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 cyclin inhibitory protein p27Kip1 (p27) plays a vital role in regulating cell proliferation in response to the extracellular growth environment. Active proliferation requires the suppression of p27 levels throughout the cell cycle. Late in the cell cycle, p27 degradation requires phosphorylation of Thr 187 by cyclin dependent kinase 2, leading to recognition by the SCF ubiquitin ligase containing the Skp2 F-box protein. Suppression of p27 is also essential for cell proliferation early in the cell cycle, but this occurs independently of Skp2, whose expression is suppressed during G1 phase. In this study, we use a time lapse and quantitative imaging approach to study the connection between proliferative signaling and the degradation of p27 during each cell cycle period in actively cycling cells. Ras activity was required for the suppression of p27 levels throughout the cell cycle, but separate pathways downstream of Ras signaling were required in different cell cycle periods. For example, inhibitors of MEK and phosphatidylinositol-3-kinase induced p27 expression primarily in G1 phase, while inhibitors of AKT activity stimulated these levels primarily in S phase. Skp2 was expressed in a Ras-dependent manner at higher levels late in the cell cycle. Its ablation resulted in higher p27 levels primarily in G2 phase as expected. The fact that separate signaling pathways downstream of Ras function in each cell cycle phase to suppress p27 levels helps explain the vital connection between proliferative signaling, cell cycle control, and p27 expression.
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PMID:P27 expression is regulated by separate signaling pathways, downstream of Ras, in each cell cycle phase. 1547 7

The E3 ubiquitin ligase IMP (impedes mitogenic signal propagation) was isolated as a novel Ras effector that negatively regulates ERK1/2 activation. Current evidence suggests that IMP limits the functional assembly of Raf/MEK complexes by inactivation of the KSR1 adaptor/scaffold protein. Interaction with Ras-GTP stimulates IMP autoubiquitination to relieve limitations on KSR function. The elevated sensitivity of IMP-depleted cells to ERK1/2 pathway activation suggests IMP acts as a signal threshold regulator by imposing reversible restrictions on the assembly of functional Raf/MEK/ERK kinase modules. These observations challenge commonly held concepts of signal transmission by Ras to the MAPK pathway and provide evidence for the role of amplitude modulation in tuning cellular responses to ERK1/2 pathway engagement. Here we describe details of the methods, including RNA interference, ubiquitin ligase assays, and protein complex analysis, that can be used to display the Ras-sensitive contribution of IMP to KSR-dependent modulation of the Raf/MEK/ERK pathway.
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PMID:Ras-sensitive IMP modulation of the Raf/MEK/ERK cascade through KSR1. 1675 28

Cell death plays a ubiquitous role in plant-microbe interactions, given that it is associated with both susceptible and resistance interactions. A class of cell death-inducing proteins, termed Nepl-like proteins (NLPs), has been reported in bacteria, fungi, and oomycetes. These proteins induce nonspecific necrosis in a variety of dicotyledonous plants. Here, we describe three members of the NLP family from the oomycete Phytophthora infestans (PiNPP1.1, PiNPP1.2, and PiNPP1.3). Using agroinfection with a binary Potato virus X vector, we showed that PiNPP1.1 induces cell death in Nicotiana benthamiana and the host plant tomato. Expression analyses indicated that PiNPP1.1 is up-regulated during late stages of infection of tomato by P. infestans. We compared PiNPP1.1 necrosis-inducing activity to INF1 elicitin, a well-studied protein that triggers the hypersensitive response in Nicotiana spp. Using virus-induced gene silencing, we showed that the cell death induced by PiNPP1.1 is dependent on the ubiquitin ligase-associated protein SGT1 and the heat-shock protein HSP90. In addition, cell death triggered by PiNPP1.1 but not that by INF1 was dependent on the defense-signaling proteins COI1, MEK2, NPR1, and TGA2.2, suggesting distinct signaling requirements. Combined expression of PiNPP1.1 and INF1 in N. benthamiana resulted in enhanced cell death, suggesting synergistic interplay between the two cell-death responses. Altogether, these results point to potentially distinct but interacting cell-death pathways induced by PiNPP1.1 and INF1 in plants.
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PMID:Synergistic interactions of the plant cell death pathways induced by Phytophthora infestans Nepl-like protein PiNPP1.1 and INF1 elicitin. 1690 51

The RING finger ubiquitin ligase Siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the PHD3, which controls the stability of HIF-1alpha. In the present study we determined the role of Siah2 phosphorylation in the regulation of its activity toward PHD3. We show that Siah2 is subject to phosphorylation by p38 MAPK, which increases Siah2-mediated degradation of PHD3. Consistent with these findings, MKK3/MKK6 double-deficient cells, which cannot activate p38 kinases, exhibit impaired Siah2-dependent degradation of PHD3. Phosphopeptide mapping identified T24 and S29 as the primary phospho-acceptor sites. Phospho-mutant forms of Siah2 (S29A or T24A/S29A) exhibit impaired degradation of PHD3, particularly after hypoxia. Conversely, a phospho-mimic form of Siah2 (T24E/S29D) exhibits stronger degradation of PHD3, compared with wild type Siah2. Whereas phospho-mutant Siah2 exhibits weaker association with PHD3, phospho-mimic Siah2 associates as well as wild type and is localized within the perinuclear region, suggesting that phosphorylation of Siah2 affects its subcellular localization and, consequently, the degree of its association with PHD3. In all, our findings reveal the phosphorylation of Siah2 by p38 and the implications of such phosphorylation for Siah2 activity toward PHD3.
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PMID:Regulation of the ring finger E3 ligase Siah2 by p38 MAPK. 1700 45

Mdm2 inactivates the tumor suppressor p53 and Akt has been shown to be a major activator of Mdm2 in many cell types. We have investigated the regulation of Mdm2 in hepatocytes. We found that growth factor-induced Ser-166 phosphorylation of Mdm2 was inhibited by the MEK inhibitors U0126 and PD98059 in HepG2 cells and in a rat liver cell line, TRL 1215. Also, bile acids and oxidative stress induced phosphorylation of Mdm2 at Ser-166 by an apparently MEK-ERK-dependent mechanism. In contrast, Ser-166 phosphorylation of Mdm2 in lung cells was mediated by Akt. Further studies revealed that phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin induced phosphorylated ERK Tyr-204 and pMdm2 Ser-166 phosphorylations in hepatocytes in culture and in rat hepatocytes in vivo. In HepG2 cells, this effect was inhibited by U0126 and PD98059. LY294002 also reduced the level of pRaf Ser-259. Furthermore, we have shown that myr-Akt-induced overexpression of pAkt suppressed the levels of pMdm2 Ser-166 in hepatocytes. These data indicate a reversed relationship between Akt and Mdm2 in hepatocytes and suggest that Akt is a negative regulator of Raf-MEK-ERK-Mdm2 in this cell type. Ser-166 phosphorylation of Mdm2 has been shown to increase its ubiquitin ligase activity and increase p53 degradation, and our data indicated an attenuated p53 response to DNA damage in hepatocytes exhibiting high levels of pMdm2 Ser-166. Taken together, our data indicate that Mdm2 phosphorylation is regulated via MEK-ERK in hepatocytes. This Mdm2 signaling might be important for the regeneration of hepatocytes after centrilobular cell death.
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PMID:MEK-ERK-mediated phosphorylation of Mdm2 at Ser-166 in hepatocytes. Mdm2 is activated in response to inhibited Akt signaling. 2798 70

We previously reported that overexpression of cell division autoantigen 1 (CDA1) in HeLa cells arrests cell growth and inhibits DNA synthesis at S-phase. Here we show that CDA1-induced arrest of cell growth is accompanied by increases in protein and mRNA levels of the cyclin-dependent kinase (Cdk) inhibitor protein, p21(Waf1/Cip1) (p21). Both p21 induction and cell growth arrest are reversed when CDA1 expression is inhibited. CDA1 also increases p53 protein, but not its mRNA, in a time- and dose-dependent manner. MDM2, a ubiquitin ligase regulating p53 degradation, is inactivated by CDA1, suggesting that p53 protein accumulation is due to decreased protein degradation. Knockdown of p53, using siRNA targeting two sites of p53 mRNA, abrogates transcriptional induction of p21 by CDA1. Deletion of the p53 responsive element in the distal region of p21 promoter attenuates promoter activity in response to CDA1. DNA damage caused by camptothecin treatment increases mRNA and protein levels of CDA1, accompanied by induction of p53. The DNA damage-induced p53 induction is markedly attenuated by CDA1 knockdown. CDA1 induces phosphorylation of ERK1/2(p44/42), an activity blocked by PD98059 and U0126, inhibitors of the upstream kinase MEK1/2. The MEK inhibitors also block induction of p21 mRNA and abrogate p21 promoter activity stimulated by CDA1. Cell cycle kinases, Cdk1, -2, -4, and -6 are inhibited by CDA1 overexpression. We conclude that CDA1 induces p53- and MEK/ERK1/2 MAPK-dependent expression of p21 by acting through the p53 responsive element in the p21 promoter and that this contributes to its antiproliferative activity.
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PMID:Antiproliferative autoantigen CDA1 transcriptionally up-regulates p21(Waf1/Cip1) by activating p53 and MEK/ERK1/2 MAPK pathways. 1731 70

Interferon alpha (IFNalpha) is widely used in treatment of malignant melanoma patients. This cytokine acts on cells by engaging Type I IFN receptor consisting of two subunits, (IFNAR1 and IFNAR2) followed by activation of Janus kinases (Jak). Levels of IFNAR1 (regulated via degradation mediated by the betaTrcp E3 ubiquitin ligase) and IFNalpha signaling were reduced in 1205Lu melanoma cell line that harbors activated BRAF and exhibits high levels of betaTrcp ubiquitin ligase. Expression of stabilized IFNAR1 in melanoma cells decreased their tumorigenicity. Furthermore, RNAi-mediated BRAF knockdown and pharmacologic inhibition of either Raf or MEK1 decreased levels of betaTrcp and stabilized IFNAR1. However, despite causing stabilization of IFNAR1, Raf inhibitor BAY 43-9006 interfered with cellular responses to IFNalpha most likely due to its ability to directly inhibit Jak activity. We discuss the implications of this result for combination therapy with BAY 43-9006 and IFNalpha in melanoma patients.
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PMID:Raf inhibitor stabilizes receptor for the type I interferon but inhibits its anti-proliferative effects in human malignant melanoma cells. 1787 16

Many bacteria pathogenic for plants or animals, including Shigella spp., which is responsible for shigellosis in humans, use a type III secretion apparatus to inject effector proteins into host cells. Effectors alter cell signaling and host responses induced upon infection; however, their precise biochemical activities have been elucidated in very few cases. Utilizing Saccharomyces cerevisiae as a surrogate host, we show that the Shigella effector IpaH9.8 interrupts pheromone response signaling by promoting the proteasome-dependent destruction of the MAPKK Ste7. In vitro, IpaH9.8 displayed ubiquitin ligase activity toward ubiquitin and Ste7. Replacement of a Cys residue that is invariant among IpaH homologs of plant and animal pathogens abolished the ubiquitin ligase activity of IpaH9.8. We also present evidence that the IpaH homolog SspH1 from Salmonella enterica can ubiquitinate ubiquitin and PKN1, a previously identified SspH1 interaction partner. This study assigns a function for IpaH family members as E3 ubiquitin ligases.
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PMID:Type III secretion effectors of the IpaH family are E3 ubiquitin ligases. 1800 83

Inactivation of tumor suppressors is among the rate-limiting steps in carcinogenesis that occur during the tumor promotion stage. The translation inhibitor programmed cell death 4 (Pdcd4) suppresses tumorigenesis and invasion. Although Pdcd4 is not mutationally inactivated in human cancer, the mechanisms controlling Pdcd4 inactivation during tumorigenesis remain elusive. We report that tumor promoter 12-O-tetradecanoylphorbol-13-acetate exposure decreases protein levels of Pdcd4 in mouse skin papillomas and keratinocytes as well as in human HEK293 cells. This decrease is attributable to increased proteasomal degradation of Pdcd4 and is mediated by protein kinase C-dependent activation of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin-p70(S6K) and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK signaling. Both Akt and p70(S6K) phosphorylate Pdcd4, allowing for binding of the E3-ubiquitin ligase beta-TrCP and consequently ubiquitylation. MEK-ERK signaling on the other hand facilitates the subsequent proteasomal degradation. We further show that Pdcd4 protein levels in vivo are limiting for tumor formation, establishing Pdcd4 as a haploinsufficient tumor suppressor in Pdcd4-deficient mice. Thus, because endogenous Pdcd4 levels are limiting for tumorigenesis, inhibiting signaling to Pdcd4 degradation may prove a valid strategy for cancer prevention and intervention.
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PMID:Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion. 1829 47

Cdc20, an activator of the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase, initiates the destruction of key mitotic regulators to facilitate mitosis, while it is negatively regulated by the spindle assembly checkpoint (SAC) to prevent premature anaphase entry. Activation of the p38 mitogen-activated protein kinase could contribute to mitotic arrest, but the underlying mechanism is unknown. Here we report a novel pathway in which the p38 signaling triggers Cdc20 destruction under SAC elicited by cadmium, a human carcinogen. We found that the cadmium-induced prometaphase arrest was linked to decreased Cdc20 and accumulated cyclin A protein levels in human cells, whereas the activity of cyclin B1-Cdk1 was unaffected. The Cdc20 half-life was markedly shortened along with its ubiquitination and degradation via 26S proteasome in cadmium-treated asynchronous or G(2)-enriched cells. Depletion of APC3 markedly suppressed the cadmium-induced Cdc20 ubiquitination and proteolysis, while depletion of Cdh1, another activator of APC/C, did not. Intriguingly, blockage of p38 activity restored the Cdc20 levels for continuing mitosis under cadmium, while inhibition of JNK activity had no effect. The cadmium-induced Cdc20 proteolysis was also suppressed during transient depletion of p38alpha or stable expression a dominant negative form of p38. Inhibition of p38 abolished the induction of Mad2-Cdc20-APC3 complex by cadmium. Moreover, forced expression of MKK6-p38 signaling could promote Cdc20 degradation in a Cdh1-independent APC/C pathway. In summary, accelerated ubiquitination and proteolysis of Cdc20 is essential for prometaphase arrest that is mediated via the p38 signaling during SAC activation.
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PMID:Cdc20 proteolysis requires p38 MAPK signaling and Cdh1-independent APC/C ubiquitination during spindle assembly checkpoint activation by cadmium. 2005 26


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