Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cdc kinase subunit 1 (Cks1) has been shown to involve in the regulation of cell cycle progression and p27Kip1 degradation. To define the role of Cks1 in lung tumorigenesis, we examined the expression of Cks1 in human lung cancer cell lines and tested the effect of Cks1-specific small interfering RNA (siRNA) on these cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analysis showed that Cks1 was highly expressed in human lung cancer cells. Transfection of Cks1 siRNA down-regulated Cdc2 kinase activity and induced G2/M arrest in Cks1- overexpressing H358 lung cancer cells. Long-term treatment of Cks1 siRNA induced caspase activation and apoptosis in H358 cells. On the contrary, Cks1 siRNA did not affect viability of normal human lung fibroblasts under the same experimental condition. Collectively, our results suggest that Cks1 participates in the steps of lung tumorigenesis and this gene may be a target for the treatment of lung cancer.
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PMID:RNA silencing of Cks1 induced G2/M arrest and apoptosis in human lung cancer cells. 1611 16

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II transcription. Several pharmacological CDK inhibitors (PCIs) are currently in clinical trials as potential cancer therapeutics since CDK hyperactivation is detected in the majority of neoplasias. Within the last few years, the anti-viral effects of PCIs have also been observed against various viruses, including human immunodeficiency virus (HIV), herpes simplex virus, and murine leukemia virus. Through the inhibition of CDK2 and 9, the cellular co-factors for HIV-1 Tat transactivation, HIV-1 replication is blocked by two specific PCIs, CYC202 and flavopiridol, respectively. In this article, we will review the inhibitory mechanisms of flavopiridol and CYC202 and discuss their possible usage in AIDS treatment.
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PMID:Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics. 1678 40

Cyclin-dependent kinase 7 (Cdk7) is the catalytic subunit of the metazoan Cdk-activating kinase (CAK). Activation of Cdk7 requires its association with a regulatory subunit, Cyclin H. Although the Cdk7/Cyclin H complex has been implicated in the regulation of RNA polymerase in several species, the precise function of their orthologs in zebrafish has not been fully elucidated. In this study, we isolated from zebrafish blastula embryos two cDNAs encoding the orthologs of human Cyclin H and Cdk7, and examined the role of Cdk7/Cyclin H in zebrafish embryogenesis. Sequence analysis showed that the zebrafish Cyclin H and Cdk7 cDNAs encode proteins with 65% and 86% identity to the respective human orthologs. RT-PCR and whole-mount in situ hybridization analyses of their expression in unfertilized eggs, embryos and organs of adult fish suggested that Cyclin H and Cdk7 messages are maternally loaded. Our data also showed that their transcripts were detected throughout development. Distribution of Cyclin H transcripts was found to be ubiquitous during early stages of development and become restricted to the anterior neural tube, brain, eyes, procreate tissues, liver and heart by 5 days post-fertilization. Expression of a dominant-negative form of Cyclin H delayed the onset of zygotic transcription in the early embryo, resulting in apoptosis at 5 hours post-fertilization and leading to sever defects in tissues normally exhibiting high levels of Cyclin H expression. These results implicate Cyclin H in the regulation of the transcriptional machinery during midblastula transition and suggest that it is an essential gene in early zebrafish larval development.
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PMID:Developmental expression of cyclin H and Cdk7 in zebrafish: the essential role of cyclin H during early embryo development. 1728 31

Cyclin-dependent kinase (cdk) inhibitors have the potential to induce growth arrest and apoptosis in cancer cells. The genes encoding cdks involved in G1-S progression are often amplified in B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Here, we evaluated the in vitro cytotoxic activity of the cdk2 inhibitor CVT-313 against several human DLBCL cells. Treatment of DLBCL cells with CVT-313 resulted in apoptosis. CVT-313 treatment reduced cdk2-mediated phosphorylation of the retinoblastoma gene product (Rb) on T821, but did not affect cyclin D-cdk4/6-mediated Rb phosphorylation on S807/811. Depletion of endogenous cdk2 by short interfering (si)RNA also resulted in apoptosis in human LY3, LY8 and LY18 DLBCL cells. Importantly, inhibition of cdk2 with CVT-313 or knockdown of endogenous cdk2 with siRNA resulted in down-regulation of the anti-apoptotic factor Myeloid cell leukemia-1 (Mcl-1), suggesting that decreased levels of cellular Mcl-1 contribute to apoptosis. In support of this, siRNA-mediated knockdown of Mcl-1 was sufficient to induce apoptosis in LY3 and LY18 DLBCL. Further, cdk2 inhibition led to decreased Mcl-1 mRNA levels, which was proceeded by reduced phosphorylation of serine 2 on the carboxyl terminal domain (CTD) of RNA polymerase II. Taken together, these data suggest that cdk2 activity is necessary for the survival of human DLBCL.
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PMID:Inhibition of cyclin-dependent kinase-2 induces apoptosis in human diffuse large B-cell lymphomas. 1815 99

Cyclin-dependent kinases (CDKs) are subunits of transcription factor (TF) IIH and positive transcription elongation factor b (P-TEFb). To define their functions, we mutated the TFIIH-associated kinase Mcs6 and P-TEFb homologs Cdk9 and Lsk1 of fission yeast, making them sensitive to inhibition by bulky purine analogs. Selective inhibition of Mcs6 or Cdk9 blocks cell division, alters RNA polymerase (Pol) II carboxyl-terminal domain (CTD) phosphorylation, and represses specific, overlapping subsets of transcripts. At a common target gene, both CDKs must be active for normal Pol II occupancy, and Spt5-a CDK substrate and regulator of elongation-accumulates disproportionately to Pol II when either kinase is inhibited. In contrast, Mcs6 activity is sufficient-and necessary-to recruit the Cdk9/Pcm1 (mRNA cap methyltransferase) complex. In vitro, phosphorylation of the CTD by Mcs6 stimulates subsequent phosphorylation by Cdk9. We propose that TFIIH primes the CTD and promotes recruitment of P-TEFb/Pcm1, serving to couple elongation and capping of select pre-mRNAs.
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PMID:TFIIH and P-TEFb coordinate transcription with capping enzyme recruitment at specific genes in fission yeast. 1932 67

The trimeric Cdk7.cyclin H.Mat1 complex functions in cell cycle regulation, as the Cdk-activating kinase, and in transcription, as a module of the general transcription factor TFIIH. As a component of TFIIH, Cdk7 phosphorylates serines 5 and 7 of the carboxyl-terminal domain of RNA polymerase II and can also directly phosphorylate transcription factors to regulate gene expression. Here we have investigated the function of the Cdk7.cyclin H.Mat1 complex in murine embryonic stem (ES) cells and preimplantation embryos to determine whether it regulates the unique cell cycle structure and transcriptional network of pluripotent cells. We demonstrate that depletion of cyclin H leads to differentiation of ES cells independent of changes in cell cycle progression. In contrast, we observed that developmental genes are acutely up-regulated after cyclin H down-regulation, likely perturbing normal ES self-renewal pathways. We further demonstrate that Spt5, a known phosphorylation target of Cdk7, similarly regulates ES pluripotency and gene expression. Consistent with its function in ES cells, cyclin H depletion from mouse embryos also leads to defects in the expansion of the inner cell mass of blastocysts, a transient pluripotent stem cell population in vivo. Our findings indicate that cyclin H has an essential function in promoting the self-renewal of the pluripotent stem cells of blastocyst stage embryos. Collectively, these studies demonstrate a critical and novel role for cyclin H in maintaining ES cell identity and suggest that cyclin H has important functions in early embryonic development.
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PMID:Functional analysis of the Cdk7.cyclin H.Mat1 complex in mouse embryonic stem cells and embryos. 2023 Dec 80

Viruses manipulate multiple processes of the host cell machinery in order to replicate successfully in the infected cell. Among these, stimulation of transcription of the viral genes is crucial for lentiviruses such as HIV for increased protein expression levels and generation of escape mutants. The transactivation response (TAR) element at the 5'-end of HIV, SIV, BIV, EIAV or JDV retroviruses forms a unique RNA based promoter element that together with the transcription activator protein Tat stimulates viral gene expression at the level of transcription elongation. TAR is a double stranded non-coding RNA of typically 24-40 nucleotides length. Together with Tat it interacts with the Cyclin T subunit of the positive transcription elongation factor P-TEFb to recruit Cyclin T and its corresponding Cyclin-dependent kinase Cdk9 to the RNA polymerase II. In vitro formations of these Tat-TAR containing ribonucleoprotein complexes are a key requisite for biochemical characterizations and interaction studies that eventually will allow structural analyses. Here, we describe purification methods of the different factors employed and chromatography techniques that yield highly specific complex assemblies suitable for crystallization.
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PMID:Formation of Tat-TAR containing ribonucleoprotein complexes for biochemical and structural analyses. 2038 37

Transcription factor II H (TFIIH) is comprised of core TFIIH and Cdk-activating kinase (CAK) complexes. Here, we investigated the molecular and cellular manifestation of the TFIIH compositional changes by XPG truncation mutations. We showed that both core TFIIH and CAK are rapidly recruited to damage sites in repair-proficient cells. Chromatin immunoprecipitation against TFIIH and CAK components revealed a physical engagement of CAK in nucleotide excision repair (NER). While XPD recruitment to DNA damage was normal, CAK was not recruited in severe XP-G and XP-G/CS cells, indicating that the associations of CAK and XPD to core TFIIH are differentially affected. A CAK inhibition approach showed that CAK activity is not required for assembling pre-incision machinery in vivo or for removing genomic photolesions. Instead, CAK is involved in Ser5-phosphorylation and UV-induced degradation of RNA polymerase II. The CAK inhibition impaired transcription from undamaged and UV-damaged reporter, and partially decreased transcription of p53-dependent genes. The overall results demonstrated that a) XP-G/CS mutations affect the disassembly state of TFIIH resulting in the dissociation of CAK, but not XPD from core TFIIH, and b) CAK activity is not essential for global genomic repair but involved in general transcription and damage-induced RNA polymerase II degradation.
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PMID:Dissociation of CAK from core TFIIH reveals a functional link between XP-G/CS and the TFIIH disassembly state. 2054 86

The differentiation of the blood-brain barrier (BBB) is an essential process in the development of a complex nervous system and depends on alternative splicing. In the fly BBB, glial cells establish intensive septate junctions that require the cell-adhesion molecule Neurexin IV. Alternative splicing generates two different Neurexin IV isoforms: Neurexin IV(exon3), which is found in cells that form septate junctions, and Neurexin IV(exon4), which is found in neurons that form no septate junctions. Here, we show that the formation of the BBB depends on the RNA-binding protein HOW (Held out wings), which triggers glial specific splicing of Neurexin IV(exon3). Using a set of splice reporters, we show that one HOW-binding site is needed to include one of the two mutually exclusive exons 3 and 4, whereas binding at the three further motifs is needed to exclude exon 4. The differential splicing is controlled by nuclear access of HOW and can be induced in neurons following expression of nuclear HOW. Using a novel in vivo two-color splicing detector, we then screened for genes required for full HOW activity. This approach identified Cyclin-dependent kinase 12 (Cdk12) and the splicesosomal component Prp40 as major determinants in regulating HOW-dependent splicing of Neurexin IV. Thus, in addition to the control of nuclear localization of HOW, the phosphorylation of the C-terminal domain of the RNA polymerase II by Cdk12 provides an elegant mechanism in regulating timed splicing of newly synthesized mRNA molecules.
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PMID:The regulation of glial-specific splicing of Neurexin IV requires HOW and Cdk12 activity. 2246 65

Cyclin-dependent kinase (Cdk)7, the catalytic subunit of the Cdk-activating kinase (CAK) complex has been implicated in the control of cell cycle progression and of RNA polymerase II (RNA pol II)-mediated transcription. Genetic inactivation of the Cdk7 locus revealed that whereas Cdk7 is completely dispensable for global transcription, is essential for the cell cycle via phosphorylation of Cdk1 and Cdk2. In vivo, Cdk7 is also indispensable for cell proliferation except during the initial stages of embryonic development. Interestingly, widespread elimination of Cdk7 in adult tissues with low proliferative indexes had no phenotypic consequences. However, ablation of conditional Cdk7 alleles in tissues with elevated cellular turnover led to the efficient repopulation of these tissues with Cdk7-expressing cells most likely derived from adult stem cells that may have escaped the inactivation of their targeted Cdk7 alleles. This process, a physiological attempt to maintain tissue homeostasis, led to the attrition of adult stem cell pools and to the appearance of age-related phenotypes, including telomere shortening and early death.
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PMID:Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion. 2250 32


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