms underlying the onset of DNA replication after fertilization remain less clear. In this study we demonstrate that calcium-dependent activation of ERK1 promotes accumulation of cyclinE/cdk2 into the male and female pronucleus and entry into first S-phase. We show that cdk2 activity rises quickly after fertilization to a maximum at 4 min, corresponding in timing to the early ERK1 activity peak. Abolishing MAP kinase activity after fertilization with MEK inhibitor, U0126, substantially reduces the early peak of cdk2 activity and prevents cyclinE and cdk2 accumulation in both sperm pronucleus and zygote nucleus in vivo. Both p27(kip1) and roscovitine, cdk2 inhibitors, prevented DNA replication suggesting cdk2 involvement in this process in sea urchin. Inhibition of cdk2 activity using p27(kip1) had no effect on the phosphorylation of MBP by ERK, but completely abolished phosphorylation of retinoblastoma protein, a cdk2 substrate, indicating that cdk2 activity is downstream of ERK1 activation. This pattern of regulation of DNA synthesis conforms to the pattern observed in mammalian somatic cells.
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PMID:MAP kinase dependent cyclinE/cdk2 activity promotes DNA replication in early sea urchin embryos. 1966 13


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