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)

The gene encoding the mouse vitamin D receptor has been cloned. A new exon 1 has been found that changes the numbering established for the human VDR gene. Exons 2 and 3 in the human VDR gene (coding for the zinc fingers 1 and 2, respectively) are named exons 3 and 4 in the mouse vitamin D receptor. The 1.5-kb 5'-flanking region of the new exon 1 was analyzed and revealed the presence of putative cis-acting elements. Despite the absence of a TATA box, this 5'-flanking region contains several characteristics of a GC-rich promoter including four Sp1 sites present in tandem and two CCAAT boxes. Interestingly, the Sp1 site that is the most proximal to the new exon 1 overlaps a perfect site for Krox-20/24. Krox-20 is a transcription factor involved in brain development, and also in bone remodeling. In luciferase reporter gene expression assays, we showed that sequences from this 5'-flanking region elicit high transactivation activity. Furthermore, in the NIH 3T3 cell line, a 3- to 5-fold increase in response to forskolin treatment (an activator of adenylate cyclase and in turn of protein kinase A pathway) was observed.
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PMID:Cloning and characterization of the mouse vitamin D receptor promoter. 929 76

Affinity chromatography on columns containing the immobilized monomeric transcriptional elongation factor TFIIS or the essential large subunit, Elongin A, of the trimeric elongation factor, Elongin, was used to purify a human RNA polymerase II holoenzyme from HeLa whole cell extract. This holoenzyme contained nearstoichiometric amounts of all the general transcription factors, TFIIB, TFIID (TBP + TAFIIs), TFIIE, TFIIF, and TFIIH, required to accurately initiate transcription in vitro at the adenovirus major late promoter. It behaved as a large complex, slightly smaller than 70 S ribosomes, during gel filtration chromatography, and contained nearly half the TFIID that was present in the extract used for the affinity chromatography. It also contained the cyclin-dependent kinase CDK8, a human homologue of the Saccharomyces cerevisiae holoenzyme subunit SRB10, and many other polypeptides. Efficient interaction of holoenzyme with TFIIS or Elongin A required only the amino-terminal region of either protein. These regions are similar in amino acid sequence but dispensable for TFIIS or Elongin to regulate elongation in vitro by highly purified RNA polymerase II. The transcriptional activators GAL4-VP16 and GAL4-Sp1 activated transcription in vitro by purified holoenzyme in the absence of any additional factors.
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PMID:Interaction of elongation factors TFIIS and elongin A with a human RNA polymerase II holoenzyme capable of promoter-specific initiation and responsive to transcriptional activators. 930 22

p27Kip1 is a member of the family of cyclin-dependent kinase inhibitors (CKIs), which play critical roles in the regulation of cell cycle. To study the transcriptional regulation that controls the expression of p27, we have isolated the p27 promoter, defined its transcription initiation site, and performed various analyses for sequences upstream to 3 kb. Transient transfection assays using fusion reporters containing progressively truncated p27 promoter fragments showed that a region of 170 bp upstream of the start site is sufficient for maximal transcription activity. Detailed sequence analysis of this 170 bp region identified several GC-rich segments, putative sites of the transcription factor Sp1. Footprinting experiments revealed two Sp1-protected boxes, named BoxI and BoxII, which are located at positions -133 to -117 and -87 to -72, respectively. Binding of Sp1 to the two boxes was further demonstrated by gel mobility shift assays and supershift assays. Co-transfection studies in Drosophila Schneider line 2 cells showed that Sp1 indeed activates the p27 promoter constructs that harbor one or both of the GC-rich sequences. Furthermore, the GC-rich sequences could confer Sp1-dependent transactivation to a heterologous prolactin minimal promoter. Mutations in the GC-rich sequences abolished both binding and transactivation by Sp1. Taken together, our data strongly show that the p27 promoter is activated by the ubiquitously expressed transcription factor Sp1, which may provide a molecular mechanism for the constitutive nature of p27 transcription.
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PMID:Molecular characterization of the cyclin-dependent kinase inhibitor p27 promoter. 934 26

The Slc12a2 gene encodes a widely expressed bumetanide-sensitive Na+-K+-2Cl- cotransporter that participates in various functions such as Cl- secretion and cell volume regulation. We isolated and characterized 75 kilobases of the murine gene encoding the cotransporter. The cotransport protein is encoded by 27 exons. Ribonuclease protection assay and primer extension demonstrated tissue-specific transcription initiation sites located within 270 base pairs upstream of the start codon. Nucleotide sequence analysis of the proximal 5'-flanking region revealed the presence of a weak TATA box, multiple Sp1/GC consensus sites, and the consensus sequence of a putative transcriptional initiator. Transfection of luciferase reporter gene constructs in mouse inner medullary collecting duct (mIMCD-3) cells confirmed the location of the minimal promoter within a 120-base pair fragment upstream of the cDNA. We also report the identification of an alternatively spliced variant of the cotransporter, expressed primarily in brain. This new spliced variant lacks exon 21, which encodes a 16-amino acid peptide located in the COOH-terminal tail of the protein. The absence of this exon causes the loss of the single protein kinase A consensus site of the cotransport protein.
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PMID:Partial cloning and characterization of Slc12a2: the gene encoding the secretory Na+-K+-2Cl- cotransporter. 935 71

The Plk gene encodes a serine/threonine protein kinase believed to be important for the normal progression of mammalian cells through the cell cycle. In this paper, we report the genomic organization of the mouse Plk gene. The mouse Plk gene encompasses 16 kb of the mouse genome and is organised into 10 exons. Based on homology with the human PLK1 promoter region, the putative mouse promoter region includes a CCAAT motif but lacks the conventional TATA motif. The proposed promoter region contains consensus binding sites for several transcriptional regulators, including Sp1 and AP2. In addition to the active copy of Plk, Plk exists as a processed pseudogene. Using RFLP analysis, we have localized the active Plk gene to mouse Chromosome 7 and the processed pseudogene to mouse Chromosome 5. Southern blot analysis of DNA from a limited number of other mammalian species suggests that the duplication is confined to the mouse. Parsimony analysis suggests that the gene duplication leading to the mouse Plk pseudogene occurred after the rat-mouse split.
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PMID:The mouse Plk gene: structural characterization, chromosomal localization and identification of a processed Plk pseudogene. 937 Feb 99

Recently, a family of novel, serine/threonine protein kinases has been identified. One of these transcriptionally inducible, immediate-early genes encodes serum/glucocorticoid inducible-protein kinase, sgk. By in situ hybridization, we show that sgk expression in the rat ovary is selectively localized to granulosa cells. In culture, FSH or forskolin, activators of the protein kinase A (PKA) pathway, rapidly (2 h) and transiently increased sgk mRNA levels in undifferentiated granulosa cells. Sgk mRNA exhibited a biphasic expression pattern, with maximal levels observed at 48 h of FSH/forskolin as granulosa cells differentiate to the preovulatory phenotype. Deletion analyses using sgk promoter-reporter constructs (-4.0 kb to -35 bp) identified a region between -63 and -43 bp that mediated FSH and forskolin-responsive transcription in undifferentiated and differentiated granulosa cells. This G/C-rich region 1) conferred both basal and inducible transcription to the minimal -35 sgk promoter chloramphenicol acetyltransferase reporter construct, 2) specifically bound Sp1 and Sp3 present in granulosa cell extracts, and 3) bound recombinant Sp1. Mutation of 2 bp in this region not only prevented Sp1 and Sp3 binding, but also abolished the PKA-mediated transactivation observed when using the wild type construct. Sp1 and Sp3 DNA-binding activity and protein levels did not change significantly during sgk induction. Collectively, these data indicate that Sp1/Sp3 transactivation of the sgk promoter likely involves regulated, phosphorylation-dependent interaction with other factors. Thus the novel, biphasic induction of sgk that correlates with granulosa cell progression from proliferation to differentiation appears to involve sequential, coordinated actions of FSH, PKA, and transcription factors, including Sp1 and Sp3.
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PMID:Follicle stimulating hormone-regulated expression of serum/glucocorticoid-inducible kinase in rat ovarian granulosa cells: a functional role for the Sp1 family in promoter activity. 941 98

The expression of multidrug-resistance (MDR) in breast carcinoma cell line MCF-7/ADR50 is primarily dependent on the transcriptional activation of the MDR1 gene. We now report that MDR in this cell line is partially reversed by the type I cAMP-dependent protein kinase (PKA) inhibitor, 8-Cl-cAMP. MDR1 promoter activity was also regulated through a PKA-dependent pathway and was inhibited by 8-Cl-cAMP, and stimulated by the enantiomeric agonist, SpcAMP[S]. MDR1 promoter activity through an Sp1 response element was stimulated by exogenous Sp1, a factor that we have shown to be activated by PKA. These results indicate that MDR1 promoter activity is linked to the cAMP/PKA signaling pathway, and that PKA antagonists may be useful for reversing the multidrug-resistant phenotype.
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PMID:Regulation of the MDR1 promoter by cyclic AMP-dependent protein kinase and transcription factor Sp1. 945 66

TESK1 (testis-specific protein kinase 1) is a protein serine-threonine kinase, containing characteristic structural features composed of an N-terminal kinase domain and a C-terminal proline-rich domain. Tesk1 mRNA is predominantly expressed in testicular germ cells, and developmental changes of expression in mouse testis suggest a role for this kinase in spermatogenesis. In the present study, we isolated and determined the overall sequence of the mouse Tesk1 gene, which spans 6.1 kilobases (kb) and contains 10 exons and 9 introns. The protein kinase domain is located in exons 1-9, while the proline-rich domain is in exons 9 and 10. The deduced 627 amino acid sequence of mouse TESK1 shows 97% and 94% identity with the rat and human TESK1, respectively. Sequence of the 5'-flanking and -untranslated region is devoid of a TATA box, but does contain several potential binding sites for transcription factors, including Sp1, AP-1, c-Myc, SRY and CREM (cyclic AMP-responsive element modulator). As CREM is implicated in the activation of several male germ cell-specific genes, it is suggested that the expression of the Tesk1 gene is under the control of CREM transcription activity. The Tesk1 gene was mapped to mouse chromosome 4A5-C1 by fluorescence in situ hybridization.
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PMID:Structural organization and chromosomal localization of the mouse tesk1 (testis-specific protein kinase 1) gene. 946 38

Mig1p, a zinc-finger protein that is related to the Krox/Egr, Wilms' tumor and Sp1 proteins, mediates glucose repression in the yeast Saccharomyces cerevisiae. Mig1p is inactive in the absence of glucose, and this inhibition is dependent on the Snf1p (Cat1p) protein kinase. The regulation is mediated by an internal part of Mig1p, and it can be transferred to a Mig1-viral protein 16 (VP16) fusion protein that functions as an activator [Ostling, J., Carlberg, M. & Ronne, H. (1996) Mol. Cell. Biol. 16, 753-761]. We have used Mig1-VP16 to identify three target sites for phosphorylation that mediate Snf1p-dependent inhibition of its activity in the absence of glucose. Two of the sites, Ser278 and Ser311, fit the consensus sequence for phosphorylation by the kinase Snf1p, as determined in vitro. However, a third phosphorylated site, Ser108, does not resemble a Snf1p site. We tested the effect of deleting residues 181-245, which contain two conserved alanine-leucine-serine motifs. We found that the deletion produces a partially constitutive activator, indicating that this region plays a general negative role in regulating Mig1p.
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PMID:Negative control of the Mig1p repressor by Snf1p-dependent phosphorylation in the absence of glucose. 952 26

Just previous to the onset of parturition, a number of genes such as the one that codes for connexin-43 (Cx43) gap junction protein are induced in the myometrium. We have shown previously that activation of protein kinase C in human myometrial cultured cells leads to an up-regulation of cx43 transcription through an activating protein-1 element in the 5'-flanking promoter. Analyses were now performed on extracts of term myometrial tissue to test for an association between the up-regulation of cx43 expression and the expression of transcription factors and steroid hormone receptors that might regulate cx43 expression at term. Immunoblot analyses were performed on extracts of term myometrial tissue from women receiving elective or indicated cesarean sections to test for an association between the up-regulation of cx43 expression and the up-regulation of expression of the transcription factors c-Jun, c-Fos, and Sp1, which have cognate binding elements in the cx43 5'-flanking promoter. Immunoblot analysis, immunohistochemistry, and receptor binding assays were also performed to analyze the levels of progesterone receptors (PR) and estrogen receptors (ER) in the same term myometrial tissue, and these were compared to the levels in nonpregnancy myometrial tissue. The levels of PR were consistently 2- to 3-fold higher in term myometrial tissue than in nonpregnancy values and did not fluctuate during the menstrual cycle as did ER levels. Surprisingly, in term myometrium, ER was barely detectable by immunoblot and had whole cell diffuse staining by immunohistochemistry. In addition, very low levels of estrogen binding were observed in the term myometrial tissue. Treatment of primary myometrial cultures containing ER with estrogen for 3 or 48 h did not result in up-regulation of c-Jun or c-Fos proteins or in trans-activation from the proximal cx43 promoter with the activating protein-1 element. In contrast, an activated form of c-Jun protein was 10- to 18-fold higher in term myometrial tissue that also had elevated cx43 expression compared to c-Jun levels in term myometrial tissue with low cx43 expression. Likewise, c-Fos and Sp1 levels were 2-4 fold higher in term myometrial tissue with elevated cx43 expression. Although c-Fos and Sp1 proteins could be detected by immunoblot in myometrial tissue from nonpregnant women, c-Jun and Cx43 proteins could not. In summary, these results suggest that up-regulation of human myometrial cx43 gene expression at term involves induction of primarily c-jun expression through a mechanism that does not directly involve myometrial ER or the loss of PR. Peptide hormones that activate protein kinase cascades, such as the protein kinase C cascade, may be important to signal the onset of labor in humans.
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PMID:Elevated connexin-43 expression in term human myometrium correlates with elevated c-Jun expression and is independent of myometrial estrogen receptors. 954 37


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