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)

Cyclins control the transition between the phases of the eukaryotic cell cycle as regulatory subunits of the cyclin-dependent kinases (CDKs). Phase-specific activation of the CDK is in part regulated by phase-specific expression of their cyclin component. In most eukaryotic cells including higher plant, B-type cyclin genes are expressed specifically at G2/M phase during the cell cycle. Promoters from yeast, plant and animal B-type cyclin genes are all activated in a cell cycle-regulated manner. In yeast, a transcription factor, Mcm1, in cooperation with an uncloned factor SFF, regulates the cell cycle-dependent promoter activation of mitotic B-type cyclin genes, CLB1 and CLB2. Activity of the human cyclin B1 promoter is regulated by a complex mechanism involving multiple cis-acting elements, none of which are sufficient for G2/M-specific promoter activation. In contrast, plants employ a simple mechanism for cell cycle-regulated promoter activation of B-type cyclin genes. Plant B-type cyclin gene promoters contain a common cis-acting element, called the MSA element, which is necessary and sufficient for the phase-specific promoter activation. MSA-like sequences are also found in the promoters of G2/M-specific genes encoding kinesin-like proteins, suggesting that a defined set of G2/M-specific genes are co-regulated by a common MSA-mediated mechanism in plants. Thus, the molecular mechanisms regulating B-type cyclin gene expression are evolutionarily divergent, and the MSA-mediated mechanism seems to be specific to plants. The consensus sequence of the MSA element resembles the binding sites of animal Myb transcription factors. A set of our data suggest the possibility that plant Myb may have unexpected roles in G2/M by inducing B-type cyclin genes, together with other cell cycle-related genes in plants.
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PMID:Factors controlling cyclin B expression. 1108 69

Polo-like kinase (PLK), a cell cycle-regulated, cyclin-independent serine/threonine protein kinase, has been shown in recent reports to play a critical role during tumorigenesis. To investigate whether PLK plays a general role as a tumor marker of ovarian cancers, we examined the expression of PLK protein in ovarian cancers, and analyzed the relationship between PLK protein expression and histological grade. Immunohistochemically, the majority of PLK was found in the cytoplasm (around the nucleus), and a portion was found in the nucleus of ovarian cancer glands and also in the fluid secreted from these glands. PLK was expressed at the basement membrane of cancer glands and partly expressed in the head portion of papillary cancer tissues. A significant correlation was found between percentages of PLK-positive cells and histological grade of ovarian cancer (P<0.001). However, the expression of proliferating cell nuclear antigen, Ki-67, and cyclin B1 was independent of PLK expression. Taken together, these findings suggest that PLK expression may reflect the degree of malignancy rather than the degree of proliferation in ovarian cancer. Thus, in addition to being of diagnostic value, PLK activity in ovarian tumors may be modulated by chemotherapeutic agents or gene therapy to therapeutic effect.
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PMID:Expression of polo-like kinase in ovarian cancer is associated with histological grade and clinical stage. 1116 14

Squamous cell carcinoma antigen (SCC-Ag) is produced by the two almost identical, tandemly arrayed genes, SCCA1 and SCCA2. In this study, we investigated the mechanism of increased expression of SCC-Ag in a cell line SCCMM derived from an aggressive adenoid SCC with high titer of SCC-Ag in the patient serum. The differential polymerase chain reaction using specific primers for SCCA1 and SCCA2 revealed no gene amplification in SCCMM. However, RT-PCR demonstrated that levels of SCCA1 and SCCA2 mRNAs in SCCMM were 80- and 120-fold higher than those in CaSki as a reference SCC cell, respectively. Western blot analysis showed that the levels of these two SCC-Ag proteins in SCCMM were 15-fold higher than those in CaSki, suggesting that expression of the SCC-Ag in SCCMM was controlled at both the transcriptional and post-transcriptional levels. To investigate highly malignant character of SCCMM, expression of cell cycle regulatory proteins was investigated by Western blotting. Cyclin E and cyclin B1 were expressed at approximately 100-fold higher levels in SCCMM than in CaSki, but Cip/Kip cyclin-dependent kinase inhibitors (CDKIs) were expressed at low levels and p16 and p19 ink4 CDKIs were not detected. These results suggest that the aggressive growth of SCCMM is due, at least in part, to large increases in cyclin E and cyclin B1 expression with low levels of CDKIs.
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PMID:Overexpression of SCC antigen and cyclins in an adenoid squamous carcinoma cell line derived from the maxillary sinus. 1117 95

In this paper, we show that substrate specificity is primarily conferred on human mitotic cyclin-dependent kinases (CDKs) by their subcellular localization. The difference in localization of the B-type cyclin-CDKs underlies the ability of cyclin B1-CDK1 to cause chromosome condensation, reorganization of the microtubules, and disassembly of the nuclear lamina and of the Golgi apparatus, while it restricts cyclin B2-CDK1 to disassembly of the Golgi apparatus. We identify the region of cyclin B2 responsible for its localization and show that this will direct cyclin B1 to the Golgi apparatus and confer upon it the more limited properties of cyclin B2. Equally, directing cyclin B2 to the cytoplasm with the NH(2) terminus of cyclin B1 confers the broader properties of cyclin B1. Furthermore, we show that the disassembly of the Golgi apparatus initiated by either mitotic cyclin-CDK complex does not require mitogen-activated protein kinase kinase (MEK) activity.
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PMID:The localization of human cyclins B1 and B2 determines CDK1 substrate specificity and neither enzyme requires MEK to disassemble the Golgi apparatus. 1123 51

In vertebrate cells, the nuclear entry of Cdc2-cyclin B1 (MPF) during prophase is thought to be essential for the induction and coordination of M-phase events. Phosphorylation of cyclin B1 is central to its nuclear translocation, but the kinases that are responsible remain unknown. Here we have purified a protein kinase from Xenopus M-phase extracts that phosphorylates a crucial serine residue (S147) in the middle of the nuclear export signal sequence of cyclin B1. We have identified this kinase as Plx1 (ref. 16), a Xenopus homologue of Polo-like kinase (Plk)-1. During cell-cycle progression in HeLa cells, a change in the kinase activity of endogenous Plk1 toward S147 and/or S133 correlates with a kinase activity in the cell extracts. An anti-Plk1 antibody depletes the M-phase extracts of the kinase activity toward S147 and/or S133. An anti-phospho-S147 antibody reacts specifically with cyclin B1 only during G2/M phase. A mutant cyclin B1 in which S133 and S147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin B1 accumulates in the nucleus during prophase. Co-expression of constitutively active Plk1 stimulates nuclear entry of cyclin B1. Our results indicate that Plk1 may be involved in targeting MPF to the nucleus during prophase.
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PMID:Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. 1124 82

DNA damage produces delayed mitosis (G2/M delay) in proliferating cells, and shortening the delay sensitizes human malignant glioma and medulloblastoma cells to cytotoxic chemotherapy. Although activation of the cyclin-dependent kinase CDC2 mediates G2/M transition in all tumor cells studied to date, regulation of CDC2 varies between tumor types. Persistent hyperphosphorylation of kinase and reduced cyclin expression have been implicated as mediators of treatment-induced G2 delay in different tumor models. To evaluate regulation of G2/M transition in human brain tumors, we studied the expression and/or activity of CDC2 kinase and cyclins A and B1 in U-251 MG and DAOY medulloblastoma cells after their treatment with camptothecin (CPT). Synchronized cells were treated during S phase, then harvested at predetermined intervals for evaluation of cell cycle kinetics, kinase activity mRNA, and protein expression. CPT produced G2 delay associated with decreased CDC2 kinase activity and cyclin B1 expression. Kinase activity was associated with CDC2 bound to cyclin B1, not cyclin A, in both cell lines. Cyclin A mRNA and protein expression were reduced after CPT treatment; however, decreased protein expression was short lived and moderate in the glioma and primitive neuroectodermal tumor/medulloblastoma cells, respectively. We conclude that G2 delay is a common response of brain tumor cells to chemotherapy with topoisomerase I inhibitors and that a mechanism of this delay may be reduced expression of cyclin B1.
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PMID:Decreased cyclin B1 expression contributes to G2 delay in human brain tumor cells after treatment with camptothecin. 1130 12

p53 protects mammals from neoplasia by inducing apoptosis, DNA repair and cell cycle arrest in response to a variety of stresses. p53-dependent arrest of cells in the G1 phase of the cell cycle is an important component of the cellular response to stress. Here we review recent evidence that implicates p53 in controlling entry into mitosis when cells enter G2 with damaged DNA or when they are arrested in S phase due to depletion of the substrates required for DNA synthesis. Part of the mechanism by which p53 blocks cells at the G2 checkpoint involves inhibition of Cdc2, the cyclin-dependent kinase required to enter mitosis. Cdc2 is inhibited simultaneously by three transcriptional targets of p53, Gadd45, p21, and 14-3-3 sigma. Binding of Cdc2 to Cyclin B1 is required for its activity, and repression of the cyclin B1 gene by p53 also contributes to blocking entry into mitosis. p53 also represses the cdc2 gene, to help ensure that cells do not escape the initial block. Genotoxic stress also activates p53-independent pathways that inhibit Cdc2 activity, activation of the protein kinases Chk1 and Chk2 by the protein kinases Atm and Atr. Chk1 and Chk2 inhibit Cdc2 by inactivating Cdc25, the phosphatase that normally activates Cdc2. Chk1, Chk2, Atm and Atr also contribute to the activation of p53 in response to genotoxic stress and therefore play multiple roles. p53 induces transcription of the reprimo, B99, and mcg10 genes, all of which contribute to the arrest of cells in G2, but the mechanisms of cell cycle arrest by these genes is not known. Repression of the topoisomerase II gene by p53 helps to block entry into mitosis and strengthens the G2 arrest. In summary, multiple overlapping p53-dependent and p53-independent pathways regulate the G2/M transition in response to genotoxic stress.
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PMID:Regulation of the G2/M transition by p53. 1131 28

Tuberous sclerosis (TSC) is a multi-system disorder characterized by hamartomatous tumors and abnormal brain development, with multiple foci of disrupted neuronal migration and giant dysmorphic neurons within cortical tubers. TSC is associated with mutations in 2 genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively. The functions of these proteins have yet to be determined. Recently, the Drosophila homologue of TSC2, gigas, has been shown to be required for the G2/M transition of the cell cycle. However, the mechanism of this action remains unknown. Because the cyclin-dependent kinase CDK1 forms a complex with cyclin B1 to trigger the G2/M transition, we hypothesized that tuberin interacts with CDK1 to regulate its activity. In the study reported in this paper, we have used co-immunoprecipitation and confocal microscopy to demonstrate that tuberin interacts with and co-localizes with CDK1 and its binding partner cyclin B1 in multiple cell types. We also demonstrate that hamartin interacts with CDK1 and cyclin B1. We further present evidence that tuberin interacts with the other regulatory subunit of CDK1, cyclin A. These findings suggest a direct role for tuberin and hamartin in modulating the activity of CDK1 during G2 and the G2/M transition. This is the first description of a role for both tuberin and hamartin in a common cellular function, providing a potential mechanism for the identical clinicopathologic manifestations that result when either of these proteins are inactivated.
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PMID:Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. 1144

The roles of extracellular signal-regulated kinase (ERK) and p38 mitogen-activation protein kinase (MAPK) in guarding genome stability and regulating cell cycle progression were explored in CL3 human lung adenocarcinoma cells treated with cadmium (Cd), a human carcinogen. Exposing asynchronous cells to CdCl(2) for 2 h (45% viability) caused irreversible mitotic arrest. Exposing early-G(2) cells to Cd markedly delayed mitotic exit and subsequently induced sub-G(1) populations; however, this did not alter the levels of Cdc2 and cyclin B1. These results suggest that Cd elicits mitotic arrest without affecting the progression of G(2) to mitosis. Using counterflow centrifugal elutriation and flow cytometry analysis, CL3 cells synchronized at G(1)-, S-, and G(2)/M-phases were collected and treated with CdCl(2). G(2)/M was the most sensitive cell cycle phase to Cd for the induction of ERK and p38 MAPK activities, cytotoxicity, apoptosis, micronucleus, and intracellular peroxide; despite that similar Cd accumulation was observed in G(1)-, S-, and G(2)/M-cells. Co-treatment early-G(2) cells with Cd and SB202190, an inhibitor of p38 MAPK, significantly decreased the induction of micronucleus, mitotic arrest, and apoptosis. Conversely, PD98059, an inhibitor of the ERK upstream activators MKK1/2, enhanced micronucleus and apoptosis in Cd-treated early-G(2) cells. Together, the results suggest that intracellular peroxide may participate in the activation of ERK and p38 MAPK by Cd; also, the activated-p38 MAPK may contribute to mitotic arrest and genome instability, whereas the activated-ERK may help to maintain genome integrity and survival.
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PMID:Opposite roles of ERK and p38 mitogen-activated protein kinases in cadmium-induced genotoxicity and mitotic arrest. 1155 33

The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX-independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX-dependent and COX-independent mechanisms further, we assessed the effects of celecoxib (selective COX-2 inhibitor) and SC560 (selective COX-1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX-2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX-2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin-dependent kinase-1 and an increased expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1. In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX-2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT-15 (COX-2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT-29 tumors, which express COX-2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX-2 independent mechanisms and are not restricted to COX-2 over-expressing tumors.
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PMID:COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. 1160 77


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