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)

The activity of the E2F transcription factor is regulated in part by pRB, the protein product of the retinoblastoma tumor suppressor gene. Studies of tumor cells show that the p16(ink4a)/cdk4/cyclin D/pRB pathway is mutated in most forms of cancer, suggesting that the deregulation of E2F, and hence the cell cycle, is a common event in tumorigenesis. Extragenic mutations that enhance or suppress E2F activity are likely to alter cell-cycle control and may play a role in tumorigenesis. We used an E2F overexpression phenotype in the Drosophila eye to screen for modifiers of E2F activity. Coexpression of dE2F and its heterodimeric partner dDP in the fly eye induces S phases and cell death. We isolated 33 enhancer mutations of this phenotype by EMS and X-ray mutagenesis and by screening a deficiency library collection. The majority of these mutations sorted into six complementation groups, five of which have been identified as alleles of brahma (brm), moira (mor) osa, pointed (pnt), and polycephalon (poc). osa, brm, and mor encode proteins with homology to SWI1, SWI2, and SWI3, respectively, suggesting that the activity of a SWI/SNF chromatin-remodeling complex has an important impact on E2F-dependent phenotypes. Mutations in poc also suppress phenotypes caused by p21(CIP1) expression, indicating an important role for polycephalon in cell-cycle control.
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PMID:A genetic screen for modifiers of E2F in Drosophila melanogaster. 1047 12

The Saccharomyces cerevisiae genes PHO80 and PHO85 encode, respectively, a cyclin and cyclin-dependent kinase, which negatively regulate PHO5 gene transcription by phosphorylating the transcription activator Pho4p. Cyclin-dependent kinases (CDKs) are highly conserved proteins, both within and between species. It was previously demonstrated, using reporter genes activated in yeast by Pho4p, that hybrid proteins in which over two-thirds of Pho85p were replaced with the homologous region from human Cdk2 retained the function of native Pho85p with respect to promoter repression. In the present study, various truncated forms of the hybrid human-yeast CDKs were tested for function. Surprisingly, truncations in which significant portions of the C-terminal region of the 291-residue hybrid CDK were deleted retained activity. Genes encoding human Cdk2 proteins which terminated after amino acids 151, 140, 130, 120 and 90 each complement a chromosomal pho85 gene disruption in which the HIS3 gene is inserted at codon 49. Truncated Cdk2 proteins containing less than 60 amino acids failed to complement the pho85::HIS3 gene disruption. Although the functional C-terminal truncations disrupt the ATP-binding and active sites of Cdk2, reporter gene repression mediated by these truncated proteins is apparently due to phosphorylation of Pho4p, since a gene in which the essential lysine codon at position 33 was converted to an arginine codon does not complement the chromosomal gene disruption. The human Cdk2 truncations were demonstrated to function through intergenic complementation. The intact Cdk2-Pho85 hybrid CDK complemented the pho85 mutation in yeast strains in which the entire PHO85 coding region was deleted from chromosome XVI. The C-terminal Cdk2 truncations, however, were non-functional in these strains and thus dependent for activity on the pho85 coding region which remained in the mutant pho85::HIS3 chromosomal locus. These genetic results are consistent with a model involving protein fragment complementation in which the active site of the CDK is bisected.
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PMID:Intergenic complementation truncation mutants of cyclin-dependent kinase. 1077 40

Cyclin E-Cdk2 is essential for S phase entry. To identify genes interacting with cyclin E, we carried out a genetic screen using a hypomorphic mutation of Drosophila cyclin E (DmcycE(JP)), which gives rise to adults with a rough eye phenotype. Amongst the dominant suppressors of DmcycE(JP), we identified brahma (brm) and moira (mor), which encode conserved core components of the Drosophila Brm complex that is highly related to the SWI-SNF ATP-dependent chromatin remodeling complex. Mutations in genes encoding other Brm complex components, including snr1 (BAP45), osa and deficiencies that remove BAP60 and BAP111 can also suppress the DmcycE(JP) eye phenotype. We show that Brm complex mutants suppress the DmcycE(JP) phenotype by increasing S phases without affecting DmcycE protein levels and that DmcycE physically interacts with Brm and Snr1 in vivo. These data suggest that the Brm complex inhibits S phase entry by acting downstream of DmcycE protein accumulation. The Brm complex also physically interacts weakly with Drosophila retinoblastoma (Rbf1), but no genetic interactions were detected, suggesting that the Brm complex and Rbf1 act largely independently to mediate G(1) arrest.
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PMID:Drosophila cyclin E interacts with components of the Brahma complex. 1209 39

The ubiquitous mammalian chromatin-remodeling SWI/SNF-like BAF complexes play critical roles in tumorigenesis. It was suggested that the direct interaction of BRG1 with the retinoblastoma protein pRB is required for regulation of cell cycle progression by pRB. We present evidence that the BRG1-containing complexes regulate the expression of the cdk inhibitor p21(CIP1/WAF1/SDI). Furthermore, we show that the physical interaction between BRG1 and pRB is not required for induction of cell growth arrest and transcriptional repression of E2F target genes by pRB. Instead, BRG1 activates pRB by inducing its hypophosphorylation through up-regulation of the cdk inhibitor p21. The hypophosphorylation of pRB is reinforced by down-regulation of critical components, including cdk2, cyclin E, and cyclin D, in the pRB regulatory network. We demonstrate that up-regulation of p21 by BRG1 is necessary to induce formation of flat cells, growth arrest, and finally, cell senescence. Our results suggest that the BRG1-containing complexes control cellular proliferation and senescence by modulating the pRB pathway via multiple mechanisms.
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PMID:BRG1 controls the activity of the retinoblastoma protein via regulation of p21CIP1/WAF1/SDI. 1472 64

Human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of AIDS. Following entry into the host cell, the viral RNA is reverse transcribed into DNA and subsequently integrated into the host genome as a chromatin template. Chromatin structure may be responsible for silencing retroviral gene expression. Transcriptional activation occurs after ATP-dependent chromatin remodeling complexes alter chromatin structure and positioning of nucleosomes. Histone acetyltransferases (HATs), histone deacetylases (HDACs), kinases, and methyltransferases (HMTs), covalently modify nucleosomes by adding or removing chemical moieties in the N-terminal tails of histones. Recent advances have indicated that HIV-1 encoded proteins interact with chromatin remodeling complexes and histone modifying enzymes, implying that chromatin remodeling plays an important role in the HIV-1 life cycle. Nucleosomes are positioned on the HIV-1 LTR and are barriers to transcription. Following cellular activation, these nucleosomes are modified and repositioned allowing for activation of viral gene expression. Tat recruits various HATs to the HIV-1 promoter region and can also be acetylated by some of these enzymes. Unmodified Tat is involved in binding to the CBP/p300 and cdk9/cyclin T complexes and facilitates transcription initiation. Acetylated Tat dissociates from the TAR RNA structure and recruits bromodomain-containing chromatin modifying complexes such as p/CAF and SWI/SNF to facilitate transcription elongation. This review summarizes our current knowledge and understanding of chromatin remodeling complexes and their regulation of HIV-1 replication, and highlights the important contributions HIV-1 research has made to further our understanding of the transcription process.
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PMID:Chromatin remodeling and modification during HIV-1 Tat-activated transcription. 1504 58

STAT transcription factors (signal transducers and activators of transcription) are cytoplasmic proteins that induce gene activation in response to cytokine receptor stimulation. Following tyrosine phosphorylation, STAT proteins translocate into the nucleus and activate specific target genes. We have previously reported that STAT3 activates the expression of the p21waf1 gene through its association with the NcoA/SRC1a and CBP coactivators. In this study, we explore the role of BRG1, a component of the SWI/SNF chromatin-remodeling complex, and the role of cdk9, a component of the elongation factor P-TEFb, in the STAT3-mediated expression of p21waf1. We found using pull-down experiments and co-immunoprecipitation assays that both proteins associate with STAT3. Chromatin immunoprecipitation (ChIP) experiments indicate that STAT3 DNA binding results in histone H3 acetylation and BRG1 recruitment. Using Southern blot analysis, we found that the loading of BRG1 is followed by an increased accessibility of the proximal p21waf1 promoter and by the association of RNA polymerase II. As a next step, STAT3 then recruits the cdk9 kinase to phosphorylate the carboxy-terminal domain of the RNA polymerase at serine 2. Accordingly, the elongating form of the polymerase can be detected by ChIP experiments on the coding region of the gene, probably initiating mRNA synthesis. Therefore, STAT3 not only promotes the initiation of transcription but also regulates chromatin remodeling and transcription elongation through its interaction with BRG1 and cdk9.
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PMID:Implication of BRG1 and cdk9 in the STAT3-mediated activation of the p21waf1 gene. 1528 5

During skeletal myogenesis, muscle-regulatory factors bHLH and MEF2 promote the expression of muscle-specific genes by recruiting several chromatin-modifying complexes on specific DNA regulatory sequences. A number of MyoD-interacting proteins have been reported, but whether they are recruited to the chromatin of myogenic loci, and the relationship with other chromatin bound proteins is unknown. We show that MyoD recruits cdk9/cyclin T2, together with the histone acetyltransferases p300 and PCAF, and the chromatin remodeling complex SWI/SNF, on promoters and enhancers of muscle-specific genes, and that this event correlates with the acetylation of histone tails, remodeling of chromatin, and phosphorylation of the C-terminal domain (CTD) of the RNA polymerase II at these elements.
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PMID:MyoD recruits the cdk9/cyclin T2 complex on myogenic-genes regulatory regions. 1624 9

SNF2L, a chromatin remodeling gene expressed in diverse tissues, cancers, and derived cell lines, contributes to the chromatin remodeling complex that facilitates transcription. Because of this wide expression, it has not been exploited as a cancer therapeutic target. However, based on our present studies, we find that cancer cells, although expressing SNF2L at similar levels as their normal counterparts, are sensitive to its knockdown. This is not observed when its imitation SWI ortholog, SNF2H, is inhibited. SNF2L siRNA inhibition using two different siRNAs separately reduced SNF2L transcript levels and protein in both normal and cancer lines, but only the cancer lines showed significant growth inhibition, DNA damage, a DNA damage response, and phosphorylation of checkpoint proteins and marked apoptosis. DNA damage and the damage response preceded apoptosis rather than being consequences of it. The damage response consisted of increased phosphorylation of multiple substrates including ATR, BRCA1, CHK1, CHK2, and H2AX. Both the total and phosphorylated levels of p53 increased. The downstream targets of p53, p21, GADD45A, and 14-3-3sigma, were also upregulated. The alterations in checkpoint proteins included increased phosphorylated cdc2 but not Rb, which resulted in a modest G(2)-M arrest. Although apoptosis may be mediated by Apaf-1/caspase 9, other caspases could be involved. Other members of the chromatin remodeling or SWI/SNF gene families exhibited overall reduced levels of expression in the cancer lines compared with the normal lines. This raised the hypothesis that cancers are sensitive to SNF2L knockdown because, unlike their normal counterparts, they lack sufficient compensation from other family members.
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PMID:Inhibition of expression of the chromatin remodeling gene, SNF2L, selectively leads to DNA damage, growth inhibition, and cancer cell death. 1999 4

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat is present on both ends of the integrated viral genome and contains regulatory elements needed for transcriptional initiation and elongation. Post-integration, a highly ordered chromatin structure consisting of at least five nucleosomes, is found at the 5' long terminal repeat, the location and modification state of which control the state of active viral replication as well as silencing of the latent HIV-1 provirus. In this context, the chromatin remodeling field rapidly emerges as having a critical role in the control of viral gene expression. In the current study, we focused on unique Baf subunits that are common to the most highly recognized of chromatin remodeling proteins, the SWI/SNF (switching-defective-sucrose non-fermenting) complexes. We find that at least two Baf proteins, Baf53 and Baf170, are highly regulated in HIV-1-infected cells. Previously, studies have shown that the depletion of Baf53 in uninfected cells leads to the expansion of chromosomal territories and the decompaction of the chromatin. Baf53, in the presence of HIV-1 infection, co-elutes off of a chromatographic column as a different-sized complex when compared to uninfected cells and appears to be predominantly phosphorylated. The innate function of Baf53-containing complexes appears to be transcriptionally suppressive, in that knocking down Baf53 increases viral gene expression from cells both transiently and chronically infected with HIV-1. Additionally, cdk9/cyclin T in the presence of Tat is able to phosphorylate Baf53 in vitro, implying that this posttranslationally modified form relieves the suppressive effect and allows for viral transcription to proceed.
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PMID:Varying modulation of HIV-1 LTR activity by Baf complexes. 2169 4

The pan-histone deacetylase (HDAC) inhibitor, trichostatin A, was found to reduce cyst progression and slow the decline of kidney function in Pkd2 knockout mice, model of autosomal dominant polycystic kidney disease (ADPKD). Here we determine whether HDAC inhibition acts by regulating cell proliferation to prevent cyst formation, or by other mechanisms. The loss of Pkd1 caused an upregulation of the inhibitor of differentiation 2 (Id2), a transcription regulator, triggering an Id2-mediated downregulation of p21 in mutant mouse embryonic kidney cells in vitro. Using mouse embryonic kidney cells, mutant for Pkd1, we found that trichostatin A decreased Id2, which resulted in upregulation of p21. Further, phosphorylated retinoblastoma (Rb), usually regulated by Cdk2/Cdk4 activity, was also reduced in these cells. Since these latter enzymes are under the control of p21, these studies suggest that the proliferation of cyst epithelial cells that is reduced by trichostatin A might result from p21 upregulation, or alternatively through the Rb-E2F pathway. Additional studies showed that Id2 directly bound to Rb, releasing the transcription activator E2F from transcriptionally inactive Rb-E2F complexes. HDAC inhibition was able to reverse this process by downregulation of Id2. Furthermore, treatment of pregnant Pkd1 mice with trichostatin A prevented cyst formation in the developing embryonic kidneys, showing that this inhibition is effective in vivo during early cyst formation. Thus, HDAC inhibition targets Id2-mediated pathways to downregulate cystic epithelial cell proliferation and hence cystogenesis.
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PMID:Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation. 2190 Aug 81


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