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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the transcription factor NF-kappaB by tumor necrosis factor (TNF) and interleukin-1 (IL-1) requires the NF-kappaB-inducing kinase (NIK). In a yeast two-hybrid screen for NIK-interacting proteins, we have identified a protein kinase previously known as CHUK. Overexpression of CHUK activates a NF-kappaB-dependent reporter gene. A catalytically inactive mutant of CHUK is a dominant-negative inhibitor of TNF-, IL-1-, TRAF-, and NIK-induced NF-kappaB activation. CHUK associates with the NF-kappaB inhibitory protein, IkappaB-alpha, in mammalian cells. CHUK specifically phosphorylates IkappaB-alpha on both serine 32 and serine 36, modifications that are required for targeted degradation of IkappaB-alpha via the ubiquitin-proteasome pathway. This phosphorylation of IkappaB-alpha is greatly enhanced by NIK costimulation. Thus, CHUK is a NIK-activated IkappaB-alpha kinase that links TNF- and IL-1-induced kinase cascades to NF-kappaB activation.
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PMID:Identification and characterization of an IkappaB kinase. 924 10

Immediately before the transition from metaphase to anaphase, the protein kinase activity of maturation or M-phase promoting factor (MPF) is inactivated by a mechanism that involves the degradation of its regulatory subunit, cyclin B. The availability of biologically active goldfish cyclin B produced in Escherichia coli and purified goldfish proteasomes (a nonlysosomal large protease) has allowed the role of proteasomes in the regulation of cyclin degradation to be examined for the first time. The 26S, but not the 20S proteasome, digested recombinant 49-kD cyclin B at lysine 57 (K57), producing a 42-kD truncated form. The 42-kD cyclin was also produced by the digestion of native cyclin B forming a complex with cdc2, a catalytic subunit of MPF, and a fragment transiently appeared during cyclin degradation when eggs were released from metaphase II arrest by egg activation. Mutant cyclin at K57 was resistant to both digestion by the 26S proteasome and degradation at metaphase/anaphase transition in Xenopus egg extracts. The results of this study indicate that the destruction of cyclin B is initiated by the ATP-dependent and ubiquitin-independent proteolytic activity of 26S proteasome through the first cutting in the NH2 terminus of cyclin (at K57 in the case of goldfish cyclin B). We also surmise that this cut allows the cyclin to be ubiquitinated for further destruction by ubiquitin-dependent activity of the 26S proteasome that leads to MPF inactivation.
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PMID:Initiation of cyclin B degradation by the 26S proteasome upon egg activation. 929 86

Significant progress has been made on the random sequencing of cDNAs (ESTs) and the genetic and physical mapping of the Arabidopsis thaliana genome. New techniques are now required to identify and map the expressed genes efficiently on A. thaliana chromosomes. A novel method to construct a transcription map of expressed genes or cDNAs in specific regions of the genome using DNA-latex particles has been developed. The region-specific DNA fragments prepared from six cosmid clones that constitute a contig covering the abi1 locus on chromosome 4 were covalently bound to latex particles. The DNA-latex particles were used for the selection of region-specific cDNAs. Sequence analysis of the cDNA clones revealed that ABI1, RPS2, casein kinase 1 (CK1), nucleosome assembly protein I (NAP) cDNAs and T20837 EST, which are situated within the contig near abi1 locus, were selected. These results indicate that the cDNAs in the specific region of the genome were faithfully selected with this method. Sequence analysis also indicated that 11 selected cDNAs were derived from novel genes located near the abi1 locus and that four of the selected cDNAs encode putative proteins that have sequence similarity to cationic peroxidase, phosphatidylserine decarboxylase 2 (PSD2), trans-caffeoyl CoA 3-O-methyltransferase (CCoAMT), and proteasome subunit XC3.
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PMID:Rapid construction of a transcription map for a cosmid contig of Arabidopsis thaliana genome using a novel cDNA selection method. 930 Oct 97

The Raf-1-MEK-MAPK pathway plays an important role in transducing extracellular growth factor signaling into altered nuclear transcription factor function. The benzoquinone ansamycin Geldanamycin (GA) specifically binds to the heat shock protein HSP90 and alters its complex with Raf-1. This leads to a decrease in Raf-1 levels and to disruption of the Raf-1-MEK-MAPK signaling pathway. The enhanced degradation of Raf-1 protein was prevented by inhibitors of the proteasome, while inhibition of lysosomal or other proteases was ineffective. Raf-1 that was protected from GA-induced degradation was of higher molecular weight and showed a laddering pattern consistent with its polyubiquitination. Unlike Raf-1 in untreated cells, the protein was insoluble in Triton X100- or NP40-based buffers. Signaling through this pathway was inhibited by GA, concomitant with loss of Raf-1 protein, but was restored if Raf-1 was protected from GA-induced degradation by proteasome inhibitors.
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PMID:Geldanamycin-induced destabilization of Raf-1 involves the proteasome. 936 23

In eukaryotes the activity of CDK1 (CDC2), a cyclin-dependent kinase that initiates the structural changes that culminate in the segregation of chromosomes at mitosis, is regulated by the synergistic and opposing activities of a cascade of kinases and phosphatases. Dephosphorylation of threonine 14 and tyrosine 15 of CDK1 by the CDC25 phosphatases is a key step in the activation of the CDK1-cyclin B protein kinase. Little is currently known about the role and the regulation of CDC25B. Here we report in vitro and in vivo data that indicate that CDC25B is degraded by the proteasome. This degradation is dependent upon phosphorylation by the CDK1-cyclin A complex but not by CDK1-cyclin B. These results indicate that CDK1-cyclin A phosphorylation targets CDC25B for degradation and that this might be an important component of cell cycle regulation at the G2/M transition.
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PMID:Phosphorylation of human CDC25B phosphatase by CDK1-cyclin A triggers its proteasome-dependent degradation. 940 44

Selective degradation of cyclins, inhibitors of cyclin-dependent kinases and anaphase inhibitors is responsible for several major cell cycle transitions. The degradation of these cell cycle regulators is controlled by the action of ubiquitin-protein-ligase complexes, which target the regulators for degradation by the 26S proteasome. Recent results indicate that two types of multisubunit ubiquitin ligase complexes, which are connected to the protein kinase regulatory network of the cell cycle in different ways, are responsible for the specific and programmed degradation of many cell cycle regulators.
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PMID:Roles of ubiquitin-mediated proteolysis in cell cycle control. 942 43

The well-known Rel/NF-kappaB family of vertebrate transcription factors comprises a number of structurally related, interacting proteins that bind DNA as dimers and whose activity is regulated by subcellular location. This family includes many members (p50, p52, RelA, RelB, c-Rel, ...), most of which can form DNA-binding homo- or hetero-dimers. All Rel proteins contain a highly conserved domain of approximately 300 amino-acids, called the Rel homology domain (RH), which contains sequences necessary for the formation of dimers, nuclear localization, DNA binding and IkappaB binding. Nuclear expression and consequent biological action of the eukaryotic NF-kappaB transcription factor complex are tightly regulated through its cytoplasmic retention by ankyrin-rich inhibitory proteins known as IkappaB. The IkappaB proteins include a group of related proteins that interact with Rel dimers and regulate their activities. The interaction of a given IkappaB protein with a Rel complex can affect the Rel complex in distinct ways. In the best characterized example, IkappaB-alpha interacts with a p50/RelA (NF-kappaB) heterodimer to retain the complex in the cytoplasm and inhibit its DNA-binding activity. The NF-kappaB/IkappaB-alpha complex is located in the cytoplasm of most resting cells, but can be rapidly induced to enter the cell nucleus. Upon receiving a variety of signals, many of which are probably mediated by the generation of reactive oxygen species (ROS), IkappaB-alpha undergoes phosphorylation at serine residues by a ubiquitin-dependent protein kinase, is then ubiquitinated at nearby lysine residues and finally degraded by the proteasome, probably while still complexed with NF-kappaB. Removal of IkappaB-alpha uncovers the nuclear localization signals on subunits of NF-kappaB, allowing the complex to enter the nucleus, bind to DNA and affect gene expression. Like proinflammatory cytokines (e.g. IL-1, TNF), various ROS (peroxides, singlet oxygen, ...) as well as UV (C to A) light are capable of mediating NF-kappaB nuclear translocation, while the sensor molecules which are sensitive to these agents and trigger IkappaB-alpha proteolysis are still unidentified. We also show that a ROS-independent mechanism is activated by IL-1beta in epithelial cells and seems to involve the acidic sphingomyelinase/ceramide transduction pathway.
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PMID:Multiple redox regulation in NF-kappaB transcription factor activation. 942 83

In fission yeast, the cyclin-dependent kinase (CDK) inhibitor p25(rum1) is a key regulator of progression through the G1 phase of the cell cycle. We show here that p25(rum1) protein levels are sharply periodic. p25(rum1) begins to accumulate at anaphase, persists in G1 and is destroyed during S phase. p25(rum1 )is stabilized and polyubiquitinated in a mutant defective in the 26S proteasome, suggesting that its degradation normally occurs through the ubiquitin-dependent 26S proteasome pathway. Phosphorylation of p25(rum1 )by cdc2-cyclin complexes at residues T58 and T62 is important to target the protein for degradation. Mutation of one or both of these residues to alanine causes stabilization of p25(rum1) and induces a cell cycle delay in G1 and polyploidization due to occasional re-initiation of DNA replication before mitosis. The CDK-cyclin complex cdc2-cig1, which is insensitive to p25(rum1 )inhibition, seems to be the main kinase that phosphorylates p25(rum1). Phosphorylation of p25(rum1) in S phase and G2 serves as the trigger for p25(rum1) proteolysis. Thus, periodic accumulation and degradation of the CDK inhibitor p25(rum1 )in G1 plays a role in setting a threshold of cyclin levels important in determining the length of the pre-Start G1 phase and in ensuring the correct order of cell cycle events.
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PMID:Regulation of the G1 phase of the cell cycle by periodic stabilization and degradation of the p25rum1 CDK inhibitor. 943 Jun 40

We previously reported that insulin activates nuclear factor kappaB (NF-kappaB) in Chinese hamster ovary (CHO)-R cells overexpressing wild-type insulin receptors (IRs) through a pathway requiring IR tyrosine kinase and Raf-1 kinase activities. We now investigated whether the activation of NF-kappaB by insulin could serve an antiapoptotic function. Insulin (10(-9)-10(-7) M) inhibited apoptosis induced by serum withdrawal in CHO-R cells in a concentration-dependent manner. Insulin antiapoptotic signaling: (i) was dependent on IR number and IR tyrosine kinase activity since it was reduced in parental CHO cells and was abolished in CHO-Y2 cells overexpressing IRs mutated at Tyr1162/1163; (ii) was, like insulin activation of NF-kappaB, dependent on Raf-1 but not on mitogen-activated protein kinase activity since both processes were decreased by the dominant-negative Raf-1 mutant Raf-C4 whereas they persisted in mitogen-activated protein kinase-depleted cells; and (iii) required NF-kappaB activation since it was decreased by proteasome inhibitors and the dominant-negative IkappaB-alpha (A32/36) mutant and was mimicked by overexpression of the NF-kappaB c-Rel subunit. We also show that insulin antiapoptotic signaling but not insulin activation of NF-kappaB involved phosphatidylinositol 3-kinase (PI 3-kinase), as supported by the inhibition of the former but not of the latter process by the PI 3-kinase inhibitor LY294002. Inhibition of both NF-kappaB and PI 3-kinase totally abolished insulin antiapoptotic signaling. Thus insulin exerts a specific antiapoptotic function which is dependent on IR tyrosine kinase activity and is mediated by both a Raf-1-dependent pathway that leads to NF-kappaB activation and a PI 3-kinase-dependent pathway.
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PMID:A role for nuclear factor kappaB in the antiapoptotic function of insulin. 944 5

A variety of studies have demonstrated the critical role of the Rb/E2F pathway in the control of cell growth and have highlighted a complexity in the accumulation of both the E2F family proteins and the Rb family of proteins. Whereas the Rb protein is found in both growing and quiescent cells, the accumulation of p130 and p107 is tightly regulated with respect to the growth state of the cell. The p130 protein is found in quiescent cells but not in growing cells, whereas the inverse is true for the p107 protein. Control of p130 accumulation is posttranscriptional, because p130 RNA is relatively constant in growing and quiescent cells. The disappearance of the p130 protein after stimulation of cell growth coincides with cyclin-dependent kinase-mediated phosphorylation and is blocked by inhibitors of the 26S proteasome. In contrast, the cell growth-dependent regulation of p107 expression reflects the transcriptional regulation of the p107 gene. Similar to several other growth-regulated genes, the control of p107 expression is largely the result of E2F-dependent repression in quiescent cells. These experiments thus demonstrate a control of Rb family member expression mediated through distinct mechanisms of both transcriptional and posttranslational control and also suggest an intimate relationship in which p130 controls the expression of p107.
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PMID:Distinct mechanisms control the accumulation of the Rb-related p107 and p130 proteins during cell growth. 956 49


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