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

---

Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Raf/MEK/ERK (extracellular regulated kinase) signal transduction pathway controls the ability of cells to respond to proliferative, apoptotic, migratory and differentiation signals. We have investigated the combined contribution of A-Raf and Raf-1 isotypes to signalling through this pathway by generating mice with knockout mutations of both A-raf and raf-1 genes. Double knockout (DKO) mice have a more severe phenotype than single null mutations of either gene, dying in embryogenesis at E10.5. The DKO embryos show no changes in apoptosis, but staining for Ki67 indicates a generalized reduction in proliferation. DKO mouse embryonic fibroblasts (MEFs) exhibit a delayed ability to enter S phase of the cell cycle. This is associated with a reduction in levels of transiently induced MEK and ERK phosphorylation and reduced expression of c-Fos and cyclin Dl. Levels of sustained ERK phosphorylation are not significantly altered. Thus, Raf-1 and A-Raf have a combined role in controlling physiological transient ERK activation and in maintenance of cell cycle progression at its usual rate.
...
PMID:A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression. 1585 7

Expression of mutationally activated RAS is a feature common to the vast majority of human pancreatic adenocarcinomas. RAS elicits its effects through numerous signaling pathways including the RAF-->mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase [MEK]-->ERK MAP kinase pathway. To assess the role of this pathway in regulating cell proliferation, we tested the effects of pharmacologic inhibition of MEK on human pancreatic cancer cell lines. In eight cell lines tested, MEK inhibition led to a cessation of cell proliferation accompanied by G0-G1 cell cycle arrest. Concomitant with cell cycle arrest, we observed induced expression of p27Kip1, inhibition of cyclin/cyclin-dependent kinase 2 (cdk2) activity, accumulation of hypophosphorylated pRb, and inhibition of E2F activity. Using both antisense and RNA interference techniques, we assessed the role of p27Kip1 in the observed effects of MEK inhibition on pancreatic cancer cell proliferation. Inhibition of p27Kip1 expression in Mia PaCa-2 cells restored the activity of cyclin/cdk2, phosphorylation of pRb, and E2F activity and partially relieved the effects of U0126 on pancreatic cancer cell cycle arrest. Consistent with the effects of p27Kip1 on cyclin/cdk2 activity, inhibition of CDK2 expression by RNA interference also led to G0-G1 cell cycle arrest. These data suggest that the expression of p27Kip1 is downstream of the RAF-->MEK-->ERK pathway and that the regulated expression of this protein plays an important role in promoting the proliferation of pancreatic cancer cells. Moreover, these data suggest that pharmacologic inhibition of the RAF-->MEK-->ERK signaling pathway alone might tend to have a cytostatic, as opposed to a cytotoxic, effect on pancreatic cancer cells.
...
PMID:Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. 1593 Mar 8

Male germ cell-associated kinase (MAK) and intestinal cell kinase (ICK) are nuclear Cdc2-related kinases with nearly identical N-terminal catalytic domains and more divergent C-terminal noncatalytic domains. The catalytic domain is also related to mitogen-activated protein kinases (MAPKs) and contains a corresponding TDY motif. Nuclear localization of ICK requires subdomain XI and interactions of the conserved Arg-272, but not kinase activity or, surprisingly, any of the noncatalytic domain. Further, nuclear localization of ICK is required for its activation. ICK is activated by dual phosphorylation of the TDY motif. Phosphorylation of Tyr-159 in the TDY motif requires ICK autokinase activity but confers only basal kinase activity. Full activation requires additional phosphorylation of Thr-157 in the TDY motif. Coexpression of ICK with constitutively active MEK1 or MEK5 fails to increase ICK phosphorylation or activity, suggesting that MEKs are not involved. ICK and MAK are related to Ime2p in budding yeast, and cyclin-dependent protein kinase-activating kinase Cak1p has been placed genetically upstream of Ime2p. Recombinant Cak1p phosphorylates Thr-157 in the TDY motif of recombinant ICK and activates its activity in vitro. Coexpression of ICK with wild-type CAK1 but not kinase-inactive CAK1 in cells also increases ICK phosphorylation and activity. Our studies establish ICK as the prototype for a new group of MAPK-like kinases requiring dual phosphorylation at TDY motifs.
...
PMID:Activation of a nuclear Cdc2-related kinase within a mitogen-activated protein kinase-like TDY motif by autophosphorylation and cyclin-dependent protein kinase-activating kinase. 1598 18

The inhibition of mitogen activated protein kinase (MAPK) activation during porcine oocyte maturation leads to decreased maturation promoting factor (MPF) activity and to the induction of parthenogenetic activation. In the present study, in order to analyze the mechanism underlying the suppression of MPF activity in MAPK-inhibited porcine oocytes, we injected mRNA of SASA-MEK, a dominant negative MAPK kinase, or antisense RNA of c-mos, a MAPK kinase kinase, into immature porcine oocyte cytoplasm. The injection of SASA-MEK mRNA or c-mos antisense RNA inhibited the MAPK activity partially or completely, respectively, decreased the MPF activity slightly or significantly, respectively, and induced parthenogenetic activation in 17.1% or 96.6% of mature oocytes, respectively, although no parthenogenetic activation was observed in the control oocytes. Immunoblotting experiments revealed that cyclin B accumulation in these MAPK-suppressed porcine oocytes was increased significantly after 50 h of culture and that a considerable amount of MPF was converted into inactive pre-MPF by hyperphosphorylation. These results indicate that the inhibition of MAPK activity in porcine oocytes did not promote cyclin B degradation but rather suppressed it; also the decrease in MPF activity in MAPK-suppressed porcine oocytes correlated with the conversion of active MPF into inactive pre-MPF.
...
PMID:Inhibition of mitogen activated protein kinase activity induces parthenogenetic activation and increases cyclin B accumulation during porcine oocyte maturation. 1603 93

Among normal organs and tissues, the MAPKK-like mitotic protein kinase TOPK is expressed exclusively in the testis. We analyzed the expression and phosphorylation of TOPK to address the functional role of this kinase during spermatogenesis. TOPK protein is expressed mainly in the cytosol of spermatocytes and spermatids, but not in spermatids and spermatogonia in situ. TOPK-Thr-9, a cdk1/cyclin B target residue, was specifically phosphorylated during mitotic and meiotic phases, while TOPK-Thr-198, a key amino acid for the ATP pocket, was constantly phosphorylated irrespective of the cell cycle. These data indicate that spermatogenic germ cells with vital proliferation activity express TOPK. As TOPK-Thr-9 was phosphorylated during both mitosis and meiosis, TOPK was indicted to play a role in cytokinesis and/or chromosomal segregation but not in DNA replication.
...
PMID:Expression and phosphorylation of TOPK during spermatogenesis. 1631 8

During mitosis, a select pool of MEK1 and p42/p44 MAPK becomes activated at the kinetochores and spindle poles, without substantial activation of the bulk of the cytoplasmic p42/p44 MAPK. Recently, we set out to identify the MAP kinase kinase kinase (MAPKKK) responsible for this mitotic activation, using cyclin-treated Xenopus egg extracts as a model system, and presented evidence that Mos was the relevant MAPKKK . However, a second MAPKKK distinct from Mos was readily detectable as well. Here, we partially purify this second MAPKKK and identify it as B-Raf. No changes in the activity of B-Raf were detectable during progesterone-induced oocyte maturation, after egg fertilization, or during the early embryonic cell cycle, arguing against a role for B-Raf in the mitotic activation of MEK1 and p42 MAPK. Ras proteins can bring about activation of MEK1 and p42 MAPK in extracts, and Ras may contribute to signaling from the classical progesterone receptor during oocyte maturation and from receptor tyrosine kinases during early embryogenesis. We found that both B-Raf and C-Raf, but not Mos, are required for Ras-induced MEK1 and p42 MAPK activation. These data indicate that two upstream stimuli, active Ras and active Cdc2, utilize different MAPKKKs to activate MEK1 and p42 MAPK.
...
PMID:B-Raf and C-Raf are required for Ras-stimulated p42 MAP kinase activation in Xenopus egg extracts. 1643 71

Cyclin-dependent kinase 5 (Cdk5) is predominantly active in postmitotic neurons. Despite its structural homology with other cyclin-dependent kinases, Cdk5 is apparently not involved in the cell cycle process. The monomeric form of Cdk5 is inactive and requires the association of p35 or p39 in order to perform its kinase activity. This kinase is essential for normal brain development and function, but uncontrolled activity of Cdk5 may lead to numerous neurodegenerative processes. Although Cdk5 activity has been implicated in several neuronal functions, its precise role in the peripheral nervous system has not been determined. Recently we reported for the first time the essential role for Cdk5 in pain signaling (Pareek et al., PNAS 2006; 103:791-6). Altered nociceptive responses to basal thermal noxious stimuli in p35 knockout (p35(-/-)) and p35-overexpresing transgenic mice (Tgp35) have established the important role of this gene in the nociceptive process. Here, we report that Cdk5 regulates mitogen-activated protein kinase kinase1/2 (MEK1/2) activity through a negative feedback loop during the peripheral inflammatory response. Moreover a differential nociceptive response after chronic morphine exposure in p35(-/-) and Tgp35 mice suggests that Cdk5 activity is important for opioid tolerance. In conclusion, our data indicate important molecular roles for Cdk5 in pain signaling and opioid tolerance, which makes it a potential target for analgesic drug development.
...
PMID:Cdk5: a new player in pain signaling. 1655 89

The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.
...
PMID:Tau therapeutic strategies for the treatment of Alzheimer's disease. 1671 93

D-type cyclins regulate G1 cell cycle progression by enhancing the activities of cyclin-dependent kinases (CDKs), and their expression is frequently altered in malignant cells. We and others have previously shown that cyclin D1 is up-regulated in melanoma cells through adhesion-independent MEK-ERK1/2 signaling initiated by mutant B-RAF. Here, we describe the regulation and role of cyclin D3 in human melanoma cells. Cyclin D3 expression was enhanced in a cell panel of human melanoma cell lines compared with melanocytes and was regulated by fibronectin-mediated phosphatidylinositol 3-kinase/Akt signaling but not MEK activity. RNA interference experiments demonstrated that cyclin D3 contributed to G1-S cell cycle progression and proliferation in melanoma cells. Overexpression of cyclin D1 did not recover the effects of cyclin D3 knockdown. Finally, immunoprecipitation studies showed that CDK6 is a major binding partner for cyclin D3, whereas CDK4 preferentially associated with cyclin D1. Together, these findings demonstrate that cyclin D3 is an important regulator of melanoma G1-S cell cycle progression and that D-type cyclins are differentially regulated in melanoma cells.
...
PMID:Cyclin D3 expression in melanoma cells is regulated by adhesion-dependent phosphatidylinositol 3-kinase signaling and contributes to G1-S progression. 1681 49

Oocytes from higher chordates, including man and nearly all mammals, arrest at metaphase of the second meiotic division before fertilization. This arrest is due to an activity that has been termed 'Cytostatic Factor'. Cytostatic Factor maintains arrest through preventing loss in Maturation-Promoting Factor (MPF; CDK1/cyclin B). Physiologically, Cytostatic Factor - induced metaphase arrest is only broken by a Ca2+ rise initiated by the fertilizing sperm and results in degradation of cyclin B, the regulatory subunit of MPF through the Anaphase-Promoting Complex/Cyclosome (APC/C). Arrest at metaphase II may therefore be viewed as being maintained by inhibition of the APC/C, and Cytostatic Factor as being one or more pathways, one of which inhibits the APC/C, consorting in the preservation of MPF activity. Many studies over several years have implicated the c-Mos/MEK/MAPK pathway in the metaphase arrest of the two most widely studied vertebrates, frog and mouse. Murine downstream components of this cascade are not known but in frog involve members of the spindle assembly checkpoint, which act to inhibit the APC/C. Interesting these downstream components appear not to be involved in the arrest of mouse eggs, suggesting a lack of conservation with respect to c-Mos targets. However, the recent discovery of Emi2 as an egg specific APC/C inhibitor whose degradation is Ca2+ dependent has greatly increased our understanding of MetII arrest. Emi2 is involved in both the establishment and maintenance of metaphase II arrest in frog and mouse suggesting a conservation of metaphase II arrest. Its identity as the physiologically relevant APC/C inhibitor involved in Cytostatic Factor arrest prompted us to re-evaluate the role of the c-Mos pathway in metaphase II arrest. This review presents a model of Cytostatic Factor arrest, which is primarily induced by Emi2 mediated APC/C inhibition but which also requires the c-Mos pathway to set MPF levels within physiological limits, not too high to induce an arrest that cannot be broken, or too low to induce parthenogenesis.
...
PMID:How eggs arrest at metaphase II: MPF stabilisation plus APC/C inhibition equals Cytostatic Factor. 1725 29


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

---