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  • proteins
  • Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. (wikipedia.org)
  • These findings suggest that the pro-drug form of another β-lactone, lovastatin, similar in structure to lactacystin, may inhibit the ubiquitin-mediated proteolysis of key regulatory proteins such as the cyclins and CKIs. (pnas.org)
  • LAQ824 also induced the acetylation of heat shock protein (hsp) 90, resulting in inhibition of its binding to ATP, which has been shown to impair the chaperone association of hsp 90 with its client proteins, Her-2, AKT, and c-Raf-1. (aacrjournals.org)
  • Geldanamycin (GA) and its less toxic analogue 17-allylamino-demethoxygeldanamycin (17-AAG) are inhibitors of the heat shock protein (hsp) 90, which is an intracellular chaperone for a number of client proteins that include protein kinases and nuclear hormone receptors ( 20 -22 ). (aacrjournals.org)
  • As a consequence, the GRB2/GAB2/SOS complex causes constitutive activation of the RAS downstream pathway, thereby activating mitogen-activated protein (MAP) extracellular signal-regulated kinase (ERK)1/2 (MEK) and MAP kinase proteins and resulting in abnormal cell proliferation. (aacrjournals.org)
  • TG02 exerts its antitumor activity primarily via its potent CDK9 inhibition, which leads to the depletion of key survival proteins, such as Mcl-1, resulting in p53-independent apoptosis of a wide range of tumor cells. (prweb.com)
  • Subsequent development will focus on an important group of solid tumors with unmet medical need, such as small cell lung cancer, triple negative breast cancer, and melanoma, which will also benefit from this mechanism of action, complemented with the benefits of inhibiting both JAK2 and ERK5, and depleting other CDK9-dependent proteins such as c-MYC and VEGF. (prweb.com)
  • Cells expressing MLL fusion proteins turned out to be sensitive to inhibitors of GSK3. (medpagetoday.com)
  • complexes
  • The INK4 family consists of p16 INK4a , p15 INK4b , p18 INK4c , and p19 INK4d , which narrow specifically to form stale complexes with CDK4/6 before binding with cyclin D ( Vidal and Koff, 2000 ). (aspetjournals.org)
  • Based on their protein sequence homologies and putative cdk targets, cdk inhibitors belong to one of two families: the CIP/KIP family (p21 Waf1/Cip1 , p27 kip1 , and p57 kip2 ), which inhibits a broad range of cyclin/cdk complexes and the INK4 family (p15 Ink4b , p16 Ink4a , p18 Ink4c , and p19 Ink4d ), which inhibit mainly cdk4 and cdk6. (aacrjournals.org)
  • Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. (wikipedia.org)
  • Cyclin D-CDK4 complexes are major integrators of various mitogenic and antimitogenic signals. (wikipedia.org)
  • The main role of p21 is cell-cycle regulation, performed by inhibiting the activity of cyclin-CDK complexes thanks to direct interaction through specific sequences (termed CDK and Cy motifs) in the N-terminal domain of the protein [ 10 - 13 ]. (intechopen.com)
  • Forms a complex with cyclin type D- CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1 - CDK4 complex activation. (rcsb.org)
  • The binding of p21 to CDK complexes occurs through p21's N-terminal domain, which is homologous to the other CIP/KIP CDK inhibitors p27 and p57 . (wikipedia.org)
  • specific inhibitor
  • MDL-72,527, a specific inhibitor of PAO and SMO, decreased apoptotic potential of CDK inhibitors on HCT 116 cells. (iku.edu.tr)
  • most importantly, these inhibitory effects were enhanced by the combination of palbociclib with BYL719 (specific inhibitor of the p110α PI3K-subunit), which promoted a stronger inhibition of GLUT-1 glucose transporter expression, glucose uptake and consumption in comparison with individual treatments, under both normoxic and hypoxic conditions. (springer.com)
  • induces
  • Application of IN-1 antibodies induces the upregulation of c-Jun, JunD, and NADPH diaphorase in Purkinje cells, showing that their expression is suppressed constitutively by myelin-associated neurite growth inhibitors. (jneurosci.org)
  • Furthermore, we demonstrate that pharmacological inhibition of GSK3 activity by kenpaullone, a known antagonist of GSK3 activity, as well as by lithium, a direct inhibitor of GSK3 and the most common treatment for BPD, induces a phase delay inmPer2transcription that resembles the effect observed with GSK3 knockdown. (jcircadianrhythms.com)
  • the interaction is required for cyclin D and CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. (rcsb.org)
  • inhibit
  • In this study, we report that small interfering RNAs (siRNA) against the breakpoint of EWS-Fli1 mRNA might be a very efficient agent with which to inhibit the expression of EWS-Fli1 and the growth of EFT cells, and that EWS-Fli1 might have functions that prevent the induction of senescence in cells through the promotion of Skp2-mediated and 26S proteasome-dependent degradation of p27 protein. (aacrjournals.org)
  • mitotic
  • We looked for but did not obtain strong evidence for cyclin specificity in the use of different mechanisms to control rereplication: both the S-phase cyclin Clb5 and the mitotic cyclins Clb1-4 were inferred to be capable of imposing ORC-based and MCM-based controls. (genetics.org)
  • Clb6-dependent toxicity is also relieved when early accumulation of mitotic cyclins is allowed to impose rereplication controls. (genetics.org)
  • proteasome
  • In addition, many of the properties of proteasome inhibition by the pro-drug are the same as the specific proteasome inhibitor lactacystin. (pnas.org)
  • Lastly, mevalonate (used to rescue cells from lovastatin arrest) unexpectedly abrogates the lactacystin and lovastatin pro-drug inhibition of the proteasome. (pnas.org)
  • The lovastatin-mediated inhibition of the proteasome suggests a unique mechanism for the chemopreventative effects of this agent seen in human cancer. (pnas.org)
  • In the present study, we investigated the effect of proteasome inhibition in proliferating B-CLL cells. (biomedsearch.com)
  • METHODS: The effect of proteasome inhibition was analyzed using thymidine incorporation, annexin V assays, and TUNEL staining. (biomedsearch.com)
  • glycogen
  • Glycogen synthase kinase 3 (GSK3) appeared to be required for survival of MLL cells in vitro and in a mouse model of the disease, reported Michael L. Cleary, M.D., of Stanford, and colleagues online in Nature . (medpagetoday.com)
  • activation
  • This action blocks downstream signal transduction and inhibits the tumorigenic effects associated with ligand-dependent and ligand-independent EGFR activation ( 1 , 2 ). (aacrjournals.org)
  • Activation of the ABL tyrosine kinase is a primary event in the genesis of CML, as shown by the retrovirally mediated insertion of a human BCR-ABL gene into murine hematopoietic stem cells and the creation of BCR-ABL transgenic mice ( 3 ). (aacrjournals.org)
  • Specifically it contains a Cy1 motif in the N-terminal half, and weaker Cy2 motif in the C-terminal domain that allow it to bind CDK in a region that blocks its ability to complex with cyclins and thus prevent CDK activation. (wikipedia.org)
  • Activation of two kinases, Dbf4-Cdc7 and cyclin-dependent kinases (CDK), coupled with B-type cyclins are necessary to form replisomes at two nascent replication forks and to initiate DNA replication ( B ell and D utta 2002 ). (genetics.org)
  • metabolism
  • GSK3, an essential kinase with widespread roles in development, cell survival, and metabolism has been demonstrated to be an essential component of theDrosophilacircadian clock. (jcircadianrhythms.com)
  • GSK3
  • Moreover, a GSK3 inhibitor prolonged survival in mice with transplanted MLL cells, the researchers said. (medpagetoday.com)
  • Dr. Cleary and colleagues said the research "provides a rationale to develop inhibitors with suitable pharmacodynamic properties for clinical trials to determine whether GSK3 inhibition may have therapeutic efficacy in a distinctive subset of poor prognosis leukemia. (medpagetoday.com)
  • Dr. Cleary and colleagues also found that when mice were implanted with MLL-type cells, treatment with oral lithium -- the same drug used for bipolar disorder, but also a weak inhibitor of GSK3 -- their survival was prolonged. (medpagetoday.com)
  • Dr. Cleary said in an interview, however, that lithium would not be suitable for clinical use because it's a relatively weak inhibitor of GSK3, requiring toxic doses in humans. (medpagetoday.com)