Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinase (Cdk)2/cyclin E is imported into nuclei assembled in Xenopus egg extracts by a pathway that requires importin-alpha and -beta. Here, we identify a basic nuclear localization sequence (NLS) in the N-terminus of Xenopus cyclin E. Mutation of the NLS eliminated nuclear accumulation of both cyclin E and Cdk2, and such versions of cyclin E were unable to trigger DNA replication. Addition of a heterologous NLS from SV40 large T antigen restored both nuclear targeting of Cdk2/cyclin E and DNA replication. We present evidence indicating that Cdk2/cyclin E complexes must become highly concentrated within nuclei to support replication and find that cyclin A can trigger replication at much lower intranuclear concentrations. We confirmed that depletion of endogenous cyclin E increases the concentration of cyclin B necessary to promote entry into mitosis. In contrast to its inability to promote DNA replication, cyclin E lacking its NLS was able to cooperate with cyclin B in promoting mitotic entry.
 ...
PMID:Identification of the nuclear localization signal in Xenopus cyclin E and analysis of its role in replication and mitosis. 1247 60

In this study we show that panaxadiol, a ginseng saponin with a dammarane skeleton, induces apoptotic cell death by depolarization of mitochondrial membrane potential in human hepatoma SK-HEP-1 cells. Sequential activation of caspases-9, -3, and -7, but not of caspase-8, occurs after mitochondrial membrane depolarization and cytochrome c release from the mitochondria of panaxadiol-treated cells. Moreover, Cdk2 kinase activity, but not Cdc2 kinase activity, is markedly upregulated in the early stages of apoptosis. Olomoucine or roscovitine, specific Cdks inhibitors, effectively prevent mitochondrial membrane depolarization as well as apoptotic cell death in panaxadiol-treated cells. Thus, panaxadiol-treatment induces cell death-dependent activation of Cdk2 kinase activity, which is functionally associated with depolarization of mitochondrial membrane potential and subsequent cytochrome c release.
 ...
PMID:Cdk2 activity is associated with depolarization of mitochondrial membrane potential during apoptosis. 1276 26

Cyclin-dependent kinase (cdks) are key components of the engine that drives the cell proliferation cycle in all eukaryotes. These kinases are related to p34(cdc2) and associate with regulatory subunits belonging to the cyclin family. To understand how cdks promote cell cycle progression, it will be important to identify their physiological substrates and to determine how phosphorylation influences the functions of these substrates. This article discusses recent progress as well as some of the problems related to the quest for cdk substrates.
 ...
PMID:Cellular substrates of p34(cdc2) and its companion cyclin-dependent kinases. 1473 46

Endothelial cells (ECs) are quiescent in normal blood vessels, but undergo rapid bursts of proliferation after vascular injury, hypoxia or induced by powerful angiogenic cytokines like fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Deregulated proliferation of ECs facilitates angiogenic processes and promotes tumor growth. In dividing cells, cell cycle-associated protein kinases, which are referred as cyclin-dependent kinases (cdks), regulate proliferation, differentiation, senescence, and apoptosis. Cyclin-dependent kinase-5 (cdk5) is expressed in neuronal cells and plays an important role in neurite outgrowth, of neuronal migration and neurogenesis, its functions in non-neuronal cells are unclear. Here, we show for the first time that the cdk5 is expressed at high levels in proliferating bovine aortic endothelial (BAE) cells, by contrast insignificant low levels of cdk5 expression in quiescent BAE cells. In addition, bFGF up-regulates cdk5 expression in a dose-dependent fashion. Interestingly, temporal expression data suggests that cdk5 expression is very low between 24-48 h, but high level of cdk5 expression was detected during 60-72 h. This later time corresponds to the time of completion of one cell cycle (doubling of cell population) of BAE cell culture. Angiostatin (AS), a powerful inhibitor of angiogenesis inhibits ECs proliferation in dose-dependent manner with concomitant down-regulation of cdk5 expression. The role of cdk5 in ECs, proliferation and apoptosis was confirmed by selective inhibition of cdk5 expression by the purine derivative roscovitine, which inhibits bFGF-stimulated BAE cells proliferation and induces apoptosis in dose-specific manner. By contrast, the roscovitine analog olomoucine, which is a specific inhibitor of cdk4, but not of cdk5 failed to affect ECs proliferation and apoptosis. These data suggest for the first time that neuron specific protein cdk5 may have significant role in the regulation of ECs proliferation, apoptosis, and angiogenesis and extends beyond its role in neurogenesis.
 ...
PMID:Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5. 1474 98

Cyclin-dependent kinases (CDKs) and their related pathways represent some of the most attractive targets in the development of anticancer therapeutics. Among a variety of CDK inhibitors under development, flavopiridol, UCN-01, CYC202, and BMS-387032 are undergoing clinical evaluation based on evidence of preclinical antitumor activity. Flavopiridol exerts multiple effects in tumor cells, including inhibition of multiple CDKs, transcriptional inhibition secondary to disruption of P-TEFb (CDK9/cyclin T), induction of apoptosis, and antiangiogenesis. UCN-01 was initially developed as a protein kinase C (PKC) inhibitor, but its major antitumor effects appear to be related to CDK inhibition or "inappropriate" activation of cdc2/CDK1 abrogating the G2 and S checkpoints, inhibition of PDK1/Akt, and induction of apoptosis through a PKC-independent mechanism. Significantly, combining these CDK inhibitors with either conventional cytotoxic drugs or novel agents targeting signal transduction pathways can markedly enhance antitumor activity, particularly induction of apoptosis, in various preclinical models. Such findings may serve as a basis for the introduction of novel combination regimens into clinical trials.
 ...
PMID:Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents. 1475 Oct 90

Cyclin-dependent kinase-5 (CDK5), a unique CDK family member, is active primarily in the central nervous system (CNS). Previous studies suggest that CDK5 is proapoptotic and contributes to tau hyperphosphorylation and neurodegeneration in Alzheimer's disease. The objective of this study was to examine CDK5 effects on apoptotic progression and tau phosphorylation. Immortalized embryonic mouse brain cortical cells were used to establish a stable cell line that overexpressed wild-type human tau. In these studies, thapsigargin, which induces endoplasmic reticulum stress and can cause accumulation of misfolded proteins, was used to induce apoptosis. Caspase-3 activity and poly-(ADP-ribose)-polymerase (PARP) cleavage, as measures of apoptosis, were significantly increased 24 and 48 hr after thapsigargin treatment, and these events were unaffected by tau expression. Although transient coexpression of CDK5 and its activator, p25, increased CDK5 activity greater than tenfold, increases in caspase-3 activity in response to thapsigargin treatment were unaffected by the presence of CDK5/p25. Tau phosphorylation at the PHF-1 epitope, but not the Tau-1 epitope, was increased significantly in CDK5/p25-transfected cells compared to cells transfected with dominant negative CDK5 (DNCDK5). The PHF-1 epitope remained phosphorylated until 48 hr after thapsigargin treatment in the CDK5/p25-transfected cells. Over the course of apoptosis in this model, phosphorylation of the Tau-1 epitope was unaffected in cells transfected with DNCDK5, vector, or CDK5/p25. In summary, these results demonstrate that CDK5 does not have a significant impact on tau phosphorylation and thapsigargin-induced apoptosis in this neuronal cell model.
 ...
PMID:Effects of cyclin-dependent kinase-5 activity on apoptosis and tau phosphorylation in immortalized mouse brain cortical cells. 1504 35

Cdc2 kinase is inactivated when DNA damage occurs during the spindle assembly checkpoint. Here, we show that the level of mitotic Bloom syndrome protein phosphorylation reflects the level of cdc2 activity. A complete inactivation of cdc2 by either introduction of DNA double-strand breaks or roscovitine treatment prevents exit from mitosis. Thus, mitotic cdc2 inactivation plays a major role in the establishment of the mitotic DNA damage checkpoint. In response to mitotic cdc2 inactivation, the M/G(1) transition is delayed after releasing the drug block in nonmalignant cells, whereas tumor cells exit mitosis without dividing and rereplicate their DNA, which results in mitotic catastrophe. This opens the way for new chemotherapeutic strategies.
 ...
PMID:A major role for mitotic CDC2 kinase inactivation in the establishment of the mitotic DNA damage checkpoint. 1560 58

Cyclin-dependent kinase activating kinase (CAK) is a trimeric complex composed of cdk7, cyclin H and MAT1. CAK/cdk7 functions as a master cell cycle regulator by phosphorylating cyclin-dependent kinases for cell cycle progression. We have previously reported that protein kinase C-iota (PKC-iota) associates with CAK/cdk7. In this investigation, immunofluorescence confocal microscopy was used to provide further evidence for the co-localization of PKC-iota with CAK/cdk7. PKC-iota was labeled with Alexa Fluor 488 (green fluorescent dye) and CAK/cdk7 was labeled with Alexa Fluor 555 (red fluorescent dye). The fusion of the red and green fluorescent colors produced a yellow color, which was used to quantify co-localization of PKC-iota and CAK/cdk7. Confocal microscopy revealed the co-localization of PKC-iota with CAK/cdk7 in both the cytoplasm and nucleus of U-373 MG cells.
 ...
PMID:Cyclin-dependent kinase activating kinase/Cdk7 co-localizes with PKC-iota in human glioma cells. 1569 76

Cdk-activating kinase (CAK) is a trimeric complex consisting of cdk7, cyclin H, and MAT1, which activates the cell-cycle-regulating cdks through T loop phosphorylation. In addition, other substrates of the CAK complex have been identified when CAK is assembled with the TFIIH core proteins, thereby regulating transcription and nucleotide excision repair. Little is known about the regulation of the CAK complex through cyclin H. In this study we further analyzed cyclin H regulation and identified two basic clusters in the C terminus of the protein as putative nuclear localization sequences (NLSs). Fusion constructs of full-length and truncated cyclin H sequences demonstrated the functionality of the NLSs. A peptide-binding assay revealed that at least one NLS interacts with the nuclear import receptors importin alpha/beta. Phosphorylation in the vicinity of the NLSs by cyclin C/cdk8 or protein kinase CK2, however, does not influence the nuclear translocation of cyclin H.
 ...
PMID:Cyclin H is targeted to the nucleus by C-terminal nuclear localization sequences. 1597 Nov 11

Cyclin-dependent kinases (CDKs) restrict DNA replication origin firing to once per cell cycle by preventing the assembly of prereplicative complexes (pre-RCs; licensing) outside of G1 phase. Paradoxically, under certain circumstances, CDKs such as cyclin E-cdk2 are also required to promote licensing. Here, we show that CDK phosphorylation of the essential licensing factor Cdc6 stabilizes it by preventing its association with the anaphase promoting complex/cyclosome (APC/C). APC/C-dependent Cdc6 proteolysis prevents pre-RC assembly in quiescent cells and, when cells reenter the cell cycle from quiescence, CDK-dependent Cdc6 stabilization allows Cdc6 to accumulate before the licensing inhibitors geminin and cyclin A which are also APC/C substrates. This novel mechanism for regulating protein stability establishes a window of time prior to S phase when pre-RCs can assemble which we propose represents a critical function of cyclin E.
 ...
PMID:CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. 1617 49


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