• Cyclin-dependent kinases (CDKs), are members of the serine-threonine protein kinase family and are responsible for taking control of cell cycle regulation in eukaryotic cells. (spandidos-publications.com)
  • CDKs show their action by interacting with cyclins and different CDK-cyclin complexes regulate the cell cycle in the G1, S and G2/M phases ( 1 ). (spandidos-publications.com)
  • Indirubin-3-oxime (I3O), a synthetic derivative of indirubin, was originally designed as potent inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3β (GSK3β) for leukemia therapy. (edu.hk)
  • Flavopiridol is a synthetic flavone that has been postulated to be an inhibitor of cyclin-dependent kinases (CDKs) (Schmerwitz et al. (researchsquare.com)
  • Progression through the cell cycle is driven by the oscillating activity of Cyclin Dependent Kinases (CDKs). (intechopen.com)
  • The activity of CDKs is controlled by their binding to coactivator subunits termed Cyclins, as well as by CDK inhibitory proteins termed CKIs. (intechopen.com)
  • The cyclin-dependent kinase (CDK) inhibitors p21 and p16 inhibit the activity of CDKs, such as CDK4. (medscape.com)
  • The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase. (wikipedia.org)
  • The cell cycle is driven by proteins called cyclin dependent kinases that associate with cyclin regulatory proteins at different checkpoints of the cell cycle. (wikipedia.org)
  • Early signaling proteins in the checkpoint pathway are members of a family of phosphatidylinositol 3-kinases, rad3 in yeast and ATR in vertebrates, that are believed to localize to sites of DNA damage. (wikipedia.org)
  • Various physiological and pathological conditions such as glucose starvation, inhibition of protein glycosylation and oxidative stress may cause an accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response (UPR) and autophagy. (spandidos-publications.com)
  • These proteins were rescued by the proteasome inhibitor MG132, indicating the autocatalytic degradation of F-box proteins upon loss of CSN2 or CSN5. (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)
  • FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E2-promoted anchorage-independent growth. (elsevierpure.com)
  • Different phases of the cell cycle experience activation and/or deactivation of specific cyclin-CDK complexes. (wikipedia.org)
  • New anticancer therapy strategies refer to the inhibition of CDK-cyclin complexes as an important target to prevent uncontrolled proliferation and induce apoptosis in cancer cells ( 2 ). (spandidos-publications.com)
  • Transcriptional and translational control, sequestration in cyclin D1 complexes and localization all regulate p27 in G1 phase. (biomedcentral.com)
  • Upon phosphorylation, R-SMADs form a complex with the common SMAD, SMAD4, resulting in nuclear accumulation of activated complexes. (shu.edu)
  • 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)
  • Thus, treatment with the pure antiestrogen ICI 182 780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E2-stimulated ERα transactivation. (elsevierpure.com)
  • RAD001 (everolimus), a mammalian target of rapamycin (mTOR) pathway inhibitor in phase II clinical trials in oncology, exerts potent antiproliferative/antitumor activities. (aacrjournals.org)
  • Here we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. (bace-signal.com)
  • SnCs exhibit irreversible growth arrest accompanied by increased expression of cyclin-dependent kinase inhibitors (CDKi) such as p16 INK4a , and p21 Cip1 , accumulation of DNA damages, and secretion of diverse bioactive molecules known as the senescence-associated secretory phenotype (SASP). (aging-us.com)
  • 2011 ). In addition to antitumor activities, CDK inhibitors (CDKi) show prominent anti-inflammatory effects (Leitch et al. (researchsquare.com)
  • The promising anticancer drug milciclib potently inhibits cyclin-dependent kinase (CDK) 2 and tropomyosin receptor kinase (TRK) A, and is currently in phase II clinical studies. (srcinhibitors.com)
  • It potently inhibits the complex formed between cyclin-dependent kinase (CDK) 2 and cyclin A, and the tropomyosin receptor kinase (TRK) A, with a half-maximal inhibitory concentration (IC50) of 45 and 53 nM, respectively (Brasca et al. (srcinhibitors.com)
  • b) 4-Hydroxytamoxifen (but not tamoxifen), genistein (but not genistin), daidzein, and probably other nutritional and chemopreventive anti-cancer agents could up-regulate expression of p27 via receptor protein tyrosine kinases (RPTKs), phosphoinositide 3-kinase (PI3K), phosphoinosite-dependent kinase (PDK), Akt/PKB and mTOR. (biomedcentral.com)
  • The cyclin D1-Cdk4 complex phosphorylates the pRB protein leading to sequential phosphorylation by cyclin E-Cdk2 and release of free E2F. (shu.edu)
  • 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)
  • Moreover, PD-1 and PD-L1 inhibitors are being tested in combination with other checkpoint inhibitors, targeted therapies, cancer vaccines, monoclonal antibodies, and other modalities. (shu.edu)
  • Immunotherapy mainly includes immune checkpoint inhibitors (ICIs), such as inhibitors of PD-1 (programmed cell death 1)/programmed cell death ligand 1 (PD-L1). (nature.com)
  • Up-regulation appears to be specific to p27 because expression of cyclin D1, E, and A, and p21Cip1/Waf1 was not modulated by these agents. (biomedcentral.com)
  • In the present study, our aim was to determine the time-dependent, ER-mediated apoptotic and autophagy induction of purvalanol in HCT 116 colon cancer cells. (spandidos-publications.com)
  • Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect ( Er1 F/− ) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. (nature.com)
  • CSN2 knockdown resulted in non-apoptotic cell death associated with accumulation of both the autophagy marker LC3-II and autophagic vacuoles. (biomedcentral.com)
  • Treatment of vector control K562 cells with the autophagy inhibitors 3-methyladenine and bafilomycin A1 recapitulated the growth kinetics, vacuolar morphology and LC3-II accumulation of CSN2 knockdown cells indicating that the cellular phenotype of CSN2 cells arises from autophagy inhibition. (biomedcentral.com)
  • An inhibitor of autophagy, 3-methyladenine (3-MA), was used to pretreat RAW 264.7 cells. (researchsquare.com)
  • These events resulted in upregulation of the Cdk4/6 inhibitor p15 INK4B and repression of the Cdk-activating phosphatase Cdc25A. (shu.edu)
  • The main rad3 effector is the kinase Chk1, which is required for the G2-M arrest in response to DNA-damaging agents. (wikipedia.org)
  • Receptor-regulated SMADs (R-SMADs), SMAD1, 2, 3, 5, and 8, are the only SMADs directly phosphorylated and activated by the kinase domain of type I receptors. (shu.edu)
  • 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)
  • TGF-β1 acts predominantly through phosphorylation of the C-terminal MH2 domains of SMAD2 and SMAD3 via activin receptor-like kinase 5 (ALK5), of which activity is located at the C-terminal part of TGFBR1. (springer.com)
  • 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)
  • Two schools of thought exist, one states that SK develops from an accumulation of senescent cells, whereas the other states that cells hyperproliferate. (globale-dermatologie.com)
  • In the current study, we have shown, for the first time, that I3O prevented 6-hydroxydopamine (6OHDA)-induced neuronal apoptosis and intracellular reactive oxygen species accumulation in PC12 cells in a concentration-dependent manner. (edu.hk)
  • p27(Kip1) is a cyclin-dependent kinase inhibitor. (biomedcentral.com)
  • The cyclin-dependent kinase (CDK) inhibitor p27(Kip1) is a key cell-cycle regulator of G1-to-S phase transition [ 1 ]. (biomedcentral.com)
  • PD-1 suppressed the transcription of SKP2 , the substrate recognition component of the SCF Skp2 ubiquitin ligase that leads p27 kip1 to degradation and resulted in accumulation of p27 kip1 (Figure 2). (shu.edu)
  • however, nuclear accumulations of pSMAD2-C and CLDN3 redistribution were observed with similar time course in ciliated and non-ciliated cells. (springer.com)
  • It was identified that the nuclear division cycle 80, cyclin B2 and topoisomerase 2‑α may serve important roles in adrenocortical tumor development. (cancerindex.org)
  • The ability of FASN to regulate E2/ERα signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors. (elsevierpure.com)
  • 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)
  • Precis: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a pro-apoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. (bace-signal.com)
  • Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. (bace-signal.com)
  • Several hallmarks of cellular senescence, such as cell cycle arrest, expression of cyclin-dependent kinase inhibitors, DNA damages, and senescence-associated secretory profile were evaluated. (aging-us.com)
  • Purvalanol, a novel cyclin-dependent kinase inhibitor, is referred to as a strong apoptotic inducer which causes cell cycle arrest in various cancer cells such as prostate, breast and colon cancer cell lines. (spandidos-publications.com)
  • Accumulation of p27 in the nucleus, therefore, blocks cell cycle progression of T-lymphocytes that are being induced to act against cancer antigens. (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)
  • 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)
  • 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)
  • Through the inhibition of ADP-activated transductional kinases it was found that PKC-δ was responsible for JNK1/2 activation. (unisalento.it)
  • Through a positive feedback loop, CyclinB-Cdc2 activates the phosphatase Cdc25 which in turn deactivates the CyclinB-Cdc2 inhibitors, Wee1 and Myt1. (wikipedia.org)
  • The combined activity and complex of Cdc2, Cdc25, and Plk1 with the accumulation of cyclin B activates the CyclinB-Cdc2 complex, promoting entry into mitosis. (wikipedia.org)
  • On the other hand, etoposide treatment reliably induces DNA damage-related senescence in human articular chondrocytes evidenced by loss of proliferative capacity, DNA damage accumulation, and expression of some SASP components. (aging-us.com)
  • In this issue, we generally review the mechanisms of cellular senescence in diabetic nephropathy, which involve telomere attrition, DNA damage, epigenetic alterations, mitochondrial dysfunction, loss of Klotho, Wnt/ β -catenin signaling activation, persistent inflammation, and accumulation of uremic toxins. (hindawi.com)
  • Many breast cancers are dependent for proliferation on estrogens synthesized from androgens (i.e., androstenedione) by aromatase. (aacrjournals.org)
  • Letrozole (Femara) is an aromatase inhibitor used for treatment of postmenopausal women with hormone-dependent breast cancers. (aacrjournals.org)
  • Cdc2 activity is further regulated by phosphorylation/dephosphorylation of its corresponding activators and inhibitors. (wikipedia.org)
  • 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)
  • Histone deacetylation was essential during a specific temporal window of development and was dependent on the enzymatic activity of histone deacetylases, whose expression was detected in the developing corpus callosum. (rupress.org)
  • During the first 10 postnatal days, administration of valproic acid (VPA), the specific inhibitor for histone deacetylase activity, resulted in significant hypomyelination with delayed expression of late differentiation markers and retained expression of progenitor markers. (rupress.org)
  • Olomoucine, roscovitine and purvalanol are examples of CDK inhibitors (CDKIs) designed and investigated for their apoptotic potential on cancer cells ( 3 ). (spandidos-publications.com)
  • Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. (bace-signal.com)
  • Accumulation of cyclin B increases the activity of the cyclin dependent kinase Cdk1 human homolog Cdc2 as cells prepare to enter mitosis. (wikipedia.org)
  • Full holoenzyme activity of the cyclin D1-Cdk4 complex is induced by mitogen recruitment of CAK. (shu.edu)
  • The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E2)-stimulated, ERα-driven transcription. (elsevierpure.com)
  • Up-regulation of the expression of p27 is likely due to the activation of translation rather than transcription of p27 because (a) up-regulation is mediated by the 5'-untranslated region (-575) of the p27 gene and (b) the antibiotic actinomycin D, an inhibitor of transcription, did not attenuate the up-regulation of p27. (biomedcentral.com)
  • DNA damage increases TP53 levels through an ATM-dependent pathway. (medscape.com)
  • During the G2 phase, Bora accumulates and forms an activation complex with Aurora A. This complex then regulates the activation of Polo-like kinase 1 (Plk1). (wikipedia.org)
  • Once cyclin concentration reaches a certain minimum activation threshold, Cdc2 is rapidly activated. (wikipedia.org)
  • In the case of unreplicated DNA, the cyclin concentration threshold for Cdc2 activation is further increased. (wikipedia.org)
  • inositol-requiring enzyme 1 (IRE1α), PRKR-like ER kinase (PERK) and activating transcription factor-6 (ATF-6). (spandidos-publications.com)
  • It is widely recognized that the accumulation of various harmful genetic alterations in normal cells may induce malignant cancer cells ( 1 ). (spandidos-publications.com)
  • This loop is further amplified indirectly through the coordinated interaction of the Aurora A kinase and the Bora cofactor. (wikipedia.org)
  • It also blocks Cyclin A-CDK2 from further phosphorylating pRb to maintain S phase. (shu.edu)
  • 2018 ). Currently, CDK9 inhibitors are considered potential treatments for inflammatory diseases (Hou et al. (researchsquare.com)
  • According to modern concepts, inflammation plays a leading role in the genesis of almost all age-dependent diseases, which ultimately lead the body to death. (vechnayamolodost.ru)
  • Although clinically relevant lesions become evident in middle-aged adults, it has been demonstrated that fat accumulation (known as fatty streaks) begins in early childhood [ 5 ]. (hindawi.com)