AnatomyOrganismsChemicals and DrugsAnalytical, Diagnostic and Therapeutic Techniques and EquipmentPhenomena and ProcessesDisciplines and OccupationsInformation Science
Cyclin-Dependent Kinase Inhibitor p27Cyclin-Dependent Kinase Inhibitor p21Cyclin-Dependent KinasesCyclinsCell Cycle ProteinsCyclin-Dependent Kinase Inhibitor p16Cell CycleTumor Suppressor ProteinsMicrotubule-Associated ProteinsCyclin-Dependent Kinase 2Cyclin D1Cyclin ACyclin ECell ProliferationCyclin-Dependent Kinase 4CDC2-CDC28 KinasesApoptosisCell Line, TumorCyclin-Dependent Kinase Inhibitor p57Protein-Serine-Threonine KinasesProtein Kinase InhibitorsPhosphorylationCyclin-Dependent Kinase 5G1 PhaseCyclin BCDC2 Protein KinaseCyclin DCyclin-Dependent Kinase Inhibitor ProteinsCyclin CEnzyme InhibitorsRetinoblastoma ProteinCell DivisionCyclin D3Cyclin-Dependent Kinase 6S PhaseProtein KinasesCells, CulturedProto-Oncogene ProteinsCyclin B1Signal TransductionTumor Suppressor Protein p53Cell LineTumor Cells, CulturedCyclin-Dependent Kinase Inhibitor p18Blotting, WesternPhosphatidylinositol 3-KinasesMolecular Sequence DataTransfectionCyclin D2MutationProtein-Tyrosine KinasesEnzyme ActivationPurinesDNA-Binding ProteinsE2F1 Transcription FactorMAP Kinase Signaling SystemSerineMitosisCyclin A1Protein Kinase CAmino Acid SequenceCarrier ProteinsG2 PhaseNuclear ProteinsRNA, MessengerProtein BindingCalcium-Calmodulin-Dependent Protein KinasesCyclin GTranscription FactorsProliferating Cell Nuclear Antigensrc-Family KinasesTranscription Factor DP1Base SequenceCyclin-Dependent Kinase Inhibitor p15Cyclin G1TyrosineCyclin A2E2F Transcription FactorsAntineoplastic AgentsCyclic AMP-Dependent Protein KinasesIntracellular Signaling Peptides and ProteinsPhosphoproteinsMitogen-Activated Protein KinasesGene Expression RegulationDown-RegulationImmunohistochemistryProto-Oncogene Proteins c-aktMitogen-Activated Protein Kinase 1p38 Mitogen-Activated Protein KinasesTranscription, GeneticDNA DamageKineticsReverse Transcriptase Polymerase Chain ReactionMitogen-Activated Protein Kinase 33T3 CellsS-Phase Kinase-Associated ProteinsCyclin-Dependent Kinase Inhibitor p19RNA, Small InterferingTime FactorsThreonine
CDKsProteinsCDK4TyrosineProtein kinasesSubstratesProgressionSubunitsComplexesCDKN1ACip1SubstrateSerineRetinoblastoma proteinInhibitionApoptosisMouse embryonic fibroblastsHistoneCdk1PathwayProliferationAccumulationERK1VivoActivationEndothelialActivitySenescent cellsCellPromotesGenesInactivationReplicationSubsequentlyExpressionIsoformCancerComplex
CDKs15
Proteins5
  • We show that cyclin-dependent kinase (CDK) consensus motifs are frequently clustered in CDK substrate proteins. (biomedcentral.com)
  • instead of attempting to predict individual phosphorylation sites, we search for proteins that contain high densities of strong and weak consensus matches that are closely spaced in the primary amino acid sequence. (biomedcentral.com)
  • Although the senescent cells remain viable, they show typical changes with enlarged and flattened cell bodies, apoptosis resistance, increased activity of senescence-associated β -galactosidase (SA- β -gal), and upregulation of cyclin-dependent kinase (CDK) inhibitors including p16 INK4A , ARF proteins, and p21 [ 13 - 16 ]. (hindawi.com)
  • The accumulation of both Cyclin and CKI proteins is tightly regulated at the level of transcription. (intechopen.com)
  • In addition, Cyclin and CKI proteins are controlled at the level of their destruction. (intechopen.com)
CDK47
  • We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1). (rcsb.org)
  • Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates. (rcsb.org)
  • Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to clinically relevant CDK4/6 inhibitors. (rcsb.org)
  • Cells that were treated with esculetin showed increased binding of p21 with Cdk2 and Cdk4 that was paralleled by a marked decrease in the Cdk2 and Cdk4 kinase activities with no change in their expression. (dsmc.or.kr)
  • The p16INK4A protein is a cell-cycle inhibitor that acts by inhibiting activated cyclin D:CDK4/6 complexes, which play a crucial role in the control of the cell cycle by phosphorylating Rb protein. (medscape.com)
  • This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb. (cancerindex.org)
  • ST caused G0/G1 cell cycle arrest which was accompanied by a decrease in CDK4 and cyclin D1, and an increase in p21/Cip1and p27/Kip1 protein levels. (biomedcentral.com)
Tyrosine1
  • New treatment protocols are aiming to reduce the dose of the multitargeted tyrosine kinase inhibitor sunitinib, as sunitinib elicits many adverse effects depending on its dosage. (bvsalud.org)
Protein kinases3
  • Protein kinases are critical to cellular signalling and post-translational gene regulation, but their biological substrates are difficult to identify. (biomedcentral.com)
  • Protein kinases are ubiquitous components of cellular signalling networks [ 1 ]. (biomedcentral.com)
  • The protein encoded by this gene is a member of the CMGC family of serine/threonine protein kinases. (cancerindex.org)
Substrates6
  • Here we compare the specificity of two budding yeast cyclins, the S-phase cyclin Clb5 and the M-phase cyclin Clb2, in the phosphorylation of 150 Cdk1 (Cdc28) substrates. (nature.com)
  • Although we did not identify any highly Clb2-specific substrates, we found that Clb2-Cdk1 possessed higher intrinsic kinase activity than Clb5-Cdk1, enabling efficient phosphorylation of a broad range of mitotic Cdk1 targets. (nature.com)
  • Thus, Clb5 and Clb2 use distinct mechanisms to enhance the phosphorylation of S-phase and M-phase substrates. (nature.com)
  • Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors. (nature.com)
  • The sequential activation of the members of this family and their phosphorylation of certain substrates promotes the progression through the cell cycle. (biomedcentral.com)
  • In this study, we show that Tip60 is required for the early DNA damage response (DDR) to UV, including the phosphorylation of histone 2AX, c-Jun N-terminal kinases (JNKs), and ataxia telangiectasia-related substrates. (rupress.org)
Progression4
  • At the molecular level, pitavastatin induced expression of the cyclin dependent kinase (CDK) inhibitor p21 in a cholesterol independent manner, blocked repressive phosphorylation of the Retinoblastoma tumor suppressor protein at CDK targeted sites, and reduced expression of E2F target genes required for progression through the G1/S boundary. (oncotarget.com)
  • 12 The activation of cyclin/CDK complex accelerates cell cycle progression, which are regulated by phosphorylation. (jcpjournal.org)
  • The inhibitory effects of esculetin on cell viability were found to be associated with a G1 arrest in cell cycle progression that was concomitant with an inhibition of cyclin E and an induction of cyclin-dependent kinase (Cdk) inhibitor p21/WAF1/CIP1 in a p53-independent manner. (dsmc.or.kr)
  • This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. (cancerindex.org)
Subunits1
  • The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. (cancerindex.org)
Complexes4
CDKN1A1
  • This protective effect of preaccumulated p53 was mediated, at least in part, by the increased expression of CDKN1A/p21, subsequent down-regulation of BRCA1, and impaired JNK activation accompanied by decreased association of replication protein A with chromatin. (rupress.org)
Cip11
  • HDAC inhibition resulted in a transcriptional and posttranscriptional regulation of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip). (cret-signal.com)
Substrate5
  • Phosphorylation of Clb5-specific targets during S phase was reduced by replacing Clb5 with Clb2 or by mutating the substrate RXL motif, confirming the importance of Clb5 specificity in vivo . (nature.com)
  • Figure 3: Clb5-specific substrate phosphorylation occurs in vivo . (nature.com)
  • Brown, N. R., Noble, M. E., Endicott, J. A. & Johnson, L. N. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. (nature.com)
  • Schulman, B. A., Lindstrom, D. L. & Harlow, E. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. (nature.com)
  • Finally, we examine co-clustering of the CDK consensus motifs with the 'cy' or RXL motif [ 17 ], which is known to be important in determining which CDK-cyclin complex will phosphorylate a given substrate. (biomedcentral.com)
Serine3
  • Phosphorylation at serine 15 of the human p53 tumor suppressor protein is induced by DNA damage and correlates with accumulation of p53 and its activation as a transcription factor. (uthscsa.edu)
  • The DNA-dependent protein kinase (DNA- PK) can phosphorylate serine 15 of human p53 and the homologous serine 18 of murine p53 in vitro. (uthscsa.edu)
  • We found a similar pattern of serine 18 phosphorylation and accumulation of p53 in response to irradiation in both control and DNA-PKcs- null MEFs. (uthscsa.edu)
Retinoblastoma protein2
Inhibition5
  • Studies with pitavastatin in primary patient derived tumor cells and established PDA lines, revealed dose dependent growth inhibition. (oncotarget.com)
  • Finally, we provide evidence that these observations are applicable in vivo by demonstrating that HDAC inhibition decreased neointima formation and expression of cyclin D1 in a murine model of vascular injury. (cret-signal.com)
  • Through the inhibition of ADP-activated transductional kinases it was found that PKC-δ was responsible for JNK1/2 activation. (unisalento.it)
  • Further investigation showed that inhibition of the extracellular-regulated kinase (ERK) signaling pathway reduced the induction of p21 and the inhibition of pRB phosphorylation and cyclin E expression by esculetin, which in turn overcame the G1 arrest and growth inhibition that was induced by esculetin. (dsmc.or.kr)
  • In MDA-MB-231 cells, ST caused a significant dose-dependent cell growth inhibition by 31- 63% (p ≤ 0.0001) in 48 h and 40-50% (p ≤ 0.0001) in 72 h. (biomedcentral.com)
Apoptosis3
  • Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. (smpdb.ca)
  • Low PDCD4 level was associated with reduced proliferation but not apoptosis or phosphorylation of endothelial nitric oxide synthase caused by pulsatile shear stress to help maintain the homeostasis of endothelial cells. (plos.org)
  • TP53 activates the expression of genes involved in apoptosis, cell cycle regulation (p21), and MDM2. (medscape.com)
Mouse embryonic fibroblasts1
  • In order to unambiguously define the role of the DNA-PK catalytic subunit (DNA-PKcs) in p53 activation, we examined p53 phosphorylation in mouse embryonic fibroblasts (MEFs) from DNA-PKcs-null mice. (uthscsa.edu)
Histone1
  • Histone deacetylase inhibitors (HDACi) have been considered as a potential anticancer drug nowadays. (dovepress.com)
Cdk13
  • Targets of the cyclin-dependent kinase Cdk1. (nature.com)
  • EESR induced cell cycle arrest at G2/M phase in a dose-dependent manner by modulating cyclin B, cyclin-dependent kinase 1 (CDK1), and CDK inhibitor p21 expression. (jcpjournal.org)
  • 10 , 11 The major molecules responsible for G2/M transition are cyclin A /CDK1 and cyclin B/CDK1. (jcpjournal.org)
Pathway2
  • The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway was involved in this ubiquitin-proteasome-mediated degradation of PDCD4. (plos.org)
  • DNA damage increases TP53 levels through an ATM-dependent pathway. (medscape.com)
Proliferation2
  • Hypoxia and genetic defects that chronically drive proliferation leave such tumors dependent on a steady supply of nutrients, especially glucose. (springer.com)
  • The nucleotide potency profile and the blockade of the ADP-mediated inhibitory effect by the phospholipase C inhibitor U-73122 suggest that P2Y1 receptor controls ZL55 cell proliferation. (unisalento.it)
Accumulation1
  • Rather, p53 accumulation by either knockdown of Mdm2 or addition of an Mdm2 inhibitor, Nutlin-3, before irradiation strongly attenuated the UV-induced DDR and increased cell survival. (rupress.org)
ERK12
  • Conversely, the ADP-activated PKC-α provoked ERK1/2 phosphorylation. (unisalento.it)
  • Étude de la régulation et du rôle de la voie de signalisation des MAP kinases ERK1/2 dans la prolifération et différenciation cellulaire, et implication dans la pathogénèse du cancer. (umontreal.ca)
Vivo3
  • Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo. (ox.ac.uk)
  • To understand the biological importance of Ser312 phosphorylation in vivo, we generated p53Ser312Ala knock-in mice. (ox.ac.uk)
  • Thus, we demonstrate that phosphorylation of Ser312 is required for p53 to function fully as a tumor suppressor in vivo. (ox.ac.uk)
Activation4
  • Mitogen-induced AKT1 activation counteracted this process through the phosphorylation of KDM4B, which inhibited FBXO22-mediated ubiquitination. (elsevierpure.com)
  • They further link to the activation of protein kinase C- (PKC-) induced generation of reactive oxygen species (ROS) [ 6 , 7 ], which further mediates the activation of downstream transcription factor nuclear factor kappa-light-chain enhancer of activated B cells (NF- κ B). Thus, the main treatments of DN refer to modulate glycemic and blood pressure through insulin and RAS inhibitors. (hindawi.com)
  • Activation of p21 or p16 therefore causes cell cycle arrest. (medscape.com)
  • p21 and other tumor suppressor genes' inactivation are therefore most likely involved in the first steps of the cancer model, with later stages possibly involving protooncogene activation and inflammation. (medscape.com)
Endothelial1
  • En face co-immunostaining of the mouse aortic arch revealed a low level of PDCD4 in endothelial cells undergoing pulsatile shear stress. (plos.org)
Activity3
  • Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. (smpdb.ca)
  • cyclin D1 mRNA expression and cyclin D1 promoter activity. (cret-signal.com)
  • EESR showed significant antioxidant activity and inhibitory effect on HT29 cell growth in a dose-dependent manner. (jcpjournal.org)
Senescent cells1
  • Increasing evidence indicates that senescent cells could be a promising new target for therapeutic intervention known as senotherapy, which includes depleting senescent cells, modulating SASP and restoration of senescence inhibitors. (frontiersin.org)
Cell4
  • An exception is Ser315 in human p53 (Ser312 in mouse), which is predominantly phosphorylated by cell cycle-related kinases. (ox.ac.uk)
  • Transactivation of the cyclin-dependent-kinase inhibitor p21, a downstream target of p53, and the G 1 cell cycle checkpoint were also found to be normal in the DNA-PKcs -/- MEFs. (uthscsa.edu)
  • The outcome of this decision-making process is cell state dependent and, consequently, requires the integration of vast amounts of information that is encoded in the local abundance and functional state of a multitude of biomolecules acting as cell state sensors and transmitters. (biomedcentral.com)
  • Another important class of tumor suppressor genes involved in cell cycle control and in the generation of human cancers is the cyclin-dependent kinase (CDK) inhibitors. (medscape.com)
Promotes1
Genes1
  • Importantly, in the cohort studied, Ser312 mutation predisposes mice to develop thymic lymphomas and liver tumors, partly due to p53Ser312Ala's inability to fully induce a set of p53 target genes including p21 and cyclin G1. (ox.ac.uk)
Inactivation1
  • 13 The expression of CDK inhibitor p21 is upregulated by activated p53, resulting in the suppression of G2/M transition by the inactivation of cyclin/CDK complex. (jcpjournal.org)
Replication2
Subsequently1
  • Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. (smpdb.ca)
Expression3
  • In this study we tested the expression of CDKIs p15, p16, p21 and p27 by immunohistochemistry to determine the role of CDKIs in the initiation of primordial follicle growth. (biomedcentral.com)
  • Expression of p15, p16, p21 and p27 did not vary in granulosa and theca cells by the follicle stage. (biomedcentral.com)
  • p15, p16, p21 and p27 in mouse ovaries by immunohistochemistry to assess whether the initiation of primordial follicle growth was associated with the expression of CDKIs. (biomedcentral.com)
Isoform1
  • Each isoform-specific antibody recognizes endogenous levels of the specified Akt isoform independent of its phosphorylation state. (cellsignal.com)
Cancer3
  • Prominent among the hits were members of the statin class of HMG-CoA reductase inhibitors, cholesterol lowering drugs that are also being evaluated in cancer. (oncotarget.com)
  • Studies with bortezomib (VELCADE, formerly known as PS-341) and other proteasome inhibitors indicate that cancer cells are especially dependent on the proteasome for survival, and several mechanisms used by prostate cancer cells require proteasome function. (aacrjournals.org)
  • Likewise, in the early stages of prostate cancer, the growth of cancerous prostatic epithelial cells is often androgen dependent (3) . (aacrjournals.org)
Complex1
  • PCNA is a co-factor of cyclin-D and it makes a complex with cyclin-D, a cyclin dependent kinase (CDK), and a cyclin dependent kinase inhibitor (CDKI). (biomedcentral.com)