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

Some anticancer agents induce cell cycle arrest. We analyzed the effect of anticancer agents on cell-cycle regulators, such as CDK. Our data suggested that arresting cells in the G2-phase of the cell cycle by cisplatin might be regulated by dephosphorylation of cdc2 kinase. Butyrolactone I inhibits both cdc2 and CDK2 kinase in the cell-free system. The cytotoxic effect of paclitaxel shows mainly in the M-phase of the cell cycle. Suramin inhibits cdc2 kinase. UCN-01, a protein kinase-C inhibitor, also inhibits both cdc2 and CDK2 kinase. Some anticancer agents induce apoptosis.
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PMID:[Cell cycle regulation by anticancer agent]. 757 1

Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase is required for the activation of CDK enzymes. Members of two families of CDK inhibitors, p16/p18 and p21/p27, become physically associated with and inhibit the activity of CDKs in response to a variety of growth-modulating signals. Here, we show that the representative members of both families of CDK inhibitors, p21waf1,cip1, p27kip1, and p18, can prevent the phosphorylation of their CDK partners, CDK2 and CDK6, by CDK-activating kinase. No direct interaction between CDK-activating kinase and the CDK inhibitors could be detected, suggesting that binding of these CDK inhibitors to CDK subunits renders CDK inaccessible to the CDK-activating kinase phosphorylation. These findings suggest that a general mechanism of CDK inhibitor function is to block the phosphorylation of CDK enzymes by CDK-activating kinase.
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PMID:Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase. 762 34

Cyclin D-dependent kinases act as mitogen-responsive, rate-limiting controllers of G1 phase progression in mammalian cells. Two novel members of the mouse INK4 gene family, p19 and p18, that specifically inhibit the kinase activities of CDK4 and CDK6, but do not affect those of cyclin E-CDK2, cyclin A-CDK2, or cyclin B-CDC2, were isolated. Like the previously described human INK4 polypeptides, p16INK4a/MTS1 and p15INK4b/MTS2, mouse p19 and p18 are primarily composed of tandemly repeated ankyrin motifs, each ca. 32 amino acids in length, p19 and p18 bind directly to CDK4 and CDK6, whether untethered or in complexes with D cyclins, and can inhibit the activity of cyclin D-bound cyclin-dependent kinases (CDKs). Although neither protein interacts with D cyclins or displaces them from preassembled cyclin D-CDK complexes in vitro, both form complexes with CDKs at the expense of cyclins in vivo, suggesting that they may also interfere with cyclin-CDK assembly. In proliferating macrophages, p19 mRNA and protein are periodically expressed with a nadir in G1 phase and maximal synthesis during S phase, consistent with the possibility that INK4 proteins limit the activities of CDKs once cells exit G1 phase. However, introduction of a vector encoding p19 into mouse NIH 3T3 cells leads to constitutive p19 synthesis, inhibits cyclin D1-CDK4 activity in vivo, and induces G1 phase arrest.
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PMID:Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. 773 47

The cell cycle in mammalian cells is regulated by a series of cyclins and cyclin-dependent kinases (CDKs). The G1/S checkpoint is mainly dictated by the kinase activities of the cyclin D-CDK4 and/or cyclin D-CDK6 complex and the cyclin E-CDK2 complex. These G1 kinases can in turn be regulated by cell cycle inhibitors, which may cause the cells to arrest at the G1 phase. In T-cell hybridomas, addition of anti-T-cell receptor antibody results not only in G1 arrest but also in apoptosis. In searching for a protein(s) which might interact with Nur77, an orphan steroid receptor required for activation-induced apoptosis of T-cell hybridomas, we have cloned a novel human and mouse CDK inhibitor, p19. The deduced p19 amino acid sequence consists of four ankyrin repeats with 48% identity to p16. The human p19 gene is located on chromosome 19p13, distinct from the positions of p18, p16, and p15. Its mRNA is expressed in all cell types examined. The p19 fusion protein can associate in vitro with CDK4 but not with CDK2, CDC2, or cyclin A, B, E, or D1 to D3. Addition of p19 protein can lead to inhibition of the in vitro kinase activity of cyclin D-CDK4 but not that of cyclin E-CDK2. In T-cell hybridoma DO11.10, p19 was found in association with CDK4 and CDK6 in vivo, although its association with Nur77 is not clear at this point. Thus, p19 is a novel CDK inhibitor which may play a role in the cell cycle regulation of T cells.
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PMID:Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. 773 48

We have recently shown that two proteins, proliferating cell nuclear antigen (PCNA) and p21, are associated with cyclin D. Here we show that PCNA and p21 are common components of a wide variety of cyclin/cyclin-dependent kinase complexes in nontransformed cells. These include kinase complexes containing cyclin A, cyclin B, and cyclin D, associated either with CDC2, CDK2, CDK4, or CDK5. We show that PCNA and p21 form separate quaternary complex with each cyclin/CDK and that these quaternary complexes contain a substantial, if not major, fraction of the cell cycle kinases in asynchronously growing cells. These results suggest that PCNA and p21 may perform a common function for all these kinases.
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PMID:Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. 790 56

In normal human fibroblast cells, the primary cell cycle regulators, the cyclin-dependent kinases (CDKs), exist predominantly in multiple quaternary complexes, each consisting of a CDK, a cyclin, proliferating cell nuclear antigen (PCNA) and p21. p21 encodes a universal inhibitor of cyclin-dependent kinases. Here we show that the level of p21 mRNA and the interaction of p21 protein with cyclin-CDK enzymes are regulated during the cell cycle. When normal human fibroblast IMR90 cells were released from serum starvation, p21 mRNA reached its highest level immediately following serum stimulation, began to decrease at the G1/S boundary, fell to its lowest level during S phase, and accumulated again as cells exited from S phase. p21 protein associates with each cyclin-CDK complex in a cell cycle dependent manner. Cyclin A-CDK2-p21-PCNA and Cyclin B1-CDC2-p21-PCNA complexes are assembled in early S and G2 phase, respectively, indicating that p21 and/or PCNA regulates the enzymatic activity of each kinase at the time of their functioning. Cyclin D1-CDK4-p21-PCNA complexes, on the other hand, persist throughout the cell cycle, suggesting that cyclin D1-CDK4 quaternary complexes may play a role in monitoring an event(s) that may occur at any time, rather than at a specific stage of the cell cycle. The level of p21 mRNA in early passage Li-Fraumeni cells that are heterozygous for p53 mutation remained similar to that in normal fibroblasts, but was undetectable in immortalized Li-Fraumeni cells homozygous for mutant p53. This finding provides a plausible molecular explanation for the loss of genetic stability associated with cells homozygous, but not heterozygous, for p53 mutation.
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PMID:Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. 791 44

In the fission yeast Schizosaccharomyces pombe, cdc2 function is required both in G1 to enter the cell cycle and in G2 to initiate mitosis. In higher eukaryotes, these functions appeared to be shared between several cdc2-like genes including CDK2. Temperature-sensitive mutations in S. pombe cdc2 that arrest the cell cycle in both G1 and G2 phases are not complemented by CDK2. We have used S. pombe to investigate what functions CDK2 can perform. We found that overexpression of the human homologue (HsCDK2) caused cell cycle arrest in G2/M showing that HsCDK2 interfered with mitotic events. Xenopus CDK2 (XlCDK2) overexpression did not cause cell cycle arrest and could rescue the G1 block but not the G2 block of a cdc2-M26 ts strain. A mutant XlCDK2-R33, which is inactive as a kinase, failed to rescue the G1 block, suggesting that the protein kinase activity of CDK2 is required to enter the cell cycle in these circumstances. We designed screens to select mutants that would require XlCDK2 expression for viability, hoping to isolate new gene functions interacting with, or that could be replaced by, XlCDK2 in G1, or new cdc2 mutants altered solely in their G1 role. From these screens several cell cycle mutants were selected that were XlCDK2-dependent. These were all cdc2 mutants altered only in their G2/M function. Therefore XlCDK2 can influence both the G1/S and G2/M transition points of cdc2 in S. pombe.
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PMID:Study of the higher eukaryotic gene function CDK2 using fission yeast. 800 75

Phosphorylation by the CDK-activating kinase (CAK) is a required step in the activation of cyclin-dependent kinases. We have purified CAK from mammalian cells; the enzyme comprises two major polypeptides of 42 and 37 kDa. Protein sequencing indicates that the 42 kDa subunit is the mammalian homolog of MO15, a protein kinase known to be a component of CAK in amphibians and echinoderms. Cloning of a cDNA encoding the 37 kDa subunit identifies it as a novel cyclin (cyclin H). We have reconstituted CAK in vitro with the MO15 catalytic subunit and cyclin H, demonstrating that MO15 is a cyclin-dependent kinase (CDK7). Like other CDKs, MO15/CDK7 contains a conserved threonine required for full activity; mutation of this residue severely reduces CAK activity. The CAK holoenzyme activates complexes of CDK2 and CDC2 with various cyclins and also phosphorylates CDK2, but not CDC2, in the absence of cyclin. Thus, CAK is a CDK-cyclin complex implicated in the control of multiple cell cycle transitions.
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PMID:A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. 806 18

Structural models for the eukaryotic cell cycle control protein p34 from human, S. pombe and S. cerevisiae have been derived from the crystallographic coordinates of the cAMP-dependent protein kinase (cAPK) catalytic subunit (active conformation) and compared with the structure of inactive CDK2 apoenzyme. Differences between the p34 and cAPK catalytic sites provide a possible explanation for their different substrate specificities. The p34 models localize Tyr15 and Thr14 close to the sites of catalysis and substrate recognition where their phosphorylation could inhibit p34 kinase activity either by blocking MgATP or substrate binding. The conserved sequences PSTAIRE and LYLIFEFL are both close to the catalytic site and accessible on the protein surface available to mediate interactions with other proteins. It is predicted that p34 has an active-site cleft composed almost entirely of sequences common to all protein kinases and sequences unique to the p34 protein family. Genetic and biochemical analyses of p34 have shown that it interacts extensively with a number of other proteins. The model allows the relative disposition of these sites of mutation to each other and to the sites of catalysis and substrate recognition to be appreciated. Surface regions on p34 that are important for function have been identified. These sites identify residues that may interact with p13suc1, cyclin, p107wee1 and p80cdc25.
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PMID:Mutational analysis supports a structural model for the cell cycle protein kinase p34. 817 Sep 27


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