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)

DNA replication and mitosis are dependent on the activity of cyclin-dependent protein kinase (CDK) enzymes, which are heterodimers of a catalytic subunit with a cyclin subunit. Cyclin binding to specific individual proteins is thought to provide potential substrates to Cdk. Protein binding by cyclins is assessed in terms of its mechanisms and biological significance, using evidence from diverse organisms including substrate specificity in animal Cdk enzymes containing D-, A-, and B-type cyclins and extensive cyclin gene manipulations in yeasts. Assembly of protein complexes with cyclin/Cdk is noted and the capacity of the cyclin-dependent kinase subunit Cks, in such complex, to extend the range of Cdk substrates is documented and discussed in terms of cell cycle regulation. Cell cycle progression involves changing abundance of individual cyclins, due to changing rates of their transcription or proteolysis, with consequent changes in the substrates of CDK through the cell cycle. Some overlap of the functions of individual cyclins in vivo has been identified by cyclin deletions and is suggested to follow a pattern in which cyclins can commonly complete functions initiated by the preceding cyclins well enough to preserve viability as groups of cyclins are removed by proteolysis. Cyclin accumulation is particularly important in terminating the G1 phase, when it raises CDK activity and starts events leading to DNA replication. It is suggested that plants share this mechanism. The distribution of cyclins and Cdk in maize root tip cells during mitosis and cytokinesis indicates the presence of Cdk1 (Cdc2a) and cyclin CycB1zm;2 at the mature and disassembling preprophase band and the presence of CycB1zm;2 at condensing and condensed chromosomes. Both observations correlate with the earlier-reported capacity of injected metaphase cyclin/CDK to accelerate preprophase band disassembly and chromosome condensation and with observations of the location of Cdk and cyclins in other laboratories. Additionally CycB1zm;2 is seen at the nuclear envelope during its breakdown, which correlates with an acceleration of the process by injected metaphase cyclin B/CDK. A phenomenon possibly unique to the plant kingdom is the persistence of mitotic cyclins after anaphase. Participation of cyclins in cytokinesis is indicated by the concentration of the mitotic cyclin CycA1;zm;1 at the phragmoplast. It is suggested that cyclins have a general function of spatially focusing Cdk activity and that in the plant cell the concentrations of cyclins are important mediators of CDK activity at the cytoskeleton, chromosomes, spindle, nuclear envelope, and phragmoplast.
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PMID:Cyclin/Cdk complexes: their involvement in cell cycle progression and mitotic division. 1173 81

An in vitro model of neuronal precursors, primary culture of cerebellar granule progenitors (CGPs), was used to investigate the mechanisms underlying ethanol-induced cell cycle damage. The CGP cultures were generated from 3-day-old rats. Ethanol significantly inhibited the proliferation of the CGPs in culture. Analysis of cell cycle kinetics by a cumulative 5-bromo-2'-deoxyuridine (BrdU) labeling technique demonstrated that ethanol exposure increased the duration of the cell cycle and decreased the growth fraction (the cycling population). The duration of the S-phase and total cell cycle was significantly prolonged by ethanol exposure by 220% and 135%, respectively, while the growth fraction was decreased from 44% in the control groups to 22% in the ethanol-exposed cultures. Cyclin-dependent kinase 2 (Cdk2) is a key protein that regulates both the passage from G1 into S, and the S phase progression. The results from in vitro phosphorylation assay and Western blot demonstrated that ethanol dramatically down-regulated both the activity and the expression of Cdk2. In addition, ethanol significantly decreased the expression of Cyclin A and Cyclin D(2). Further studies using in situ TUNEL assay and DNA fragmentation ELISA showed that ethanol caused a delayed apoptosis, i.e. the ethanol-induced apoptosis was evident only after chronic exposure. On the other hand, ethanol did not affect the necrotic index. In conclusion, ethanol decreases the cycling pool of CGPs by inducing cell cycle delay and promoting apoptosis. Ethanol-mediated disturbance of the cyclin-dependent kinase system may be an important mechanism to account for cell cycle arrest in neuronal precursor cells.
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PMID:Disruption of cell cycle kinetics and cyclin-dependent kinase system by ethanol in cultured cerebellar granule progenitors. 1174 6

Phosphorylation of retinoblastoma protein (pRB) by cyclin-dependent kinases (CDKs) at multiple sites leads to activation of transcription of cell-cycle-related genes. Cyclin/CDK complexes thus play a pivotal role in the regulation of progression from G1 to S phase. In the present study, we developed a nonradioactive, sandwich enzyme-linked immunosorbent assay (ELISA) system for measuring activities of cyclin/CDK complexes, in which the immobilized monoclonal antibody works as a trap for phosphorylated pRB containing phosphorylated amino acids at specific sites. For this purpose, we raised monoclonal antibodies that are highly specific to ppRB phosphorylated at Ser780, Thr356, or Ser612 and used them as detectors for the individual reaction products by cyclin/CDK complexes. In particular, this approach proved useful for cyclin D1/CDK4 that specifically recognizes Ser780 in pRB with only very limited phosphorylation of a conventional substrate, histone H1. The study revealed the newly developed sandwich ELISA system to have advantages over the current radioisotope assay in terms of sensitivity, precision, and rapidity. It should find application for inhibitor screening and drug discovery related to CDKs.
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PMID:Enzyme-linked immunosorbent assay for distinct cyclin-dependent kinase activities using phosphorylation-site-specific anti-pRB monoclonal antibodies. 1181 68

The eukaryotic cell cycle is regulated by a family of serine/threonine protein kinases known as cyclin-dependent kinases (CDKs). The activation of a CDK is dependent on its association with a cyclin regulatory subunit. The formation of distinct cyclin-CDK complexes controls the progression through the first gap phase (G(1)) and initiation of DNA synthesis (S phase). These complexes are in turn regulated by protein phosphorylation and cyclin-dependent kinase inhibitors (CKIs). Cyclin E2 has emerged as the second member of the E-type cyclin family. Cyclin E2-associated kinase activity is regulated in a cell cycle dependent manner with peak activity at the G(1) to S transition. Ectopic expression of cyclin E2 in human cells accelerates G(1), suggesting that cyclin E2 is rate limiting for G(1) progression. Although the pattern and level of cyclin E2 expression in some primary tumor and normal tissue RNAs are distinct from cyclin E1, both E-type cyclins appear to have inherent functional redundancies. This functional redundancy has facilitated the rapid characterization of cyclin E2 and uncovered unique features associated with each E-type cyclin.
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PMID:Cyclin E2, the cycle continues. 1185 29

Cyclin dependent kinase 5 (Cdk5) is a proline-direct protein kinase that is most active in the CNS, and has been implicated as a contributing factor in certain neurodegenerative diseases. Further, there is evidence to suggest that Cdk5 may facilitate the progression of apoptosis. However, the mechanisms involved have not been elucidated. The tumor suppressor protein p53, a transcription factor that is regulated by phosphorylation, increases the expression of genes that control growth arrest or cell death. To understand how Cdk5 could facilitate apoptosis, the effects of Cdk5 on p53 activity were examined. In the present study it is shown that in apoptotic PC12 cells the levels of p53 and Cdk5 increase concomitantly. Further, Cdk5/p25 effectively phosphorylates recombinant p53 in vitro. Transient transfection of Cdk5/p25 into cells results in an increase in p53 levels, as well as the expression of the p53-responsive genes p21 and Bax. Furthermore, evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly, suggesting that p53 is modulated in situ by Cdk5. This is the first demonstration that p53 is a substrate of Cdk5, and that Cdk5 can modulate p53 levels and activity.
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PMID:Cdk5 phosphorylates p53 and regulates its activity. 1206 78

Cyclin-dependent kinases (cdks) coordinate progression through the eukaryotic cell cycle and require phosphorylation by a cdk-activating kinase (CAK) for full activity. In most eukaryotes Cdk7 is the catalytic subunit of a heterotrimeric CAK (Cdk7-cyclin H-Mat1) that is also involved in transcription as part of the transcription factor IIH complex. The Saccharomyces cerevisiae CAK, Cak1p, is a monomeric protein kinase with an atypical sequence and unusual biochemical properties compared with trimeric CAKs and other protein kinases. We sought to determine whether these properties were shared by a small group of monomeric CAKs that can function in place of CAK1 in S. cerevisiae. We found that Schizosaccharomyces pombe Csk1, Candida albicans Cak1, and Arabidopsis thaliana Cak1At, like Cak1p, all displayed a preference for cyclin-free cdk substrates, were insensitive to the protein kinase inhibitor 5'-fluorosulfonylbenzoyladenosine (FSBA), and were insensitive to mutation of a highly conserved lysine residue found in the nucleotide binding pocket of all protein kinases. The S. pombe and C. albicans kinases also resembled Cak1p in their kinetics of nucleotide and protein substrate utilization. Conservation of these unusual properties in fungi and plants points to shared evolutionary requirements not met by Cdk7 and raises the possibility of developing antifungal agents targeting CAKs.
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PMID:Comparison of Cak1p-like cyclin-dependent kinase-activating kinases. 1208 29

Cyclin dependent kinases are regulated by phosphorylation and dephosphorylation of the catalytic cdk subunits, by assembly with specific cyclins and by specific inhibitor molecules. Recently, it turned out that cyclins are also phosphoproteins, which means that they are also potential targets for a regulation by phosphorylation and dephosphorylation. Here, we show that cyclin H was phosphorylated by protein kinase CK2. Like most other CK2 substrates cyclin H was much better phosphorylated by the CK2 holoenzyme than by the alpha-subunit alone. By using point mutants derived from the cyclin H sequence we mapped the CK2 phosphorylation site at threonine 315 at the C-terminal end of cyclin H. Phosphorylation at this position had no influence on the assembly of the cyclin H/cdk7/Mat1 complex. However, phosphorylation at amino acid 315 of cyclin H turned out to be critical for a full cyclin H/cdk7/Mat1 kinase activity when the CTD peptide of RNA polymerase II or cdk2 was used as a substrate.
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PMID:The cyclin H/cdk7/Mat1 kinase activity is regulated by CK2 phosphorylation of cyclin H. 1214 Jul 53

Cyclin A is particularly interesting among the cyclin family because it can activate two different cyclin-dependent kinases (CDKs) and functions in both S phase and mitosis. An embryonic form of cyclin A that is only essential for spermatogenesis is also present in some organisms. In S phase, phosphorylation of components of the DNA replication machinery such as CDC6 by cyclin A-CDK is believed to be important for initiation of DNA replication and to restrict the initiation to only once per cell cycle. In mitosis, the precise role of cyclin A is still obscure, but it may contribute to the control of cyclin B stability. Cyclin A starts to accumulate during S phase and is abruptly destroyed before metaphase. The synthesis of cyclin A is mainly controlled at the transcription level, involving E2F and other transcription factors. Removal of cyclin A is carried out by ubiquitin-mediated proteolysis, but whether the same anaphase-promoting complex/cyclosome targeting subunits are used as for cyclin B is debatable. Consistent with its role as a key cell cycle regulator, expression of cyclin A is found to be elevated in a variety of tumors.
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PMID:Cyclin A in cell cycle control and cancer. 1236 35

Cyclin A is a protein kinase to act a pivotal role in the mitotic phase of the cell cycle. The purpose of the current study was to elucidate the biological significance of immunohistochemical expression of cyclin A in superficial squamous cell carcinoma (SCC) of the esophagus. Immunohistochemical staining of cyclin A was performed for 45 samples of esophageal superficial SCCs. Clinicopathological features were compared between SCCs with and without cyclin A expression. Twenty-five superficial SCCs (55.6%) had positive expression of cyclin A and the other 20 (44.4%) did not. No significant difference regarding clinicopathological characteristics between esophageal SCCs with and without cyclin A expression. Infiltration of lymphocytes with germinal center cells was observed beneath 17 (68.0%) out of 25 superficial SCCs with cyclin A expression and 15 (75.0%) out of 20 superficial SCCs without cyclin A expression. Although 16 (94.1%) out of 17 superficial SCCs with cyclin A expression were associated with cyclin A expression in germinal center cells in infiltrated lymphoid follicles beneath the tumors, only 2 (13.3%) out of 15 superficial SCCs without cyclin A expression coexisted with cyclin A expression in lymphoid follicles beneath the tumors (P<0.0001). Cyclin A expression in the germinal center cells of the lymphoid follicles beneath the superficial SCCs of the esophagus might be an immunological signal toward the proliferation and progression of the tumors.
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PMID:Cyclin A expression in superficial squamous cell carcinoma of the esophagus and coexisting infiltrated lymphocyte follicle. 1240 68

Unconstrained cell proliferation is characteristic of tumors. It is caused by the functional disorders of proteins that constitute the cell cycle mechanism. The cell cycle is controlled by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors. Many reports have proved, in cancers, that cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors are out of control. Cyclin A is a protein that regulates critical transition of the cell cycle. The expression of cyclin A in meningiomas by immunohistochemical method was investigated. Furthermore, the correlation among cyclin A expression, clinical course, and proliferative potential were also evaluated. Seventy-seven meningiomas were studied. The mean cyclin A labeling indices were as follows: benign meningiomas, 1.01% +/- 0.62%; atypical meningiomas, 4.23% +/- 1.82%; and anaplastic meningiomas, 7.72% +/- 0.88%. Analyses of variance showed that significant differences existed between tumor grades for cyclin A labeling indices. A linear positive correlation between the cyclin A labeling index and bromodeoxyuridine labeling index was observed. The multivariate analysis using Cox's hazards model showed a high cyclin A labeling index (>3%) was a significant risk factor for recurrence. A high Ki-67 labeling index (>5%) and high tumor grade (World Health Organization grade II, III) were also significant risk factors for recurrence. These results suggested that the evaluation of cyclin A expression in meningiomas provides significant clinical information, especially as an independent prognostic indicator.
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PMID:Prognostic significance of cyclin a expression in meningiomas. 1261 Mar 50


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