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)

E-type cyclins (cyclin E1 and cyclin E2) are expressed during the late G1 phase of the cell cycle until the end of the S-phase. The activity of cyclin E is limiting for the passage of cells through the restriction point "R" which marks a "point of no return" for cells entering the division cycle from a resting state or passing from G1 into S-phase. Expression of cyclin E is regulated on the level of gene transcription mainly by members of the E2F trrnscription factor family and by its degradation via the proteasome pathway. Cyclin E binds and activates the kinase Cdk2 and by phosphorylating its substrates, the so-called "pocket proteins", the cyclic/Cdk2 complexes initiate a cascade of events that leads to the expression of S-phase specific genes. Aside from this specific function as a regulator of S-phase-entry, cyclin E plays a direct role in the initiation of DNA replication, the control of genomic stability, and the centrosome cycle. Surprisingly, recent studies have shown that the once thought essential cyclin E is dispensable for the development of higher eukaryotes and for the mitotic division of eukaryotic cells. Nevertheless, high level cyclin E expression has been associated with the initiation or progression of different human cancers, in particular breast cancer but also leukemia, lymphoma and others. Transgenic mouse models in which cyclin E is constitutively expressed develop malignant diseases, supporting the notion of cyclin E as a dominant onco-protein.
 ...
PMID:Cyclin E. 1514 22

The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of proteins, many of which are crucial in oncogenesis, including epidermal growth factor receptor (EGF-R), Her-2, AKT, Raf, p53, and cdk4. These proteins are referred to as "clients" of Hsp90. Under unstressed conditions these proteins form complexes with Hsp90 and the cochaperones to attain their active conformations or enhance stability. Inhibition of Hsp90 function disrupts the complex and leads to degradation of client proteins in a proteasome-dependent manner. This results in simultaneous interruption of many signal transduction pathways pivotal to tumor progression and survival. Based on the unique role of the Hsp90 complex, extensive effort has been made in identifying Hsp90 inhibitors. Several compounds have been shown to inhibit Hsp90 in vitro and in vivo and the most advanced, 17-allylamino-17-demethoxygeldanamycin (AAG), is in phase I/II clinical trials. Recent findings with 17-AAG indicate that tumor cells utilize Hsp90 quite differently from normal cells, explaining the selectivity of the drug and suggesting a central role of Hsp90 in malignant progression. Thus these small molecule inhibitors have proved not only to be of great value in identifying new Hsp90 client proteins and in understanding the biology of Hsp90 but are also promising therapeutics in a variety of tumors.
 ...
PMID:Targeting multiple signal transduction pathways through inhibition of Hsp90. 1516 26

Cyclin-dependent kinases (cdks) represent potentially promising molecular targets for cancer therapeutic strategies. To evaluate the antitumor activity of selective cyclin/cdk inhibition, we constructed a chimeric protein composed of a F-box protein (TrCP) fused to a peptide comprising the cyclin/cdk2 binding motif in p21-like cdk inhibitors (TrCP-LFG). We now demonstrate that endogenous cyclin A and its binding substrate, cdk2, can be tethered to beta-TrCP, ubiquitinated, and effectively degraded. Degradation of cdk2 and cyclin A together, but not cdk2 alone, results in massive tumor cell apoptosis in vitro and in vivo in a proteasome-dependent manner with no toxicity to normal tissue. These data demonstrate that cyclin A and/or the cyclin A/cdk2 complex is a promising anticancer target with a high therapeutic index.
 ...
PMID:Proteasome-mediated destruction of the cyclin a/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo. 1517 7

Sulforaphane (SFN) is a natural micronutrient found in cruciferous vegetables that has been shown to possess antitumoral properties in carcinogen-treated rats. In vitro, SFN regulates phase II enzymes, cell cycle, and apoptosis. In the present study, we investigated the relationship between SFN induction of apoptosis and cell cycle arrest in HT29 human colon carcinoma cells. In previously published data, a significant increase in the G2/M phase of the cell cycle has been observed in SFN-treated cells that was associated with increased cyclin B1 protein levels. In the present study, our results show that SFN induced p21 expression. Moreover, preincubation of HT29 cells with roscovitine, a specific cdc2 kinase inhibitor, blocked the G2/M phase accumulation of HT29 cells treated with SFN and abolished its apoptotic effect (22.2 +/- 4 of floating cells in SFN-treated cells vs. 6.55 +/- 2 in cells treated with both SFN and roscovitine). These results suggest that the cdc2 kinase could be a key target for SFN in the regulation of G2/M block and apoptosis. Moreover, in SFN-treated cells the retinoblastoma tumor suppressor protein (Rb) is highly phosphorylated. Inhibition of the cdc2 kinase by roscovitine did not change the phosphorylation status of Rb in SFN-treated cells, suggesting that this cyclin-dependent kinase may not be involved. In our study, we did not observe any significant change in the proteasomal activity between control and SFN-treated cells. Moreover, inhibition of proteasomal activity through the use of MG132 diminished SFN-induced HT29 cell death, suggesting that the apoptotic effect of SFN requires a functional proteasome-dependent degradation system. In summary, we have elucidated part of the mechanism of action of SFN in the concomitant regulation of intestinal cell growth and death.
 ...
PMID:Mechanism of sulforaphane-induced cell cycle arrest and apoptosis in human colon cancer cells. 1523 55

Geminin is an unstable inhibitor of DNA replication that negatively regulates the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation in Xenopus egg extracts. Here we describe a novel function of Geminin. We demonstrate that human Geminin protects CDT1 from proteasome-mediated degradation by inhibiting its ubiquitination. In particular, Geminin ensures basal levels of CDT1 during S phase and its accumulation during mitosis. Consistently, inhibition of Geminin synthesis during M phase leads to impairment of pre-RC formation and DNA replication during the following cell cycle. Moreover, we show that inhibition of CDK1 during mitosis, and not Geminin depletion, is sufficient for premature formation of pre-RCs, indicating that CDK activity is the major mitotic inhibitor of licensing in human cells. Taken together with recent data from our laboratory, our results demonstrate that Geminin is both a negative and positive regulator of pre-RC formation in human cells, playing a positive role in allowing CDT1 accumulation in G2-M, and preventing relicensing of origins in S-G2.
 ...
PMID:Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis. 1525 90

In eukaryotic cells, the function of DNA replication licensing components (Cdc6 and Cdt1, among others) is crucial for cell proliferation and genome stability. However, little is known about their role in whole organisms and whether licensing control interfaces with differentiation and developmental programs. Here, we study Arabidopsis thaliana CDT1, its regulation, and the consequences of overriding licensing control. The availability of AtCDT1 is strictly regulated at two levels: (1) at the transcription level, by E2F and growth-arresting signals, and (2) posttranscriptionally, by CDK phosphorylation, a step that is required for its proteasome-mediated degradation. We also show that CDC6 and CDT1 are key targets for the coordination of cell proliferation, differentiation, and development. Indeed, altered CDT1 or CDC6 levels have cell type-specific effects in developing Arabidopsis plants: in leaf cells competent to divide, cell proliferation is stimulated, whereas in cells programmed to undergo differentiation-associated endoreplication rounds, extra endocycles are triggered. Thus, we propose that DNA replication licensing control is critical for the proper maintenance of proliferative potential, developmental programs, and morphogenetic patterns.
 ...
PMID:DNA replication licensing affects cell proliferation or endoreplication in a cell type-specific manner. 1531 10

CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily. It associates with cyclin L and is involved in the regulation of transcription and in premRNA splicing. During staurosporine-, Fas- and tumour necrosis factor a-induced apoptosis, CDK11p110, is cleaved by caspases to generate smaller 46-50 kDa proteins containing the catalytic kinase domain. Ectopic expression of the caspase-processed form CDK11p46 induces apoptosis. The mechanisms that regulate activation and stability of CDK11 isoforms are still unclear. In the present study, we demonstrate that in human melanoma cells CDK11p110 and CDK11p46 interact with Hsp90 (heat-shock protein 90) and its co-chaperone cdc37. Furthermore, we show that the treatment of cells with the Hsp90-specific inhibitor geldanamycin leads to ubiquitination and enhanced degradation of both CDK11p110 and CDK11p46 through a proteasome-dependent pathway. We also determined that geldanamycin-triggered degradation of CDK11p46 slows down the progression of apoptosis. These results indicate that Hsp90 and cdc37 stabilize CDK11 kinase, and suggest that this stabilization is crucial for its pro-apoptotic function.
 ...
PMID:Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90. 1534 6

TSC1 (tuberous sclerosis complex 1) encoding hamartin and TSC2 encoding tuberin are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis. These genes have been demonstrated to negatively regulate cell cycle progression, the activity of cdk2, and the degradation of the cyclin-dependent kinase inhibitor p27. To date, the underlying molecular mechanism remains elusive. Here, we show that tuberin binds to p27. Whereas tuberin also binds p27 in TSC1-negative cells, hamartin does not bind p27 without tuberin. p27 protein levels are regulated through ubiquitin-dependent degradation. Skp2 is the F-box protein, which, together with other proteins, forms an SCF (Skp1/cullin/F-box protein)-type E3 ubiquitin ligase complex whose task is to target p27 for degradation by the proteasome. We found that neither tuberin nor hamartin are in a complex with Skp2. Tuberin does not affect Skp2 protein levels, and the SCFSkp2 ubiquitin ligase does not regulate tuberin stability. But binding of tuberin to p27 sequesters p27 from Skp2 accompanied by an up-regulation of the p27 interaction with cdk2. Skp2-induced p27 degradation and cell cycle progression is abolished by tuberin's protective binding to p27. This work, the first description of the direct interaction of a tumor suppressor protein with p27, provides a molecular explanation for the effects of tuberous sclerosis complex genes on the cell cycle and demonstrates a new aspect of the SCFSkp2-mediated regulation of p27 stability.
 ...
PMID:Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2. 1535 97

SCFGrr1, one of several members of the SCF family of E3 ubiquitin ligases in budding Saccharomyces cerevisiae, is required for both regulation of the cell cycle and nutritionally controlled transcription. In addition to its role in degradation of Gic2 and the CDK targets Cln1 and Cln2, Grr1 is also required for induction of glucose- and amino acid-regulated genes. Induction of HXT genes by glucose requires the Grr1-dependent degradation of Mth1. We show that Mth1 is ubiquitinated in vivo and degraded via the proteasome. Furthermore, phosphorylated Mth1, targeted by the casein kinases Yck1/2, binds to Grr1. That binding depends upon the Grr1 leucine-rich repeat (LRR) domain but not upon the F-box or basic residues within the LRR that are required for recognition of Cln2 and Gic2. Those observations extend to a large number of Grr1-dependent genes, some targets of the amino acid-regulated SPS signaling system, which are properly regulated in the absence of those basic LRR residues. Finally, we show that regulation of the SPS targets requires the Yck1/2 casein kinases. We propose that casein kinase I plays a similar role in both nutritional signaling pathways by phosphorylating pathway components and targeting them for ubiquitination by SCFGrr1.
 ...
PMID:Regulation and recognition of SCFGrr1 targets in the glucose and amino acid signaling pathways. 1545 73

The role of the ubiquitin-proteasome pathway during roscovitine induced apoptosis was evaluated in the non-small cell lung carcinoma cell line MR65. To this end specific inhibitors of proteasome activity, MG132 and lactacystin were used. Addition of MG132 or lactacystin, 1 h prior to the addition of the CDK-inhibitor roscovitine to the cell cultures inhibited apoptosis significantly, as measured by PS exposure, cytokeratin 18 cleavage and caspase-3 activation. Furthermore, we show that inhibition of proteasome activation prior to induction of apoptosis by roscovitine prevents loss of mitochondrial inner transmembrane potential (DeltaPsim). In addition we found that MG132 and lactacystin prevent release of cytochrome c from the mitochondrion. In contrast to the above findings we see no effect of proteasome inhibition in Fas-mediated apoptosis. Taken together our data suggest a specific role for proteasomes very early in roscovitine-induced apoptosis, upstream from the caspase cascade and mitochondrion.
 ...
PMID:Proteasomes act in the pre-mitochondrial signal transduction route towards roscovitine-induced apoptosis. 1549 36


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