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)

We have constructed a galactose-inducible expression library by cloning yeast cDNAs unidirectionally under control of the GAL1 promoter in a centromeric shuttle vector. Eleven independent libraries were made each with an average size of about 1 x 10(6) clones, about 50 times larger than the reported mRNA population in a yeast cell. From this library, LEU2 and HIS3 cDNAs were recovered at a frequency of about 1 in 10(4) and in 12 out of 13 cases these were expressed in a galactose-dependent manner. Sequence analysis of leu2 and his3 complementing cDNAs indicates that they contain all the coding sequence and much of the 5' untranslated region. To test the utility of the library for the identification of genes whose overexpression confers a specific phenotype, we screened 25,000 yeast transformants for lethality on galactose. Among 15 clones that showed galactose inducible lethality were cDNAs encoding structural proteins, including ACT1 (actin), TUB2 (beta-tubulin) and ABP1 (actin-binding protein 1), and genes in signal transduction pathways, including TPK1 (a cAMP-dependent protein kinase) and GLC7 (type 1 protein phosphatase). cDNAs overexpressing NHPB (nonhistone protein B) and NSR1 (nuclear sequence recognition protein) were also found to be lethal. Among these, ACT1 was isolated four times, and NSR1 three times. The useful features of this library for cDNA cloning in yeast by complementation, and for the identification of genes whose over-expression confers specific phenotypes, are discussed.
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PMID:Construction of a GAL1-regulated yeast cDNA expression library and its application to the identification of genes whose overexpression causes lethality in yeast. 146 25

Southern blot analysis of Chinese hamster x mouse somatic cell hybrids was used to map the gene for a serine/threonine protein kinase expressed in brain and testis. This locus, termed Camk-4, encodes Ca2+/calmodulin-dependent protein kinase IV. Progeny of an interspecific backcross were analyzed to position Camk-4 in the centromeric region of chromosome 18 near two mutations known to affect neurological function and fertility. This raises the possibility that a defect in Camk-4 may be responsible for one of these mutant phenotypes.
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PMID:Genetic mapping of the gene for Ca2+/calmodulin-dependent protein kinase IV (Camk-4) to mouse chromosome 18. 198 Oct 56

By analysis of crossovers in key recombinant families and by homozygosity analysis of inbred families, the Friedreich ataxia (FRDA) locus was localized in a 300-kb interval between the X104 gene and the microsatellite marker FR8 (D9S888). By homology searches of the sequence databases, we identified X104 as the human tight junction protein ZO-2 gene. We generated a large-scale physical map of the FRDA region by pulsed-field gel electrophoresis analysis of genomic DNA and of three YAC clones derived from different libraries, and we constructed an uninterrupted cosmid contig spanning the FRDA locus. The cAMP-dependent protein kinase gamma-catalytic subunit gene was identified within the critical FRDA interval, but it was excluded as candidate because of its biological properties and because of lack of mutations in FRDA patients. Six new polymorphic markers were isolated between FR2 (D9S886) and FR8 (D9S888), which were used for homozygosity analysis in a family in which parents of an affected child are distantly related. An ancient recombination involving the centromeric FRDA flanking markers had been previously demonstrated in this family. Homozygosity analysis indicated that the FRDA gene is localized in the telomeric 150 kb of the FR2-FR8 interval.
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PMID:The Friedreich ataxia critical region spans a 150-kb interval on chromosome 9q13. 748 55

Homozygous loss of the warts (wts) gene of Drosophila, caused by mitotic recombination in somatic cells, leads to the formation of cell clones that are fragmented, rounded, and greatly overgrown compared with normal controls. Therefore, the gene is required for the control of the amount and direction of cell proliferation as well as for normal morphogenesis. The absence of wts function also results in apical hypertrophy of imaginal disc epithelial cells. Secretion of cuticle over and between the domed apical surfaces of these cells leads to a honeycomb-like structure and gives the superficial wart-like phenotype of mitotic clones on the adult. One wts allele allows survival of homozygotes to the late larval stage, and these larvae show extensive imaginal disc overgrowth. Because of the excess growth and abnormalities of differentiation that follow homozygous loss, we consider wts to be a tumor suppressor gene. The wts gene is defined by the breakpoints of overlapping deficiencies in the right telomeric region of chromosome 3, region 100A, and by lethal P-element insertions and excisions. It encodes a protein kinase that is most similar to human myotonic dystrophy kinase, the Neurospora cot-1 protein kinase, two cell-cycle regulated kinases of yeast, and several putative kinases from plants. These proteins define a new subfamily of protein kinases that are closely related to but distinct from the cyclic AMP-dependent kinases. Although myotonic dystrophy is defined by a neuromuscular disorder, it is sometimes associated with multiple pilomatrixomas, which are otherwise rare epithelial tumors, and with other tumors including neurofibromas and parathyroid adenomas. Our results raise the possibility that homozygous loss of the myotonic dystrophy kinase may contribute to the development of these tumors.
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PMID:The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. 769 44

Casein kinase II is thought to play an essential role in the control of cell division and differentiation in all eukaryotes. Through complementation of a defective casein kinase II catalytic subunit gene from Saccharomyces cerevisiae, we isolated an Arabidopsis thaliana casein kinase II regulatory subunit homologue, CKB1. A second regulatory subunit was identified by low-stringency hybridization with CKB1. Casein kinase II from S. cerevisiae is composed of two catalytic (alpha) and two regulatory (beta) subunits. Simultaneous disruption of the genes for the alpha and alpha' subunits, CKA1 and CKA2, respectively, is lethal. Strain YDH8 has disruptions of CKA1 and CKA2; its viability depends on a temperature-sensitive allele of CKA2, cka2-8, carried on a centromeric plasmid. We screened an A. thaliana cDNA library, whose inserts are under the control of the galactose-inducible GAL10 promoter, for cDNAs which enabled YDH8 cells to grow at the restrictive temperature. One cDNA, CKB1, was isolated by this screen which had homology to cDNAs of casein kinase II beta subunits. A second cDNA, CKB2, was isolated by hybridization and was also able to suppress the YDH8 mutant phenotype. The proteins encoded by CKB1 and CKB2 are 80% identical. The carboxy-terminal two thirds of both proteins is ca. 54% identical to the regulatory beta subunits of casein kinase II from other species. The amino termini are unrelated to any other known proteins. CKB1 and CKB2 lack the conserved autophosphorylation site characteristic of animal beta subunits, but have potential casein kinase II phosphorylation sites in the same region. Suppression of the cka1 delta cka2-8 mutant phenotype occurs by interaction of CKB1 with the defective, cka2-8-encoded, catalytic subunit. Cells with disruptions in CKA1 and CKA2 are not rescued by expression of CKB1.
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PMID:Isolation of an Arabidopsis thaliana casein kinase II beta subunit by complementation in Saccharomyces cerevisiae. 806 17

Myotonic dystrophy (DM) is associated with a (CTG)n trinucleotide repeat expansion in the 3'-untranslated region of a protein kinase-encoding gene, DMPK, which maps to chromosome 19q13.3. Characterisation of the expression of this gene in patient tissues has thus far generated conflicting data on alterations in the steady state levels of DMPK mRNA, and on the final DMPK protein levels in the presence of the expansion. The DM region of chromosome 19 is gene rich, and it is possible that the repeat expansion may lead to dysfunction of a number of transcription units in the vicinity, perhaps as a consequence of chromatin disruption. We have searched for genes associated with a CpG island at the 3' end of DMPK. Sequencing of this region shows that the island extends over 3.5 kb and is interrupted by the (CTG)n repeat. Comparison of genomic sequences downstream (centromeric) of the repeat in human and mouse identified regions of significant homology. These correspond to exons of a gene predicted to encode a homeodomain protein. RT-PCR analysis shows that this gene, which we have called DM locus-associated homeodomain protein (DMAHP), is expressed in a number of human tissues, including skeletal muscle, heart and brain.
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PMID:A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. 859 16

5'-Deoxy-5'-methylthioadenosine phosphorylase (methylthioadeno-sine: ortho-phosphate methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine and polyamine metabolism and in the regulation of transmethylation reactions. MTAP is abundant in normal cells but is deficient in many cancers. Recently, the genes for the cyclin-dependent kinase inhibitors p16 and p15 have been localized to the short arm of human chromosome 9 at band p21, where MTAP and interferon alpha genes (IFNA) also map. Homozygous deletions of p16 and p15 are frequent malignant cell lines. However, the order of the MTAP, p16, p15, and IFNA genes on chromosome 9p is uncertain, and the molecular basis for MTAP deficiency in cancer is unknown. We have cloned the MTAP gene, and have constructed a topologic map of the 9p21 region using yeast artificial chromosome clones, pulse-field gel electrophoresis, and sequence-tagged-site PCR. The MTAP gene consists of eight exons and seven introns. Of 23 malignant cell lines deficient in MTAP protein, all but one had complete or partial deletions. Partial or total deletions of the MTAP gene were found in primary T-cell acute lymphoblastic leukemias (T-ALL). A deletion breakpoint of partial deletions found in cell lines and primary T-ALL was in intron 4. Starting from the centromeric end, the gene order on chromosome 9p2l is p15, p16, MTAP, IFNA, and interferon beta gene (IFNB). These results indicate that MTAP deficiency in cancer is primarily due to codeletion of the MTAP and p16 genes.
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PMID:Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers. 865 Feb 44

Amplification of sequences derived from 12q13-15 is frequent in human sarcomas and brain tumors. Detailed mapping studies of the amplified region are necessary for definition of the impact of these amplification events on the tumor cell phenotype. By using the genes in this region and genomic fragments isolated by chromosome microdissection, we have established a series of ordered probes from 12q13-15 for fluorescence in situ hybridization (FISH) and Southern blot analysis. These probes have been used for physical mapping of two portions of the interval from GLI to D12S8. The centromeric region extends 1.8 Mb from GLI to microclone M79 and contains at least five genes, including the cyclin-dependent kinase gene CDK4. The more telomeric region includes the p53 regulator MDM2 and covers 1.1 Mb. We used the same group of probes to determine the pattern of amplification in three cell lines and three tumor specimens carrying amplified sequences from 12q13-15. In addition, we used a yeast artificial chromosome (YAC) contig of several megabases covering the entire region from SAS to D12S8 for FISH to determine the pattern of amplification in the neuroblastoma cell line NGP-127. The results suggest that the MDM2 and CDK4 regions may be either coamplified or amplified independently, and they illustrate how the map positions of genes and their functions may interact to determine the pattern of DNA amplification in human malignancies.
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PMID:Molecular cytogenetic characterization and physical mapping of 12q13-15 amplification in human cancers. 894 2

The RAG8 gene of Kluyveromyces lactis, which is one of the genes controlling the expression of the low-affinity carrier gene RAG1, has been cloned by in vivo complementation of the rag8 mutation. The sequence of Rag8p (535 amino acids), deduced from the nucleotide sequence of the cloned RAG8 gene, has been found to share a high degree of identity with the two casein kinases I of Saccharomyces cerevisiae, Yck1p and Yck2p, encoded by YCK1 and YCK2: the proteins are 65-66%, identical overall and show 89-90% identity in the kinase domain. The finding that the RAG8 gene of K. lactis cloned in a centromeric vector was able to complement the growth defect of a yck1 delta yck2(ts) mutant of S. cerevisiae strongly suggested that Rag8p is a casein kinase I. In contrast to the S. cerevisiae homologs, the RAG8 gene of K. lactis seems to be an essential single-copy gene, as shown by Southern blot experiments and the lethality of the rag8 null mutation. Northern blot analysis showed that the transcription of the RAG8 gene was higher on glucose media than in cells grown on a non-fermentable carbon source.
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PMID:The Kluyveromyces lactis equivalent of casein kinase I is required for the transcription of the gene encoding the low-affinity glucose permease. 903 7

Giardia duodenalis is the best-characterized example of the most ancient eukaryotes, which are primitively amitochondrial and anaerobic. The surface of Giardia is coated with cysteine-rich proteins. One family of these proteins, CRP136, varies among isolates and upon environmental stress. A repeat region within the CRP136 family is interchangeable by a cassette-like mechanism, generating further diversity in repeat size, copy number, and sequence. Flanking the 5' region of the CRP136 family is a novel protein kinase gene and an ankyrin homolog, creating a conserved unit. A short spacer separates the ankyrin gene from the variable, tandem array of rDNA gene units at a common breakpoint within the large subunit gene, which is followed by the (TAGGG)n telomeric sequence. Transcriptional up-regulation of the CRP136 family is accompanied by a switch in mRNA length and promoter, of de novo expression, and suggests that CRP136 mRNA induction is under the control of a telomerically regulated position effect, which evolved very early in the eukaryotic lineage.
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PMID:Telomeric organization of a variable and inducible toxin gene family in the ancient eukaryote Giardia duodenalis. 903


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