• Cyclin dependent kinases are a key family of kinases involved in cell cycle regulation and are an attractive target for cancer chemotherapy. (rcsb.org)
  • Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. (rcsb.org)
  • Cyclins function as regulators of CDK kinases. (novusbio.com)
  • The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). (novusbio.com)
  • Cyclins and cyclin-dependent kinases (cdks) are evolutionarily conserved proteins that are essential for cell-cycle control in eukaryotes. (bdbiosciences.com)
  • Concomitantly, p27 Kip1 levels rose and the inhibitor accumulated in both Cdk4 and Cdk2 complexes, as these kinases were inactivated. (ku.dk)
  • Cyclins regulate the cell cycle in association with cyclin dependent kinases (CDKs). (biomedcentral.com)
  • The progression of cells through the cell cycle is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs). (biomedcentral.com)
  • These kinases are expressed throughout the cell cycle, but are only activated upon complex formation with their corresponding cyclins. (shu.edu)
  • Cyclin-dependent kinases (Cdks) are principal drivers of cell division and are an important therapeutic target to inhibit aberrant proliferation. (escholarship.org)
  • This compound is a highly cell-permeable purine compound that acts as an ATP-competitive inhibitor of cyclin dependent kinases (CDKs). (guidetoimmunopharmacology.org)
  • Catalytic domain of the Serine/Threonine Kinases, Cyclin-Dependent protein Kinase 2 and 3. (umbc.edu)
  • Serine/Threonine Kinases (STKs), Cyclin-dependent protein kinase 2 (CDK2) and CDK3 subfamily, catalytic (c) domain. (umbc.edu)
  • The CDK2/3 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase. (umbc.edu)
  • As a biologically important example we have studied the complex formed by cyclins and cyclin-dependent kinases (CDKs), which play an essential role in the control of the eukaryotic cell cycle. (lu.se)
  • The new inhibitor is 1,000-fold more potent than the parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O(6)-cyclohexylmethylguanine). (rcsb.org)
  • The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. (rcsb.org)
  • The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions. (rcsb.org)
  • To confirm this we designed inhibitor-resistant (ir)-Cdk2 mutants using a novel bioinformatics approach. (rcsb.org)
  • Additionally, crystal structures and kinetics reveal alternative binding modes of Cdk1-selective and Cdk2-selective inhibitors and mechanisms of Cdk2 inhibitor resistance. (rcsb.org)
  • An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity. (expasy.org)
  • It further inhibited cell-cycle progression in the G1 phase by four different mechanisms: rapid downregulation of cyclin D1, induction of Chk2 with simultaneous downregulation of Cdc25A, induction of the Cdk-inhibitor p21 Cip/Waf and inhibition of ribonucleotide reductase activity resulting in reduced dCTP and dTTP levels. (nature.com)
  • p27 is a cyclin dependent kinase inhibitor that blocks the activity of Cyclin E-CDK2, which phosphorylates pRb, thereby ushering the cell from G1 into S phase through the Restriction point (Figure 2). (shu.edu)
  • P15 INK4 is a cyclin dependent kinase inhibitor that blocks the activity of Cyclind-CDK4,6, inhibiting it from hypophosphorylating Rb, thereby, rendering the cell cycle unresponsive to external proliferation signals. (shu.edu)
  • 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)
  • Ibrance (palbociclib) is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. (shu.edu)
  • Cyclins (regulatory subunits) bind to cdks (catalytic subunits) to form complexes that regulate the progression of the cell cycle. (bdbiosciences.com)
  • The main cyclin-cdks complexes formed in vertebrate cells are cyclin D-cdk4 (G0/G1), cyclin E-cdk2 (G1/S), cyclin A-cdk2 (S) and cyclin B1-cdk1 (G2/M). These complexes are regulated by activating and inhibitory phosphorylation events, as well as by interactions with small regulatory proteins including p21 and p27Kip1. (bdbiosciences.com)
  • CDKs are under inhibitory control of cyclin dependent kinase inhibitors (CDKIs). (biomedcentral.com)
  • Cyclins function as the positive regulators of CDKs. (biomedcentral.com)
  • D-type and E-type cyclins assemble with CDKs during the G1 phase and these holoenzymes act as rate-limiting controllers to regulate passage through the restriction point and the subsequent onset of DNA replication [ 2 , 3 ]. (biomedcentral.com)
  • Cyclins and CDKs assemble into complexes with one another as cells progress through G1 phase, cyclins being required to activate the serine-threonine kinase activity of their catalytic partners. (biomedcentral.com)
  • Furthermore, CDK-activating kinase (CAK) phosphorylates cyclin-bound CDKs on a single threonine residue, a modification that is essential for their activity [ 6 - 9 ]. (biomedcentral.com)
  • Cyclin-dependent kinase inhibitors (CDKIs) are proteins that bind to and inhibit the activity of CDKs. (biomedcentral.com)
  • CDKs belong to a large family of STKs that are regulated by their cognate cyclins. (umbc.edu)
  • Cellular studies with O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. (rcsb.org)
  • Cdk2 promotes DNA replication and is a promising cancer therapeutic target, but its functions appear redundant with Cdk1, an essential Cdk affected by most Cdk2 inhibitors. (rcsb.org)
  • Bypassing inhibition with ir-Cdk2 or with Cdk1 shows that Cdk2 is rate-limiting for replication in this system because Cdk1 is insufficiently active. (rcsb.org)
  • Cyclin A is involved in both S-phase and G2/M transitions of the cell cycle through its association with cdk2 and cdk1, respectively. (bdbiosciences.com)
  • This may be due to compensation provided by CDK1 (also called Cdc2), which can also bind cyclin E and drive the G1 to S phase transition. (umbc.edu)
  • Bayer and Cedilla Therapeutics, a biotechnology company bringing a new dimension to precision oncology, announced an exclusive license agreement to develop and commercialize Cedilla Therapeutics' CyclinE1/CDK2 complex inhibitors which selectively address oncogenic drivers. (worldpharmanews.com)
  • Cdk enzymatic activity is tightly controlled through cyclin interactions, posttranslational modifications, and binding of inhibitors such as the p27 tumor suppressor protein. (escholarship.org)
  • Here, we show that cyclin E/Cdk2 phosphorylates and stabilizes the pro-survival Bcl-2 family protein Mcl-1, a key cell death resistance determinant to the small molecule Bcl-2 family inhibitors ABT-199 and ABT-737, mimetics of the Bcl-2 homology domain 3 (BH3). (oncotarget.com)
  • Collectively, our findings identify a novel mechanism of cyclin E-mediated Mcl-1 regulation that provides a rationale for clinical use of Bcl-2 family and Cdk inhibitors for Mcl-1-dependent tumors. (oncotarget.com)
  • Mathematical modeling of enzymology data predicted conditions allowing selective chemical Cdk2 inhibition. (rcsb.org)
  • Surprisingly, this delayed arrest was molecularly distinct from contact inhibition of normal cells, as it occurred in the absence of p27 Kip1 induction and cyclin D1 levels remained high. (ku.dk)
  • Specific substrates for cdk-cyclin complexes include nuclear lamins, histones, oncogenes (e.g., c-abl and SV40 large T-Ag), tumor suppressor genes (e.g., retinoblastoma protein, Rb), nucleolin and others. (bdbiosciences.com)
  • Subsequently, T cells receiving PD-1 signals displayed impaired Cdk2 activation and failed to phosphorylate two critical Cdk2 substrates, the retinoblastoma gene product (Rb) and the TGFβ-specific transcription factor Smad3 , leading to suppression of E2F target genes but enhanced Smad3 transactivation (Figure 3). (shu.edu)
  • Spy1 lacks the cyclin-binding site that mediates p27 and substrate affinity, explaining why Cdk-Spy1 is poorly inhibited by p27 and lacks specificity for substrates with cyclin-docking sites. (escholarship.org)
  • Activation of the Cyclin B/Cdc2 kinase complex triggers entry into mitosis in all eukaryotic cells. (duke.edu)
  • Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1. (duke.edu)
  • A cyclin E-CDK2 substrate called NPAT has been found to be associated with histone gene clusters, and cyclin E-CDK2 bolsters activation of histone gene transcription by NPAT. (news-medical.net)
  • Activation of CDK4 requires binding of a D-type Cyclin and phosphorylation of Thr172 by the CAK kinase complex. (rndsystems.com)
  • Overexpression or genetic activation of Cyclin Dependent Kinase 2 (CDK2) binding partner cyclin E is a key oncogenic process in several cancers. (worldpharmanews.com)
  • During early G1 phase, mitogenic signals trigger activation of the CDK4/6-cyclin D complex, which partially deactivates Rb by phosphorylation. (shu.edu)
  • Activation of the CDK2-cyclin E complex results in hyperphosphorylation of Rb and fully releases E2F. (shu.edu)
  • We find that Spy1 confers structural changes to Cdk2 that obviate the requirement of Cdk activation loop phosphorylation. (escholarship.org)
  • CDK2 is regulated by cyclin E or cyclin A. Upon activation by cyclin E, it phosphorylates the retinoblastoma (pRb) protein which activates E2F mediated transcription and allows cells to move into S phase. (umbc.edu)
  • p27 is a protein that binds to and prevents the activation of different G1 and S phase cyclin-CDK complexes. (lu.se)
  • Notably, the first two post-translational modifications, which are required for the initial activation of these complexes, occur on solvent inaccessible (i.e., buried) tyrosine residues. (lu.se)
  • Loss of both CDK4 and CDK2 increases neural stem cell differentiation. (rndsystems.com)
  • Yet, at an elevated density the Ras-transformed cells ceased to proliferate and entered a quiescent-like state with low Cdk4 and Cdk2 activity. (ku.dk)
  • Activated complexes accumulate in the nucleus where they cooperate with DNA-binding cofactors to regulate target gene transcription. (shu.edu)
  • The protein encoded by this gene is a cyclin-dependent kinase 2 (CDK2) -associated protein which is thought to negatively regulate CDK2 activity by sequestering monomeric CDK2, and targeting CDK2 for proteolysis. (cancerindex.org)
  • Three sequential phosphorylation events on specific residues of p27, regulate the activity of these complexes and ultimately control cell cycle proliferation or arrest. (lu.se)
  • Skp2 (S-phase Kinase-associated Protein 2) belongs to the family of F-box proteins that interact with the Cyclin A-Cdk2 complex. (thermofisher.com)
  • The cell cycle is strictly regulated and controlled by a complex network of signaling pathways [ 1 ], comprised of hundreds of proteins. (biomedcentral.com)
  • CDK3 is regulated by cyclin C and it phosphorylates pRB specifically during the G0/G1 transition. (umbc.edu)
  • The cyclin D1-Cdk4 complex phosphorylates the pRB protein leading to sequential phosphorylation by cyclin E-Cdk2 and release of free E2F. (shu.edu)
  • Immunocytochemistry/ Immunofluorescence: Cyclin H Antibody (1B8) [H00000902-M01] - Analysis of monoclonal antibody to CCNH on HeLa cell. (novusbio.com)
  • Immunohistochemistry-Paraffin: Cyclin H Antibody (1B8) [H00000902-M01] - Analysis of monoclonal antibody to CCNH on formalin-fixed paraffin-embedded human testis. (novusbio.com)
  • Western Blot: Cyclin H Antibody (1B8) [H00000902-M01] - CCNH monoclonal antibody (M01), clone 1B8 Analysis of CCNH expression in HeLa. (novusbio.com)
  • Sandwich ELISA: Cyclin H Antibody (1B8) [H00000902-M01] - Detection limit for recombinant GST tagged CCNH is approximately 1ng/ml as a capture antibody. (novusbio.com)
  • ATCC CCL-243) were probed with the mouse anti-human cyclin A antibody at concentration of 2.0 µg/mL (lane 1), 1.0 µg/mL (lane 2), and 0.5 µg/mL (lane 3). (bdbiosciences.com)
  • Anti-Cyclin A Antibody was produced by repeated immunizations with a recombinant protein corresponding to the human cyclin A. (signalchem.com)
  • Immunohistochemistry using Rabbit Anti-Cyclin A antibody. (signalchem.com)
  • Fixation: formalin fixed paraffin embedded.Antigen retrieval: not required.Primary antibody: Anti-Cyclin A at 1:500 for 1 hr at RT. (signalchem.com)
  • Western Blot of Rabbit Anti-Cyclin A antibody. (signalchem.com)
  • Primary antibody: Anti-Cyclin A at 1:400 for overnight at 4°C. Predicted/Observed size: 60kDa for Cyclin A. (signalchem.com)
  • The Anti-Cyclin-A antibody is ideal for investigators involved in cell signaling, cell biology and signal transduction research. (signalchem.com)
  • Subsequently released E2F factors mediate expression of pro-proliferative genes including cyclin E and Cdc25A. (shu.edu)
  • The expression of further E2F target genes, as cyclin A, facilitates progression through S phase. (shu.edu)
  • A cyclin-dependent protein kinase holoenzyme complex that has a cyclin E2 regulatory subunit and a Cdk2 kinase subunit that has been phosphorylated. (proconsortium.org)
  • This protein also forms a core subunit of the nucleosome remodeling and histone deacetylation (NURD) complex that epigenetically regulates embryonic stem cell differentiation. (cancerindex.org)
  • Entry into the S phase in animal cells is regulated to a large extent by the cyclin E-CDK2 kinase complex. (news-medical.net)
  • It also blocks Cyclin A-CDK2 from further phosphorylating pRb to maintain S phase. (shu.edu)
  • D-type cyclins are usually synthesized by mid-G1 phase and accumulate to a maximum as cells advance through the G1/S boundary. (biomedcentral.com)
  • In order to enter S phase, cells must sequentially activate CDK4/6 and CDK2. (shu.edu)
  • JIB extract induced cell cycle arrest at the G 0 /G 1 phase and decreased cyclin and cdk protein expressions. (medsci.org)
  • Cyclin A binds to S phase CDK2 and is required for the cell to progress through the S phase. (signalchem.com)
  • In the nucleus, R-SMAD-SMAD4 complexes cooperate with transcriptional coregulators that further define target gene recognition and transcriptional regulation. (shu.edu)
  • The CDK4/Cyclin D complex is also negatively regulated by p21/CIP1/CDKN1A and p27/Kip1. (rndsystems.com)
  • Assay of the mutants with a cyclin-dependent kinase 4-selective bisanilinopyrimidine shows that the K89T mutation is primarily responsible for the selectivity of this compound. (rcsb.org)
  • Use of the cyclin-dependent kinase 2-selective 6-cyclohexylmethoxy-2-(4'-sulfamoylanilino)purine (NU6102) shows that K89T has no role in the selectivity, while the remaining three mutations have a cumulative influence. (rcsb.org)
  • Studies with Mcl-1 phosphorylation mutants show that cyclin E/Cdk2-dependent phosphorylation of Mcl-1 residues on its PEST domain resulted in increased Mcl-1 stability (Thr92, and Thr163) and Bim binding (Ser64). (oncotarget.com)
  • This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. (novusbio.com)
  • The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. (novusbio.com)
  • Here, we examined changes in cell cycle control complexes as normal and Ras-transformed cells ceased to grow exponentially, to reveal the molecular basis for Ras-dependent focus formation. (ku.dk)
  • Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1. (duke.edu)
  • Localization: Cyclin A is nuclear and cytoplasmic.Staining: Cyclin A as precipitated red signal with hematoxylin purple nuclear counterstain. (signalchem.com)
  • Upon phosphorylation, R-SMADs form a complex with the common SMAD, SMAD4, resulting in nuclear accumulation of activated complexes. (shu.edu)
  • A cyclin-E that is a translation product of the human CCNE2 gene or a 1:1 ortholog thereof. (proconsortium.org)
  • Despite these important roles, mice deleted for the cdk2 gene are viable and normal except for being sterile. (umbc.edu)
  • Cyclin E/Cdk2 kinase activity is frequently deregulated in human cancers, resulting in impaired apoptosis. (oncotarget.com)
  • This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. (novusbio.com)
  • Drosophila MCM protein complexes. (colorado.edu)
  • Full holoenzyme activity of the cyclin D1-Cdk4 complex is induced by mitogen recruitment of CAK. (shu.edu)
  • Human cyclin A has been reported to migrate between 54-60 kDa by SDS-PAGE and clone BF683 reportedly does not cross-react with mouse, rat or mink cyclin A. (bdbiosciences.com)
  • Faha B, Ewen ME, Tsai LH, Livingston DM, Harlow E. Interaction between human cyclin A and adenovirus E1A-associated p107 protein. (bdbiosciences.com)
  • A G1/S-specific cyclin-E2 that is encoded in the genome of human. (proconsortium.org)
  • Cyclin E depletion in various human tumor cell-lines and cyclin E -/- mouse embryo fibroblasts showed decreased levels of Mcl-1 protein, with no change in Mcl-1 mRNA levels. (oncotarget.com)
  • Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. (novusbio.com)
  • The p21 family (p21, p27, p28 and p57) can bind to broad range of CDK-cyclin complexes and inhibit their activities. (biomedcentral.com)
  • We identify mutations in Spy1 that ablate its ability to activate Cdk2 and to proliferate cells. (escholarship.org)