The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. (rcsb.org)
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)
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)
Displays sub-micromolar inhibition of cdk1, cdk2, cdk5, cdk7 and cdk9 (reported IC 50 values range from 0.16 - 0.28 μM for cdk5 to 0.8 μM for cdk7). (tocris.com)
However, it was discovered recently that the mitotic kinase Cdk1 (Cdc2a) compensates for the loss of Cdk2. (elsevierpure.com)
In the present study, we tested whether Cdk2 can compensate for the loss of Cdk1. (elsevierpure.com)
We generated a knockin mouse in which the Cdk2 cDNA was knocked into the Cdk1 locus (Cdk1 Cdk2KI ). (elsevierpure.com)
Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality, even though Cdk2 was expressed from the Cdk1 locus. (elsevierpure.com)
In addition, we generated Cdk2 -/- Cdk1 +/Cdk2KI mice in which one copy of Cdk2 and one copy of Cdk1 were expressed from the Cdk1 locus and the Cdk2 gene was deleted from the endogenous Cdk2 locus. (elsevierpure.com)
We found that both male and female Cdk2 -/- Cdk1 +/Cdk2KI mice were sterile, similar to Cdk2 -/- mice, even though they expressed the Cdk2 protein from the Cdk1 locus in testes. (elsevierpure.com)
The translocational and cell cycle properties of knockin Cdk2 in Cdk2 -/- Cdk1 +/Cdk2KI cells were comparable to those of endogenous Cdk2, but we detected premature transcriptional activation of Cdk1 during liver regeneration in the absence of Cdk2. (elsevierpure.com)
This study provides evidence of the molecular differences between Cdk2 and Cdk1 and highlights that the timing of transcriptional activation and the genetic locus play important roles in determining the function of Cdk proteins in vivo. (elsevierpure.com)
Functions through the formation of specific serine/threonine protein kinase holoenzyme complexes with the cyclin-dependent protein kinases CDK1 or CDK2. (wuxibiortus.com)
The cyclin subunit confers the substrate specificity of these complexes and differentially interacts with and activates CDK1 and CDK2 throughout the cell cycle. (wuxibiortus.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)
In a Phase 3 Paloma-III study of Pfizer's CDK4/6 inhibitor ( Ibrance - palbociclib) and an estrogen receptor antagonist ( Faslodex - fulvestrant), patients receiving the combination had significantly prolonged progression-free survival than women with breast cancer who received Faslodex, alone. (shu.edu)
RAD001 (everolimus), a mammalian target of rapamycin (mTOR) pathway inhibitor in phase II clinical trials in oncology, exerts potent antiproliferative/antitumor activities. (aacrjournals.org)
A Phase 1/2, Open-label, Multi-center Study to Investigate the Safety, Pharmacokinetics, and Efficacy of Fadraciclib (CYC065), an Oral CDK2/9 Inhibitor, in Subjects with Advanced Solid Tumors and Lymphoma. (cyclacel.com)
In contrast, CP110 overexpression antagonized CDK2 inhibitor-mediated anaphase catastrophe. (elsevierpure.com)
Thus, a direct link was found between CP110 and CDK2 inhibitor antineoplastic response. (elsevierpure.com)
Inhibition9
These findings indicate that specific inhibition of the Cdk2/ATR/Chk1 pathway with distinct regulating agents could differentially sensitize cancer cells to a wide range of therapeutic agents. (ascopost.com)
A precision medicine drug discovery pipeline identifies combined CDK2 and 9 inhibition as a novel therapeutic strategy in colorectal cancer. (cyclacel.com)
1) For example, the down-regulation of miR15s and miR - 16 - 1 in chronic lymphocytic leukaemia, prostate cancer and pituitary tumours, leading to the inhibition of tumour growth and induce cell cycle arrest at the G 1 - phase by target cell cycle regulators ( cyclin D1, cyclin E1, cyclin D3 and CDK6). (ukessays.com)
We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading to apoptosis, defined as anaphase catastrophe. (elsevierpure.com)
Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. (elsevierpure.com)
Live-cell imaging provided direct evidence that following CDK2 inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. (elsevierpure.com)
Furthermore, activated KRAS mutations sensitized lung cancer cells to CDK2 inhibition by deregulating CP110 expression. (elsevierpure.com)
Thus, CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe. (elsevierpure.com)
CP110 plays a mechanistic role in response of lung cancer cells to CDK2 inhibition, especially in the presence of activated KRAS mutations. (elsevierpure.com)
CDK91
A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. (rcsb.org)
Kinase7
Entry into the S phase in animal cells is regulated to a large extent by the cyclin E-CDK2 kinase complex. (news-medical.net)
This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycleG1 phase progression and G1/S transition. (cancerindex.org)
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)
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)
It was found that activation of the upstream kinase S-phase-specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to numerous and diverse chemotherapeutic agents, and that Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs. (ascopost.com)
We hypothesize that a dynamic equilibrium between the dominant buried state and an transiently open, kinase-accessible state is present in the p27-cyclin A-CDK2 complex, and aim to test this hypothesis through the use of unbiased molecular dynamics and metadynamics simulations. (lu.se)
Phosphorylation9
regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. (proteopedia.org)
Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. (proteopedia.org)
The cyclin D1-Cdk4 complex phosphorylates the pRB protein leading to sequential phosphorylation by cyclin E-Cdk2 and release of free E2F. (shu.edu)
The phosphorylation of pRB, and relief of transcriptional repression by pRB induces genes involved in the induction of S-phase entry. (shu.edu)
During early G1 phase, mitogenic signals trigger activation of the CDK4/6-cyclin D complex, which partially deactivates Rb by phosphorylation. (shu.edu)
24 hours) results in a large shift in cell-cycle populations from G1 and G2-M to S-phase with an accompanied induction of H2AX phosphorylation in U-2 OS cells [1] . (medchemexpress.com)
Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation by cyclin A/Cdk2, an event required for G2/M progression. (duke.edu)
CDC22
Most knowledge of CDK structure and function is based on CDKs of S. pombe (Cdc2), S. cerevisiae (CDC28), and vertebrates (CDC2 and CDK2). (wikipedia.org)
The cdc25 gene product is a tyrosine phosphatase that acts as an initiator of M-phase in eukaryotic cell cycles by activating p34 cdc2 . (biologists.com)
CDKs1
The structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding. (wikipedia.org)
In order to enter S phase, cells must sequentially activate CDK4/6 and CDK2. (shu.edu)
Bufalin induces G0/G1 phase arrest through inhibiting the levels of cyclin D, cyclin E, CDK2 and CDK4, and triggers apoptosis via mitochondrial signaling pathway in T24 human bladder cancer cells. (umassmed.edu)
Protein8
The precise regulations of pre-RC protein levels and assembly are effective ways to prevent reassembly of de novo MCM2-7 onto the replicated origins to re-license and re-replicate the genomic DNA in the subsequent phases of the same cell cycle ( Figure 1) . (intechopen.com)
Tan IIA inhibited proliferation of mouse keratinocytes in a dose- and time-dependent manner and induced apoptosis, resulting in S phase arrest accompanied by down-regulation of pCdk2 and cyclin A protein expression. (hindawi.com)
JIB extract induced cell cycle arrest at the G 0 /G 1 phase and decreased cyclin and cdk protein expressions. (medsci.org)
Our findings indicate that in Bat3-knockdown cells, p21 continues to be synthesized during cell-cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent delay in cell-cycle progression. (duke.edu)
By maintaining a low p21 protein level during the G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 to S phase. (duke.edu)
The siRNA-mediated repression of the CDK2 target and centrosome protein CP110 induced ana-phase catastrophe of lung cancer cells. (elsevierpure.com)
When the ORC1 protein binds to DNA, it recruits CDC6, a protein that regulates and recruits other proteins, to a liquid phase and completes the ORC ring. (cshl.edu)
p27 is a protein that binds to and prevents the activation of different G1 and S phase cyclin-CDK complexes. (lu.se)
Complexes3
Cyclin-CDK complexes phosphorylate substrates appropriate for the particular cell cycle phase. (wikipedia.org)
Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase. (wikipedia.org)
It was believed that Cdk2-cyclin E complexes are essential to drive cells through the G1-S phase transition. (elsevierpure.com)
Replication10
However, most of the vertebrate histone genes are replication dependent and are therefore more highly expressed during the cell cycle's S phase. (news-medical.net)
Given that the replication dependent histone genes all activate upon entry into the S phase, it is speculated that there exists some further upstream regulatory element. (news-medical.net)
activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. (proteopedia.org)
Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E. NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. (proteopedia.org)
Replication is catalysed by processive replication enzymes known as DNA polymerases and is limited to the synthesis phase (S phase) of the cell cycle. (lancs.ac.uk)
Here using an in vitro cell-free DNA replication system we analyse the interplay between Ciz1 and cyclin A/CDK2 in regulation of the initiation phase of DNA replication. (lancs.ac.uk)
This demonstrates that Ciz1 modulates and enhances the activity of cyclin A-CDK2 in cell free DNA replication assays and that Ciz1 increases the permissive CDK range that can promote DNA replication. (lancs.ac.uk)
Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. (cdc.gov)
Phosphorylate1
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)
Activation2
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 the CDK2-cyclin E complex results in hyperphosphorylation of Rb and fully releases E2F. (shu.edu)
Binds2
Cyclin A binds to S phase CDK2 and is required for the cell to progress through the S phase. (signalchem.com)
When they hit a certain balance, ORC begins to assemble, while CDC6 binds to another duo of molecules called Cyclin E-CDK2. (cshl.edu)
Analogues1
Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. (rcsb.org)
Transition2
It promotes the transition from G1 to S phase by phosphorylating and inactivating RB1. (rndsystems.com)
Cyclin which controls both the G1/S and the G2/M transition phases of the cell cycle. (wuxibiortus.com)
Anaphase1
Mechanisms of CDK2-mediated anaphase catastrophe and how activated KRAS enhances this effect were investigated. (elsevierpure.com)
NPAT1
Therefore, NPAT could be the link between cell cycle machinery and shared heightened transcription of histone genes during S phase. (news-medical.net)
Histone5
The S phase is characterized by DNA synthesis, and in the 1960s it was discovered that histone proteins are also synthesized during this phase. (news-medical.net)
The amount of histone mRNA increases approximately 25 to 30 times during the S phase. (news-medical.net)
This mechanism is hypothesized to transduce a shared signal that activates the transcription of histone genes when the G1/S phase boundary is reached. (news-medical.net)
This process is assumed to be under the control of the cell cycle, because of how closely linked to the S phase histone synthesis is. (news-medical.net)
Reduction2
Dusquetide previously demonstrated benefits in reducing the duration of severe oral mucositis (SOM) in a Phase 2 clinical trial and reduction in SOM rates in the per protocol population in a Phase 3 stud y. (constantcontact.com)
In addition to the reduction of severe oral mucositis, an acceleration in the clearance of tumor response and an increase in overall survival were also observed in the Phase 2 clinical study as an ancillary benefit to treating oral mucositis in patients receiving chemo-radiation for their head and neck cancer. (constantcontact.com)
In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. (shu.edu)
The expression of further E2F target genes, as cyclin A, facilitates progression through S phase. (shu.edu)
Cell cycle arrest1
Moreover, cell cycle arrest at G0/G1 phase was triggered by decreased LAPTM5 as well, which could lead to delayed BCa cell growth. (spandidos-publications.com)
Modulates1
BAT3 modulates these pro- and anti-proliferative roles of p21 at least in part by regulating cyclin A abundance, as well as p21 translocation between the cytoplasm and the nucleus to ensure that it functions in the appropriate intracellular compartment during each phase of the cell cycle. (duke.edu)
Increases1
It is seen first in late G2, and increases throughout the M phase. (news-medical.net)
Complex1
CDK2/Cyclin A is inhibited by the complex p21CIP. (signalchem.com)
DNA DAMAGE, or the deficiencies in specific cellular components or nutrients may cause the cells to halt before progressing through G1 phase. (umassmed.edu)
Oleanane-3-O-ß-D-glucoside-2'-acetamide and aridanin at 2.5 and 10 µg/mL reduced the number of cells in S-phase and raised cells in G2/M phase. (bvsalud.org)
The isoform encoded by the unspliced mRNA, XBP1(U), is constitutively expressed, and thought to function as a negative feedback regulator of XBP1(S), which shuts off transcription of target genes during the recovery phase of ER stress. (cancerindex.org)
Activity1
We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. (rcsb.org)
Decreases2
It starts increasing in the late S phase, is at its highest point in mid to late M phase, and then decreases. (news-medical.net)
It generally decreases during M phase, however, some with active promoters can maintain acetylation. (news-medical.net)
Mitosis1
Had an IC 50 of 37 nM and resulted in the G2-M population received DNA damage during S-phase but continued to progress through the cell cycle into an early mitosis. (medchemexpress.com)
Boundary1
Specifically, the boundary between G1 and S-phase is tightly regulated by the ubiquitin proteasome system. (intechopen.com)
Survival1
A phase II study showed that patients with resected local-regionally advanced head and neck squamous cell carcinoma (HNSCC) had improved survival when pembrolizumab was added to adjuvant RT (NCT02641093). (nature.com)