Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PCTAIRE-1 is a cdc2-related protein kinase of unknown function. The gene (PCTK1) has been mapped to chromosome Xp. In this study we refine the locus position by chromosome analysis with cosmid and YAC probes. PCTK1 maps distal to the t(X;18) synovial sarcoma breakpoint in Xp11.23. A 420-kb YAC clone positive for PCTK1 also contains the gene coding for ubiquitin-activating enzyme UBE1, previously mapped in Xp11.3, indicating close physical linkage of these genes. PCTK1 is a new candidate for heritable disorders mapped to Xp11.3--p11.23 region.
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PMID:Physical linkage of the cdc2-related gene (PCTK1) and the ubiquitin-activating enzyme E1 gene (UBE1) on human Xp11.3. 765 87

Oncoprotein 18 (Op18) is an 18-19-kDa cytoplasmic phosphoprotein, of unknown function, that is frequently up-regulated in transformed cells. Stimulation of various cell-surface receptors results in extensive phosphorylation of Op18 and this protein has, therefore, previously been implicated in intracellular signaling. In the present study, by expression of specific Op18 cDNA mutant constructs and phosphopeptide mapping, we have identified in vivo phosphorylation sites. In conjunction with in vitro phosphorylation experiments, using purified wild-type and mutant Op18 proteins in combination with a series of kinases, these results have identified two distinct proline-directed kinase families that phosphorylate Op18 with overlapping but distinct site preference. These two kinase families, mitogen activated protein (MAP) kinases and cyclin dependent cdc2 kinases, are involved in receptor and cell cycle-regulated phosphorylation events, respectively. Therefore, Op18 may reside at a junction where receptor and cell cycle-regulated kinase families interact with the same substrate. The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue. Only a minor fraction of the 4.5 x 10(6) Op18 molecules/cell in a leukemic T-cell line are normally in their Ser25 phosphorylated form. However, antigen receptor stimulation of this cell line is shown to result in a rapid conversion of 35-45% of all Op18 molecules to the Ser25 phosphorylated form. These results suggest that Ser25 of Op18 may be a major cytoplasmic target for the MAP kinase in cells with high expression of Op18.
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PMID:Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase. 832 80

The carboxy terminus of protein phosphatase 2A (PP2A) catalytic subunit is highly conserved. Seven out of the last nine residues, including two potential in vivo phosphorylation sites, threonine 304 and tyrosine 307, are completely invariant in all known PP2As. Mutational analysis of the carboxy terminus in vivo was facilitated by efficient immunoprecipitation of trimeric PP2A holoenzyme via an epitope-tagged catalytic subunit. The results indicate that the catalytic subunit carboxy terminus is important for complex formation with the PP2A 55 kDa regulatory B subunit, but not with polyomavirus oncogene, middle tumor antigen (MT), a viral B-type regulatory subunit. Replacing catalytic subunit threonine 304 or tyrosine 307 with a negatively charged amino acid abolished binding of the B subunit to the dimeric enzyme core and altered substrate specificity. Certain other amino acid substitutions of different size and/or charge also abolished or greatly reduced B subunit binding. Substitution of alanine at position 304 or phenylalanine at position 307 did not dramatically reduce B subunit binding or phosphatase activity in vitro, yet the latter substitutions are not found in naturally occurring PP2As. Thus, the wild-type residues are important for a yet unknown function in vivo. Additionally, deleting the carboxy terminal nine amino acids inhibited binding of the B subunit to the dimeric enzyme core, indicating a requirement for one or more of these amino acids for complex formation. MT interaction with the dimeric PP2A enzyme core was not inhibited by any of these mutations. Finally, unlike B subunit, MT does not activate the phosphatase activity of the PP2A heterodimer towards cdc2-phosphorylated histone H1.
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PMID:Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen. 928 86

During early development gene expression is controlled principally at the translational level. Oocytes of the surf clam Spisula solidissima contain large stockpiles of maternal mRNAs that are translationally dormant or masked until meiotic maturation. Activation of the oocyte by fertilization leads to translational activation of the abundant cyclin and ribonucleotide reductase mRNAs at a time when they undergo cytoplasmic polyadenylation. In vitro unmasking assays have defined U-rich regions located approximately centrally in the 3' UTRs of these mRNAs as translational masking elements. A clam oocyte protein of 82 kDa, p82, which selectively binds the masking elements, has been proposed to act as a translational repressor. Importantly, mRNA-specific unmasking in vitro occurs in the absence of poly(A) extension. Here we show that clam p82 is related to Xenopus CPEB, an RNA-binding protein that interacts with the U-rich cytoplasmic polyadenylation elements (CPEs) of maternal mRNAs and promotes their polyadenylation. Cloned clam p82/CPEB shows extensive homology to Xenopus CPEB and related polypeptides from mouse, goldfish, Drosophila and Caenorhabditis elegans, particularly in their RNA-binding C-terminal halves. Two short N-terminal islands of sequence, of unknown function, are common to vertebrate CPEBs and clam p82. p82 undergoes rapid phosphorylation either directly or indirectly by cdc2 kinase after fertilization in meiotically maturing clam oocytes, prior to its degradation during the first cell cleavage. Phosphorylation precedes and, according to inhibitor studies, may be required for translational activation of maternal mRNA. These data suggest that clam p82 may be a functional homolog of Xenopus CPEB.
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PMID:The clam 3' UTR masking element-binding protein p82 is a member of the CPEB family. 991 63

Although widely used as an operational marker of proliferation, the cell cycle-regulated Ki67 protein is of unknown function. pKi67 is found predominantly in the nucleolus in cycling interphase cells and moves to become perichromosomal during mitosis. We have performed a detailed immunochemical analysis of pKi67 in HeLa cells and report the existence of a novel hyperphosphorylated form in mitosis. Two isoforms can be identified on immunoblots as a consequence of the previously described alternative splicing. In extracts from mitotic cells both these isoforms have considerably reduced mobility. Treatment with phosphatase converts the mitotic form to the interphase form. Immunoprecipitated pKi67 can be phosphorylated in vitro both by cdc2/cyclin B and by protein kinase C, and treatment by PKC leads to the full mobility shift. Treatment of nocodazole-arrested mitotic HeLa cells with staurosporine causes a dephosphorylation of pKi67 to the interphase state and a concomitant change in the localization of pKi67 with movement away from the perichromosomal layer to cytoplasmic dots that colocalize with nucleolin. These data indicate that pKi67 localization is regulated by the action of cell cycle-specific kinase(s) and phosphatase(s). The data presented here provide a starting point for the analysis of pKi67 function and regulation.
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PMID:Biochemical characterization of pKi67 with the identification of a mitotic-specific form associated with hyperphosphorylation and altered DNA binding. 1050 11

The Ki-67 protein is a nuclear and nucleolar protein, which is tightly associated with somatic cell proliferation. Antibodies raised against the human Ki-67 protein paved the way for the immunohistological assessment of cell proliferation, particularly useful in numerous studies on the prognostic value of cell growth in clinical samples of human neoplasms. The primary structure revealed potential phosphorylation site for a range of essential kinases, PEST sequences, and a forkhead-associated domain, which are features present in a variety of cell-cycle-regulating proteins, but information about the position of the Ki-67 protein within the protein network that drives the cell cycle remained scarce. There is now evidence that posttranslational modifications based on phosphorylation by cdc2 kinase and PKC accompany the remarkable redistribution of the Ki-67 protein from the interior of the nucleus to the perichromosomal layer during mitosis and vice versa. The discovery of Ki-67 equivalents in other species is advantageous for a precise and cross-species investigation of the structural requirements for its yet unknown function. The recently published data add new pieces to the challenging puzzle of this multifaceted protein, which are waiting to be put together.
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PMID:The Ki-67 protein: fascinating forms and an unknown function. 1083 36

RNA polymerase II CTD kinases are key elements in the control of mRNA synthesis. They constitute a family of cyclin-dependent kinases activated by C-type cyclins. Unlike most cyclin-dependent kinase complexes, which are composed of a catalytic and a regulatory subunit, the yeast CTD kinase I complex contains three specific subunits: a kinase subunit (Ctk1), a cyclin subunit (Ctk2), and a third subunit (Ctk3) of unknown function that does not exhibit any similarity to known proteins. Like the Ctk2 cyclin that is regulated at the level of protein turnover, Ctk3 is an unstable protein processed through a ubiquitin-proteasome pathway. Interestingly, Ctk2 and Ctk3 physical interaction is required to protect both subunits from degradation, pointing to a new mechanism for cyclin turnover regulation. We also show that Ctk2 and Ctk3 can each interact independently with the kinase. However, despite the formation of CDK/cyclin complexes in vitro, the Ctk2 cyclin is unable to activate its CDK: both Ctk2 and Ctk3 are required for Ctk1 CTD kinase activation. The different specific features governing CTDK-I regulation probably reflect requirement for the transcriptional response to multiple growth conditions.
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PMID:Activation of the cyclin-dependent kinase CTDK-I requires the heterodimerization of two unstable subunits. 1111 53

p220(NPAT) is a substrate of cyclin E/Cdk2 that localizes in nuclear organelles called Cajal bodies in a cell cycle-regulated manner. In normal diploid fibroblasts, p220 is concentrated in two Cajal bodies tethered to histone gene clusters at chromosome 6p21 during G(1), S, and G(2) phases and two additional Cajal bodies tethered to histone genes at 1q21 during S, and G(2) phases. Overexpression of p220 in U2OS cells can promote the G(1)/S transition and can also promote transcription from histone H2B and H4 luciferase reporter constructs. How p220 expression induces these activities and whether the two activities are related are unknown. In this study, we developed a "lox-scanning" mutagenesis approach to identify functional domains in p220. We identified two distinct functional regions of p220. The C-terminal half of the protein contains multiple elements that are required for its ability to induce S phase in transfected cells. In contrast, sequences at the N terminus appear to be critical for activation of histone H4 and H2B reporter constructs. We identified an approximately 30-amino-acid motif at the N terminus of p220 that has the characteristics of a LisH motif. LisH motifs are found in a large number of proteins in the database but are of unknown function. Point mutations in conserved residues in the LisH motif of p220 block histone H4 transcriptional activity without affecting localization in Cajal bodies or phosphorylation on Cdk2 phosphorylation sites. These studies indicate that the ability of p220 to promote S phase is independent of its ability to promote histone H4 transcription and suggests that p220 may link cyclin E/Cdk2 to multiple independent downstream functions.
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PMID:The cyclin E/Cdk2 substrate and Cajal body component p220(NPAT) activates histone transcription through a novel LisH-like domain. 1272 24

Arabidopsis has over 80 genes encoding conserved and plant-specific core cell cycle regulators, but in most cases neither their timing of expression in the cell cycle is known nor whether they represent redundant and/or tissue-specific functions. Here we identify novel cell cycle regulators, including new cyclin-dependent kinases related to the mammalian galactosyltransferase-associated protein kinase p58, and new classes of cyclin-like and CDK-like proteins showing strong tissue specificity of expression. We analyse expression of all cell cycle regulators in synchronized Arabidopsis cell cultures using multiple approaches including Affymetrix microarrays, massively parallel signature sequencing and real-time reverse transcriptase polymerase chain reaction, and in plant material using the results of over 320 microarray experiments. These global analyses reveal that most core cell cycle regulators are expressed across almost all tissues and more than 85% are expressed at detectable levels in the cell suspension culture, allowing us to present a unified model of transcriptional regulation of the plant cell cycle. Characteristic patterns of D-cyclin expression in early and late G1 phase, either limited to the re-entry cycle or continuously oscillating, suggest that several CYCD genes with strong oscillatory regulation in late G1 may play the role of cyclin E in plants. Alone amongst the six groups of A and B type cyclins, members of CYCA3 peak in S-phase suggest it is a major component of S-phase kinases, whereas others show a peak in G2/M. 82 genes share this G2/M regulatory pattern, about half being new candidate mitotic genes of previously unknown function.
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PMID:Global analysis of the core cell cycle regulators of Arabidopsis identifies novel genes, reveals multiple and highly specific profiles of expression and provides a coherent model for plant cell cycle control. 1568 19

An AAA protein from the dinoflagellate Gonyaulax polyedra (GpAAA) with the unusual ability to rescue the phenotype of a yeast mutant lacking G1/S phase cyclins (cln1cln2cln3) has been isolated and the mechanism of rescue was characterized. We find that GpAAA is not a cyclin and has no similarity to any known cell cycle regulators. Instead, GpAAA forms a novel and strongly supported clade with bacterial spoIIIAA proteins and an Arabidopsis gene of unknown function. Since dinoflagellates cannot be transformed, we took advantage of the powerful genetic tools available for yeast. We find that rescue of the cln1cln2cln3 phenotype does not involve an effect on the CDK-inhibitor (CKI) Sic1p, as GpAAA does not alter the sensitivity to an inducible SIC1. Instead, Northern blot analyses show that GpAAA expression increases levels of CLB5, in agreement with the observation that GpAAA is unable to rescue the quadruple mutant cln1cln2cln3clb5. We propose that the increased transcription of CLB5 may be due to a protein remodeling function of GpAAA alleviating inhibition of the transcription factor SBF. Thus, although no known equivalents to the yeast SBF have been documented in dinoflagellates, we conclude that dinoflagellates could indeed utilize GpAAA as a cell cycle regulator.
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PMID:A dinoflagellate AAA family member rescues a conditional yeast G1/S phase cyclin mutant through increased CLB5 accumulation. 1757 41


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