Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early fruit development in tomato (Lycopersicon esculentum Mill.) proceeds in two distinct phases of growth that comprise cell division and cell expansion, respectively. In pericarp and the jelly like locular tissue of tomato fruit, the transition between cell division to cell expansion is characterized by the arrest of mitotic activity, numerous rounds of nuclear DNA endoreduplication and the inhibition of Cyclin-Dependent Kinase A (CDKA) activity. To investigate whether the WEE1 kinase may play a role during the endoreduplication process, we isolated and characterized the tomato homologue for WEE1. The LeWEE1 gene consisted of 10 exons with a predicted 510 amino acid-long protein. The accumulation of the corresponding transcripts was associated with mitotically active organs: developing fruits, seeds and roots. Interestingly, LeWEE1was expressed in the jelly like locular tissue concomitant with endoreduplication during fruit development. Using tobacco BY-2 synchronized cells, we showed that the WEE1 gene expression is cell-cycle regulated with a maximum transcript accumulation at S phase. Our data indicate the putative dual contribution of LeWEE1 in the classical cell cycle and the endocycle.
Plant Mol Biol 2004 Dec
PMID:Molecular characterization of a WEE1 gene homologue in tomato (Lycopersicon esculentum Mill.). 1582 85

Cyclin B is a well known regulatory factor that plays a crucial role in mitosis and meiosis. Although the existence of cyclin B has been reported to be universal in a wide variety of eukaryotic organisms, no molecular data are available on crustacean species. In this study, three forms of cyclin B transcripts were first identified and characterized in the ovary of the commercially important kuruma prawn Marsupenaeus japonicus. The three transcripts (2.4, 1.9 and 1.7 kb) shared the identical sequence, with variations only in the length of 3' untranslated regions (UTRs), and coexisted in the ovary as demonstrated by Northern blot analysis. The sequences of 3' UTRs indicated that the distinct length UTRs of the transcripts is attributed to an alternative usage of various polyadenylation signals in the 3' UTR. The open reading frame of 1203 bp encoded a putative 401 amino acid peptide. The deduced amino acid sequence shared 45-50% identities with the known B-type cyclin in other animals. Quantitative real-time RT-PCR revealed that the short transcript (1.7 kb) was the most abundant among the three transcripts, followed by the long (2.4 kb) and medium (1.9 kb), and the three forms of the transcripts displayed various expression profiles during oogenesis. In situ hybridization showed that the short transcript commenced expressing in the ova as early as the oogonia stage and accumulated largely at the perinucleolus (PN) stage, whereas almost no expression was found for the medium and long transcripts at the oogonia stage and moderate signals were detected at the PN stage. The differential expression of the three forms of transcripts suggested that various transcripts might perform different roles during oogenesis of the kuruma prawn.
Comp Biochem Physiol B Biochem Mol Biol 2005 Jun
PMID:Three forms of cyclin B transcripts in the ovary of the kuruma prawn Marsupenaeus japonicus: their molecular characterizations and expression profiles during oogenesis. 1587 99

Activation of the anaphase-promoting complex/cyclosome (APC/C) by Cdc20 and Cdh1 leads to ubiquitin-dependent degradation of securin and cyclin B and thereby promotes the initiation of anaphase and exit from mitosis. Cyclin B and securin ubiquitination depend on a destruction box (D box) sequence in these proteins, but how APC/C bound to Cdc20 or Cdh1 recognizes the D box is poorly understood. By using site-specific photocrosslinking in combination with mutational analyses, we show that the D box directly interacts with an evolutionarily conserved surface on the predicted WD40 propeller structure of Cdh1 and that this interaction is essential for processive substrate ubiquitination. We further show that Cdh1 specifically crosslinks to the APC/C subunit Cdc27 and that Cdh1 binding to APC/C depends on the presence of Cdc27. Our data imply that APC/C is activated by the association of Cdh1 with Cdc27, which enables APC/C to recognize the D box of substrates via Cdh1's propeller domain.
Mol Cell 2005 May 27
PMID:The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates. 1591 61

Phosphorylation governs the activity of many proteins. Insight into molecular mechanisms in biology would be immensely improved by robust, sensitive methods for identifying precisely sites of phosphate addition. An approach to selective mapping of protein phosphorylation sites on a specific target protein of interest using LC-MS is described here. In this approach multiple reaction monitoring is used as an extremely sensitive MS survey scan for potential phosphopeptides from a known protein. This is automatically followed by peptide sequencing and subsequent location of the phosphorylation site; both of these steps occur in a single LC-MS run, providing greater efficiency of sample use. The method is capable of detecting and sequencing phosphopeptides at low femtomole levels with high selectivity. As proof of the value of this approach in an experimental setting, a key Schizosaccharomyces pombe cell cycle regulatory protein, Cyclin B, was purified, and associated proteins were identified. Phosphorylation sites on these proteins were located. The technique, which we have called multiple reaction monitoring-initiated detection and sequencing (MIDAS), is shown to be a highly sensitive approach to the determination of protein phosphorylation.
Mol Cell Proteomics 2005 Aug
PMID:Multiple reaction monitoring to identify sites of protein phosphorylation with high sensitivity. 1592 65

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745-749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K(i) = 6 nM) but a low affinity with cyclin-dependent kinase 4 (K(i) = 1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4-NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4.
J Mol Model 2005 Nov
PMID:Study of a ligand complexed with Cdk2/Cdk4 by computer simulation. 1592 20

Cyclin A-associated kinases, such as cyclin-dependent kinase 2 (CDK2), participate in regulating cellular progression from G(1) to S to G(2), and CDK2 has also been implicated in the transition to mitosis. The antitumor properties of CDK inhibitors, alone or in combination with taxanes, are currently being examined in clinical trials. Here, we examined whether the activity of kinases associated with cyclin A (such as CDK2) is important in determining cellular sensitivity to paclitaxel, a taxane and mitotic inhibitor used in chemotherapy for breast and ovarian cancer. We used adenoviral suppression or overexpression to manipulate the expression of CDK2 and cyclin A in one breast cancer and three ovarian cancer cell lines with different sensitivities to paclitaxel and assessed protein expression, kinase activity, cell cycle distribution, and sensitivity to paclitaxel. Transfection of a dominant-negative (DN)-CDK2 evoked resistance to paclitaxel by preventing cellular progression to mitosis through loss of CDK1 activity. Reexpression of wild-type CDK2 in DN-CDK2-transfected cancer cells restored CDK2 activity but not paclitaxel sensitivity. However, expression of cyclin A in DN-CDK2-transfected cells restored their sensitivity to paclitaxel. Although CDK2 activity was not directly involved in paclitaxel sensitivity, cyclin A-associated kinases did up-regulate CDK1 via phosphorylation. We conclude that cyclin A-associated kinase activity is required for these cells to enter mitosis and undergo paclitaxel-induced cell death. Combining taxane chemotherapy with any drug targeting cyclin A-associated kinases (e.g., pure CDK2 inhibitors) should be done with caution, if at all, because of the potential for enhancing taxane resistance.
Mol Cancer Ther 2005 Jul
PMID:Cyclin A-associated kinase activity is needed for paclitaxel sensitivity. 1602 Jun 61

The meiotic cell cycle is modified from the mitotic cell cycle by having a premeiotic S phase which leads to high levels of recombination, a reductional pattern of chromosome segregation at the first division, and a second division with no intervening DNA synthesis. Cyclin-dependent kinases are essential for progression through the meiotic cell cycle, as for the mitotic cycle. Here we show that a fission yeast cyclin, Rem1, is present only during meiosis. Cells lacking Rem1 have impaired meiotic recombination, and Rem1 is required for premeiotic DNA synthesis when Cig2 is not present. rem1 expression is regulated at the level of both transcription and splicing, with Mei4 as a positive and Cig2 a negative factor of rem1 splicing. This regulation ensures the timely appearance of the different cyclins during meiosis, which is required for the proper progression through the meiotic cell cycle. We propose that the meiosis-specific B-type cyclin Rem1 has a central role in bringing about progression through meiosis.
Mol Cell Biol 2005 Aug
PMID:A meiosis-specific cyclin regulated by splicing is required for proper progression through meiosis. 1602 72

Cyclin-dependent kinases (CDKs) play a key role in regulating the cell cycle. The cyclins, their activating agents, and endogenous CDK inhibitors are frequently mutated in human cancers, making CDKs interesting targets for cancer chemotherapy. Our aim is the discovery of selective CDK4/cyclin D1 inhibitors. An ATP-competitive pyrazolopyrimidinone CDK inhibitor was identified by HTS and docked into a CDK4 homology model. The resulting binding model was consistent with available SAR and was validated by a subsequent CDK2/inhibitor crystal structure. An iterative cycle of chemistry and modeling led to a 70-fold improvement in potency. Small substituent changes resulted in large CDK4/CDK2 selectivity changes. The modeling revealed that selectivity is largely due to hydrogen-bonded interactions with only two kinase residues. This demonstrates that small differences between enzymes can efficiently be exploited in the design of selective inhibitors.
J Comput Aided Mol Des 2005 Feb
PMID:Understanding and modulating cyclin-dependent kinase inhibitor specificity: molecular modeling and biochemical evaluation of pyrazolopyrimidinones as CDK2/cyclin A and CDK4/cyclin D1 inhibitors. 1607 5

Cyclin-dependent kinases (CDKs) use multiple mechanisms to block reassembly of prereplicative complexes (pre-RCs) at replication origins to prevent inappropriate rereplication. In Saccharomyces cerevisiae, one of these mechanisms promotes the net nuclear export of a pre-RC component, the Mcm2-7 complex, during S, G2, and M phases. Here we identify two partial nuclear localization signals (NLSs) on Mcm2 and Mcm3 that are each necessary, but not sufficient, for nuclear localization of the Mcm2-7 complex. When brought together in cis, however, the two partial signals constitute a potent NLS, sufficient for robust nuclear localization when fused to an otherwise cytoplasmic protein. We also identify a Crm1-dependent nuclear export signal (NES) adjacent to the Mcm3 NLS. Remarkably, the Mcm2-Mcm3 NLS and the Mcm3 NES are sufficient to form a transport module that recapitulates the cell cycle-regulated localization of the entire Mcm2-7 complex. Moreover, we show that CDK regulation promotes net export by phosphorylation of the Mcm3 portion of this module and that nuclear export of the Mcm2-7 complex is sufficient to disrupt replication initiation. We speculate that the distribution of partial transport signals among distinct subunits of a complex may enhance the specificity of protein localization and raises the possibility that previously undetected distributed transport signals are used by other multiprotein complexes.
Mol Biol Cell 2005 Oct
PMID:CDK phosphorylation of a novel NLS-NES module distributed between two subunits of the Mcm2-7 complex prevents chromosomal rereplication. 1609 48

Cyclin-dependent kinases (CDKs) have been identified as potential targets for development of drugs, mainly against cancer. These studies generated a vast library of chemical inhibitors of CDKs, and some of these molecules can also inhibit kinases identified in the Plasmodium falciparum genome. Here we describe structural models for Protein Kinase 6 from P. falciparum (PfPK6) complexed with Roscovitine and Olomoucine. These models show clear structural evidence for differences observed in the inhibition, and may help designing inhibitors for PfPK6 generating new potential drugs against malaria.
J Mol Model 2005 Dec
PMID:Molecular models of protein kinase 6 from Plasmodium falciparum. 1609 6


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