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)

Human cyclin D1 has been associated with a wide variety of proliferative diseases but its biochemical role is unknown. In diploid fibroblasts we find that cyclin D1 is complexed with many other cellular proteins. Among them are protein kinase catalytic subunits CDK2, CDK4 (previously called PSK-J3), and CDK5 (also called PSSALRE). In addition, polypeptides of 21 kd and 36 kd are identified in association with cyclin D1. We show that the 36 kd protein is the proliferating cell nuclear antigen, PCNA. Cyclin D3 also associates with multiple protein kinases, p21 and PCNA. It is proposed that there exists a quaternary complex of D cyclin, CDK, PCNA, and p21 and that many combinatorial variations (cyclin D1, D3, CDK2, 4, and 5) may assemble in vivo. These findings link a human putative G1 cyclin that is associated with oncogenesis with a well-characterized DNA replication and repair factor.
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PMID:D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. 135 58

p107wee1 is a protein kinase that functions as a dose-dependent inhibitor of mitosis through its interactions with p34cdc2 in Schizosaccharomyces pombe. To characterize the kinase activity of p107wee1, its carboxyl-terminal catalytic domain was purified to homogeneity from overproducing insect cells. The apparent molecular mass of the purified protein (p37wee1KD) was determined to be approximately 37 kDa by gel filtration, consistent with it being a monomer. Serine and tyrosine kinase activities cofiltered with p37wee1KD, demonstrating that p107wee1 is a dual-specificity kinase. In vitro, p107wee1 phosphorylated p34cdc2 on Tyr-15 only when p34cdc2 was complexed with cyclin. Neither monomeric p34cdc2 nor a peptide containing Tyr-15 was able to substitute for the p34cdc2/cyclin complex in this assay. Furthermore, the phosphorylation of p34cdc2 by p107wee1 in vitro inhibited the histone H1 kinase activity of p34cdc2. These results indicate that p107wee1 functions as a mitotic inhibitor by directly phosphorylating p34cdc2 on Tyr-15 and that the preferred substrate for phosphorylation is the p34cdc2/cyclin complex.
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PMID:p107wee1 is a dual-specificity kinase that phosphorylates p34cdc2 on tyrosine 15. 137 94

Entry into mitosis in Schizosaccharomyces pombe is negatively regulated by the wee1+ gene, which encodes a protein kinase with serine-, theonine-, and tyrosine-phosphorylating activities. The wee1+ kinase negatively regulates mitosis by phosphorylating p34cdc2 on tyrosine 15, thereby inactivating the p34cdc2-cyclin B complex. The human homolog of the wee1+ gene (WEE1Hu) was overproduced in bacteria and assayed in an in vitro system. Unlike its fission yeast homolog, the product of the WEE1Hu gene encoded a tyrosine-specific protein kinase. The human WEE1 kinase phosphorylated the p34cdc2-cyclin B complex on tyrosine 15 but not on threonine 14 in vitro and inactivated the p34cdc2-cyclin B kinase. This inhibition was reversed by the human Cdc25C protein, which catalyzed the dephosphorylation of p34cdc2. These results indicate that the product of the WEE1Hu gene directly regulates the p34cdc2-cyclin B complex in human cells and that a kinase other than that encoded by WEE1Hu phosphorylates p34cdc2 on threonine 14.
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PMID:Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. 138 26

Mitotic cyclins are thought to function as key regulatory subunits of the universal M-phase-promoting p34cdc2 protein kinase. Previous immunolocalization studies have demonstrated that a fraction of p34cdc2 undergoes cell cycle-dependent accumulation at the centrosome during G2/M. In order to identify the mitotic cyclins with which this p34cdc2 fraction interacts, we carefully examined the subcellular distribution of both cyclin A and B1 in HeLa cells. We show here that part of cyclin B1 is associated with duplicating centrosomes throughout its accumulation in the cytoplasm and up to metaphase. In contrast cyclin A does not exhibit centrosomal association except at the onset of mitosis, from preprophase up to metaphase. We also present cytological and biochemical evidence that cyclin B1 is preferentially accumulated as a detergent-insoluble protein independently of the state of microtubule assembly and under experimental conditions where most of p34cdc2 is soluble. Interestingly, the electrophoretic pattern of the minor insoluble p34cdc2 fraction was previously shown to be particularly enriched in slow-migrating and presumably hyperphosphorylated isoforms, known to interact specifically with cyclin B1 during interphase. From these results we propose that the interaction of cyclin B1 with the centrosomes and with the cytoplasmic structures is a constitutive feature of the mechanism whereby a fraction of p34cdc2 is recruited and subsequently targeted to the cyclin B-dependent activation pathway.
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PMID:Cytoplasmic accumulation of cyclin B1 in human cells: association with a detergent-resistant compartment and with the centrosome. 138 77

Human cyclin E, originally identified on the basis of its ability to function as a G1 cyclin in budding yeast, associated with a cell cycle-regulated protein kinase in human cells. The cyclin E-associated kinase activity peaked during G1, before the appearance of cyclin A, and was diminished during exit from the cell cycle after differentiation or serum withdrawal. The major cyclin E-associated kinase in human cells was Cdk2 (cyclin-dependent kinase 2). The abundance of the cyclin E protein and the cyclin E-Cdk2 complex was maximal in G1 cells. These results provide further evidence that in all eukaryotes assembly of a cyclin-Cdk complex is an important step in the biochemical pathway that controls cell proliferation during G1.
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PMID:Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. 138 88

Previously, we have shown that nuclear envelope assembly in cell-free extracts of Xenopus eggs requires two distinct vesicle-containing fractions, called Nuclear Envelope Precursor Fractions A and B (NEP-A and NEP-B). These fractions are characterized further in this paper and the manner in which they are regulated during metaphase is examined. Antisera against the NEP-B fraction recognized several proteins common to NEP-B and Xenopus oocyte or liver nuclei, but not to NEP-A or cytosol. A known glycoprotein component of the nuclear pore complex, p62, also co-fractionated with NEP-B, whereas the Xenopus egg lamin LIII did not. Together, these results provide further evidence that the NEP-B fraction contains precursors of the nuclear envelope. The regulation of NEP-A and -B function during metaphase, when the nuclear envelope is disassembled, was examined by treating each fraction with metaphase cytosol or purified protein kinase preparations isolated from metaphase-arrested eggs. Treatment of NEP-B with metaphase cytosol, under conditions where proteins are irreversibly phosphorylated, inhibited the subsequent assembly of the nuclear envelope by preventing the binding of NEP-B to chromatin. In contrast, similar treatment of NEP-A did not affect its ability to form nuclear envelopes. The changes in NEP-B during metaphase did not appear to be regulated directly by either p34cdc2/cyclin B, S6 kinase II or MAP kinase.
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PMID:Regulation of nuclear envelope precursor functions during cell division. 140 Jun 33

Increasing attention has been focused on how the retinoblastoma (RB) protein regulates cell growth. Recent evidence indicates that it is a substrate for phosphorylation by cyclin-dependent kinase-cyclin complexes and suggests that this phosphorylation modulates the ability of this protein to regulate transit through the cell cycle, perhaps in its G1 phase.
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PMID:The retinoblastoma protein and the regulation of cell cycling. 141 5

The cell cycle in Saccharomyces cerevisiae is controlled by regulation of START in late G1. The CLN1, CLN2 and CLN3 family of cyclin homologues is required for cells to pass START. They probably act by activating the CDC28 protein kinase. Expression of CLN1 or CLN3 under the control of an inducible promoter shows that transcription of either gene is sufficient for cyclin-deficient strains arrested in G1 to traverse START. A model of START regulation involves activation of CDC28 kinase by any CLN protein, leading to activation of CLN1 and CLN2 transcription in a positive feedback loop and passage through START. The cell cycle-dependent transcriptional regulators SWI4 and SWI6 may be components of the feedback loop. Cell cycle commitment entails resistance to the inhibitory action of mating factor, which correlates with peak levels of CLN1 and CLN2 mRNAs. FAR1 encodes an alpha-factor-dependent inhibitor of CLN function whose expression is markedly reduced at the time of START. The interplay of all these factors may sharpen the START transition such that it is close to an all-or-nothing switch event. This may be important for several START-dependent events to be activated at the same time, leading to coordinated cell cycle progression.
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PMID:Is START a switch? 148 46

The proliferative effects of colony-stimulating factor 1 (CSF-1) on macrophages are exerted only throughout the G1 phase of the cell cycle. Genetic targets of the delayed early response to CSF-1 include novel G1 cyclin (CYL or cyclin D) genes. In macrophages, cyclin D1 is induced early in G1 and is expressed throughout the cell cycle as long as CSF-1 is present. The cyclin D1 protein turns over rapidly in CSF-1-stimulated cells and its level declines precipitously upon CSF-1 withdrawal. Cyclin D2 is induced later in G1 and its expression is periodic, whereas cyclin D3 is not expressed in macrophages but is regulated by growth factors in other cell types. The cyclin D1 protein associates during G1 with a polypeptide antigenically related to p34cdc2 and binds in vitro to a histone H1 kinase present in lysates of CSF-1-starved macrophages. The instability of the cyclin D1 protein and its ability to rescue a cyclin-dependent kinase activity from growth factor-deprived macrophages together suggest that the cyclin D protein is the dynamic partner in the complex. The timing of expression of cyclin D genes suggests that they act to link growth factor signals with cell cycle transitions during G1.
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PMID:Regulation of CYL/cyclin D genes by colony-stimulating factor 1. 148 47

Activation of the protein kinase p34cdc2 is required for entry into meiotic or mitotic M phase in all eukaryotic cells. One important mechanism regulating the activity of p34cdc2 during the cell cycle is based on phosphorylation/dephosphorylation. Avian p34cdc2 is phosphorylated on threonine 14 (Thr14), tyrosine 15 (Tyr15), threonine 161 (Thr161) and serine 277 (Ser277). Dephosphorylation of both Thr14 and Tyr15 is required for activation of p34cdc2 at the G2/M transition, indicating that phosphorylation of these residues negatively regulates p34cdc2 activity. Conversely, phosphorylation of Thr161 is required for kinase activity. Whether modification of this residue is due to intramolecular autophosphorylation or to the action of an as yet unidentified kinase remains unresolved. Likewise, the role of phosphorylation of p34cdc2 on Ser277 during G1 phase of the cell cycle remains to be determined. The function of p34cdc2 is regulated also by cell cycle-dependent complex formation with cyclin proteins. We found that chicken cyclin B2 undergoes a striking redistribution from the cytoplasm to the nucleus just prior to the onset of mitosis. Expression of a non-destructible cyclin B2 mutant causes HeLa cells to arrest in mitosis. Frequently, arrested cells displayed multiple mitotic spindles.
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PMID:Regulation of p34cdc2 protein kinase activity by phosphorylation and cyclin binding. 148 52


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