Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maternal cigarette smoking is known to disrupt placental growth and function. The polyaromatic hydrocarbon benzo[a]pyrene (BaP) is a major toxicant in cigarette smoke that has been shown to alter placental cell function. This study compared the effects of the benzo[a]pyrene (BaP) with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototype ligand for the aryl hydrocarbon (Ah) receptor, on proliferation and cell cycle progression in the human trophoblastic JEG-3 cell line. BaP, but not TCDD, significantly inhibited proliferation in a dose-dependent manner characterized by G2/M cell cycle phase arrest. No evidence of apoptosis was detected following BaP or TCDD exposure. Immunocytochemistry and Western blot analysis showed that BaP induced expression of nuclear p21CIP1 protein, the major inhibitor of cyclin-dependent kinases. In contrast, CDK1 expression, the main G2 cyclin-dependent kinase, was significantly reduced by 50% with a shift in localization from the nucleus to cytoplasm. Although BaP had no effect on total cellular p53 levels, phosphorylation of p53 at serine 15 (p53 ser-15phos) was markedly increased. The presence of Wortmannin, an inhibitor of PI-3 kinases, decreased BaP-induced p53 ser-15phos, as did the presence of the antioxidant vitamin E. In addition, vitamin E suppressed BaP-induced G2/M arrest without altering the level of induced CYP1A1 protein. Thus, the anti-proliferative effect of BaP involves activation of a p53-dependent pathway involving cell cycle arrest at G2/M, providing evidence of oxidative stress and activation of a DNA damage response pathway in JEG-3 cells.
 ...
PMID:Benzo[a]pyrene, but not 2,3,7,8-TCDD, induces G2/M cell cycle arrest, p21CIP1 and p53 phosphorylation in human choriocarcinoma JEG-3 cells: a distinct signaling pathway. 1583 74

Phosphorylation is critical to regulation of the eukaryotic cell cycle. Entry to mitosis is triggered by the cyclin-dependent kinase CDK1 (Cdc2), which is inactivated during the preceding S and G2 phases by phosphorylation of T14 and Y15. Two homologous kinases, Wee1, which phosphorylates Y15, and Myt1, which phosphorylates both T14 and Y15, mediate this inactivation. We have determined the crystal structure of the catalytic domain of human somatic Wee1 (Wee1A) complexed with an active-site inhibitor at 1.8 A resolution. Although Wee1A is functionally a tyrosine kinase, in sequence and structure it most closely resembles serine/threonine kinases such as Chk1 and cAMP kinases. The crystal structure shows that although the catalytic site closely resembles that of other protein kinases, the activation segment contains Wee1-specific features that maintain it in an active conformation and, together with a key substitution in its glycine-rich loop, help determine its substrate specificity.
 ...
PMID:Structure and inhibition of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation. 1583 93

A novel series of 2,6-diamino-3-acylpyridines were designed and synthesized as cyclin-dependent kinase (CDK) inhibitors. The representative compounds 2r and 11 showed potent CDK1 and CDK2 inhibitory activities and inhibited cellular proliferation in HeLa, HCT116, and A375 tumor cells.
 ...
PMID:3-Acyl-2,6-diaminopyridines as cyclin-dependent kinase inhibitors: synthesis and biological evaluation. 1583 97

Src and Src-family protein-tyrosine kinases are regulatory proteins that play key roles in cell differentiation, motility, proliferation, and survival. The initially described phosphorylation sites of Src include an activating phosphotyrosine 416 that results from autophosphorylation, and an inhibiting phosphotyrosine 527 that results from phosphorylation by C-terminal Src kinase (Csk) and Csk homologous kinase. Dephosphorylation of phosphotyrosine 527 increases Src kinase activity. Candidate phosphotyrosine 527 phosphatases include cytoplasmic PTP1B, Shp1 and Shp2, and transmembrane enzymes include CD45, PTPalpha, PTPepsilon, and PTPlambda. Dephosphorylation of phosphotyrosine 416 decreases Src kinase activity. Thus far PTP-BL, the mouse homologue of human PTP-BAS, has been shown to dephosphorylate phosphotyrosine 416 in a regulatory fashion. The platelet-derived growth factor receptor protein-tyrosine kinase mediates the phosphorylation of Src Tyr138; this phosphorylation has no direct effect on Src kinase activity. The platelet-derived growth factor receptor and the ErbB2/HER2 growth factor receptor protein-tyrosine kinases mediate the phosphorylation of Src Tyr213 and activation of Src kinase activity. Src kinase is also a substrate for protein-serine/threonine kinases including protein kinase C (Ser12), protein kinase A (Ser17), and CDK1/cdc2 (Thr34, Thr46, and Ser72). Of the three protein-serine/threonine kinases, only phosphorylation by CDK1/cdc2 has been demonstrated to increase Src kinase activity. Although considerable information on the phosphoprotein phosphatases that catalyze the hydrolysis of Src phosphotyrosine 527 is at hand, the nature of the phosphatases that mediate the hydrolysis of phosphotyrosine 138 and 213, and phosphoserine and phosphothreonine residues has not been determined.
 ...
PMID:Src kinase regulation by phosphorylation and dephosphorylation. 1584 50

During the first stage of Varicella-Zoster virus (VZV) infection, IE63 (immediate early 63 protein) is mostly expressed in the nucleus and also slightly in the cytoplasm, and during latency, IE63 localizes in the cytoplasm quite exclusively. Because phosphorylation is known to regulate various cellular mechanisms, we investigated the impact of phosphorylation by roscovitine-sensitive cyclin-dependent kinase (RSC) on the localization and functional properties of IE63. We demonstrated first that IE63 was phosphorylated on Ser-224 in vitro by CDK1 and CDK5 but not by CDK2, CDK7, or CDK9. Furthermore, by using roscovitine and CDK1 inhibitor III (CiIII), we showed that CDK1 phosphorylated IE63 on Ser-224 in vivo. By mutagenesis and the use of inhibitors, we demonstrated that phosphorylation on Ser-224 was important for the correct localization of the protein. Indeed, the substitution of these residues by alanine led to an exclusive nuclear localization of the protein, whereas mutations into glutamic acid did not modify its subcellular distribution. When transfected or VZV-infected cells were treated with roscovitine or CiIII, an exclusive nuclear localization of IE63 was also observed. By using a transfection assay, we also showed that phosphorylation on Ser-224 and Thr-222 was essential for the down-regulation of the basal activity of the VZV DNA polymerase gene promoter. Similarly, roscovitine and CiIII impaired these properties of the wild-type form of IE63. These observations clearly demonstrated the importance of CDK1-mediated IE63 phosphorylation for a correct distribution of IE63 between both cellular compartments and for its repressive activity toward the promoter tested.
 ...
PMID:Varicella-zoster virus IE63 protein phosphorylation by roscovitine-sensitive cyclin-dependent kinases modulates its cellular localization and activity. 1595 20

A series of 1-acyl-1H-[1,2,4]triazole-3,5-diamine analogues were synthesized as cyclin-dependent kinase (CDK) inhibitors. These compounds showed potent and selective CDK1 and CDK2 inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. Representative compound 3b demonstrated in vivo efficacy in a human melanoma A375 xenograft model in nude mice.
 ...
PMID:1-Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: synthesis and evaluation of biological activities. 1597 71

Variolin B (VAR-B) is a natural product isolated from the sponge Kirkpatrickia variolosa, found in Antarctica. VAR-B has been shown previously to possess potent pro-apoptotic activity. This study was undertaken to investigate the mechanism of action of chemically synthesised VAR-B and its analogue deoxy-variolin B (dVAR-B). In different human cancer cell lines both compounds inhibited colony formation, caused cell cycle perturbations and induced apoptosis at concentrations ranging from 0.1 to 2 microM. LoVo/Dx cells over-expressing Pgp were equally sensitive as the parental cell line to VAR-B and dVAR-B, indicating that variolins are not substrates of Pgp. Although variolins induced an increase in the levels of p53 with an increase in p21, their cytotoxicities did not appear to be dependent on p53 status as their potency was comparable in cells with wild-type p53, or in sub-lines with inactivated p53. Both VAR-B and dVAR-B prevent the cells from entering S phase, blocking cells in G1 and cause an accumulation of cells in G2. The apoptosis induced by VAR-B and dVAR-B occurs very rapidly in some cell lines (e.g., Jurkat leukaemia cells) and is already evident 4h after the beginning of treatment. Although intercalation of dVAR-B in DNA has been demonstrated, neither VAR-B nor dVAR-B produce detectable breaks in DNA. These results are consistent with the in vitro biochemical assays that also demonstrated that dVAR-B is not topoisomerase I or II poison. Instead, each of these variolins appears to inhibit cyclin-dependent kinases (CDKs) in the muM range. CDK1-cyclin B, CDK2-cyclin A and CDK2/cylin E complexes were inhibited in a range of concentrations lower than those required to inhibit the activity of CDK4/cyclin D or CDK7/cyclin H complexes. In conclusion, these variolins are a new class of CDK inhibitors that activate apoptosis in a p53-independent fashion and thus they may be effective against tumours with p53 mutations or deletions.
 ...
PMID:Variolin B and its derivate deoxy-variolin B: new marine natural compounds with cyclin-dependent kinase inhibitor activity. 1618 79

Nucleophosmin (NPM) is a multifunctional phosphoprotein, being involved in ribosome assembly, pre-ribosomal RNA processing, DNA duplication, nucleocytoplasmic protein trafficking, and centrosome duplication. NPM is phosphorylated by several kinases, including nuclear kinase II, casein kinase 2, Polo-like kinase 1 and cyclin-dependent kinases (CDK1 and 2), and these phosphorylations modulate the activity and function of NPM. We have previously identified Thr(199) as the major phosphorylation site of NPM mediated by CDK2/cyclin E (and A), and this phosphorylation is involved in the regulation of centrosome duplication. In this study, we further examined the effect of CDK2-mediated phosphorylation of NPM by using the antibody that specifically recognizes NPM phosphorylated on Thr(199). We found that the phospho-Thr(199) NPM localized to dynamic sub-nuclear structures known as nuclear speckles, which are believed to be the sites of storage and/or assembly of pre-mRNA splicing factors. Phosphorylation on Thr(199) by CDK2/cyclin E (and A) targets NPM to nuclear speckles, and enhances the RNA-binding activity of NPM. Moreover, phospho-Thr(199) NPM, but not unphosphorylated NPM, effectively represses pre-mRNA splicing. These findings indicate the involvement of NPM in the regulation of pre-mRNA processing, and its activity is controlled by CDK2-mediated phosphorylation on Thr(199).
 ...
PMID:Thr199 phosphorylation targets nucleophosmin to nuclear speckles and represses pre-mRNA processing. 1637 75

Some hepatitis C virus (HCV) proteins, including core protein, deregulate the cell cycle of infected cells, thereby playing an important role in the viral pathogenesis of HCC. Thus far, there are only few studies that have deeply investigated in depth the effects of the HCV core protein expression on the progression through the G1/S and G2/M phases of the cell cycle. To shed light on the molecular mechanisms by which the HCV core protein modulates cell proliferation, we have examined its effects on cell cycle in hepatocarcinoma cells. We show here that HCV core protein perturbs progression through both the G1/S and the G2/M phases, by modulating the expression and the activity of several cell cycle regulatory proteins. In particular, our data provided evidence that core-dependent deregulation of the G1/S phase and its related cyclin-CDK complexes depends upon the ERK1/2 pathway. On the other hand, the viral protein also increases the activity of the cyclin B1-CDK1 complex via the p38 MAPK and JNK pathways. Moreover, we show that HCV core protein promotes nuclear import of cyclin B1, which is affected by the inhibition of both the p38 and the RNA-dependent protein kinase (PKR) activities. The important role of p38 MAPK in regulating G2/M phase transition has been previously documented. It is becoming clear that PKR has an important role in regulating both the G1/S and the G2/M phase, in which it induces M phase arrest. Based on our model, we now show, for the first time, that HCV core expression leads to deregulation of the mitotic checkpoint via a p38/PKR-dependent pathway.
 ...
PMID:Role of p38 MAPK and RNA-dependent protein kinase (PKR) in hepatitis C virus core-dependent nuclear delocalization of cyclin B1. 1644 63

Because the majority of cancers exhibit direct or indirect deregulation of cyclin-dependent kinase (CDK) function, members of the CDK family are attractive targets for the development of anticancer agents. As part of an ongoing program, novel imidazopyridines were identified and developed as potent and selective CDK inhibitors. Here, we describe data on the in vitro biological activities of one of these compounds, AZ703. The selectivity profile of AZ703 was investigated in kinase assays against a range of CDK enzymes as well as a panel of protein kinases in vitro. IC50s were assessed against different tumor cell lines in vitro. The mechanism of action of AZ703 was determined by observing changes in phosphorylation of CDK substrates and cell cycle effects on tumor and normal cells. In vitro studies revealed that AZ703 is a selective inhibitor of CDK1 and CDK2 and displays a mode of action consistent with the induction of G1-, S-, and G2-M-phase arrest. AZ703 also showed potent antiproliferative activity across a wide range of tumor cell lines in vitro. Moreover, AZ703 induced reversible blockade of normal cells while causing tumor cells to undergo apoptosis. We have identified AZ703 as a novel selective imidazo[1,2-a]pyridine CDK inhibitor that shows promising antitumor properties in vitro.
 ...
PMID:The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor. 1654 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>