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

Treatment of human myeloid leukemia cells (HL-60, U-937, THP-1) with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with differentiation along the monocytic lineage. This induction by TPA is characterized in part by growth arrest and the appearance of differentiated monocytic phenotype. The present studies demonstrate that myeloid leukemia cells exit the cell cycle to G0-G1 between 24 and 36 h following TPA treatment. This G0-G1 arrest was accompanied by down-regulation of the cell cycle-regulatory genes cdc2, cyclin A, cyclin B, and cdc25. Similar findings were obtained for histones H1 and H4. Cell cycle progression of synchronized U-937 cells revealed low to undetectable mRNA levels for these genes in G1 and maximal transcription in G2-M phase. Results obtained from mRNA half-life studies demonstrate that the stability of cdc2, cyclin A, cyclin B, and cdc25 transcripts is similar in control and TPA-treated U-937 cells. Nuclear run-on assays demonstrated down-regulation of histone gene transcription, while there was no signal detectable for the cell cycle-regulatory genes. The present findings also demonstrate that long term culture of TPA-differentiated U-937 cells is associated with a decrease in G0-G1-arrested cells and an increase of cells in S and G2-M after 25 days. This reentry into the cell cycle was accompanied by loss of adherence, down-regulation of markers for the monocytic phenotype, and induction of the cell cycle-regulatory genes. This process of retrodifferentiation was completed after 36 days when patterns of cell cycle-regulatory and histone gene expression were identical to that in untreated U-937 cells.
Cancer Res 1992 Mar 15
PMID:Differentiation and retrodifferentiation of human myeloid leukemia cells is associated with reversible induction of cell cycle-regulatory genes. 153 83

Hydrolysis of the neurotransmitter acetylcholine by acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) is the rate-limiting step in the termination of cholinergic signaling at neuromuscular junctions. A growing body of evidence suggests that these enzymes also play a role in tumorigenesis. The ACHE and BCHE genes are amplified, mutated, and/or aberrantly expressed in a variety of human tumor types. These changes could be the result of chromosome breakage, since there is an unusually high frequency of chromosomal abnormalities near the map positions of these genes (3q26-ter and 11p-ter, respectively) in such tumors, particularly hemopoietic malignancies. Both ACHE and BCHE contain the consensus peptide motif S/T-P-X-Z, which is found in many substrates of cdc2-related protein kinases. Here we consider the intriguing possibility that phosphorylation by cdc2-related kinases may be the molecular mechanism linking cholinesterases with tumor cell proliferation. We also discuss the notion that inhibition of these enzymes by commonly used organophosphorous poisons may be tumorigenic in humans.
Cancer Cells 1991 Dec
PMID:A role for cholinesterases in tumorigenesis? 182 94

After exposure to ionizing radiation, eukaryotic cells undergo a division delay which is reflected by increased time spent in the G2 portion of the cell cycle. Recent information identifies increased levels of mitotic cyclins as key biochemical events initiating mitosis. In HeLa cells cyclin B mRNA and protein levels have been shown to increase in G2 and to decrease after division is completed. Cyclin B protein binds to cdc2, resulting in histone kinase activity which is necessary for the initiation of mitosis. Accordingly, we chose to investigate how cyclin B mRNA and protein levels were perturbed by irradiation in order to gain further understanding of the mechanisms by which ionizing radiation leads to a division delay. Our experiments revealed at least two effects on cyclin B regulation which might contribute to the division delay: (a) when HeLa cells were irradiated in S phase, there was a delay in the accumulation of cyclin B mRNA; (b) when cells were radiated in G2 phase, at a time when mRNA levels were increasing, a division delay was induced which coincided with a markedly lowered level of cyclin B protein despite high levels of the mRNA.
Cancer Res 1991 Oct 01
PMID:Cyclin B expression in HeLa cells during the G2 block induced by ionizing radiation. 183 48

Senescent cells fail to respond to serum-induced signals for DNA synthesis. Because a central role for the p34cdc2 protein kinase is postulated in control of the cell cycle, we examined the status of this kinase in senescent cells and other growth-arrested cells. In growing human and Syrian hamster fibroblasts, three 35S-labeled proteins of 34-36 kDa were immunoprecipitated with p34cdc2 antiserum. Only the two slower migrating forms were phosphorylated as determined by 32P labelling. In senescent cells, which failed to incorporate [3H]thymidine, no p34cdc2 protein was synthesized and very little or no cdc2 mRNA was observed. When maintained for 48 h in 0.5% serum, young cells also retained only marginal cdc2 expression. After stimulation of low serum-arrested cells by addition of 10% serum, a time-dependent increase of cdc2 mRNA was observed, whereas serum stimulation of senescent cells did not increase cdc2 mRNA. In contrast to senescent and low serum-arrested cells, cdc2 mRNA was expressed at normal levels in cells partially growth arrested by isoleucine deficiency in G1, by aphidicolin at G1-S, by etoposide in G2, or by Colcemid in the M phase of the cell cycle, indicating that cdc2 down-regulation does not always occur upon growth arrest. Following transfection of a plasmid containing the human CDC2 gene into hamster cells, expression of human cdc2 failed to overcome the block to DNA synthesis in senescent cells. Although p34cdc2 was synthesized in the transfected cells, the multiple phosphorylated forms of the proteins were not observed. Taken together, these data support the concept that a chain of events leads to senescence. While p34cdc2 kinase may be one of the critical elements, other cell cycle controls are also involved.
Cancer Res 1991 Nov 01
PMID:Down-regulation of cdc2 in senescent human and hamster cells. 193 64

The mammalian homologue of the yeast cdc2 gene product, p34cdc2, is a cell cycle-regulated protein essential for mitosis. We have used polyclonal antisera raised against a peptide corresponding to the carboxyl terminus of the sequence of human cdc2 to study p34cdc2 in Chinese hamster ovary (CHO) cells. Major bands are immunoprecipitated at a molecular weight of 34,000, although not in the presence of competing antigenic peptide. p34cdc2 is coimmunoprecipitated with proteins of molecular weights of 52,000 and 57,000. Immunoprecipitates express histone H1 kinase activity which varies throughout the cell cycle, maximal activity being observed in G2-M. The activity of the p34cdc2 kinase varies according to its association with the Mr 52,000 and 57,000 proteins and according to their phosphorylation state. Treatment of either asynchronous CHO cells or an enriched G2 population with the antitumor agent, etoposide, results in rapid inhibition of immunoprecipitated p34cdc2 kinase activity, which is not due to a direct effect of drug upon the enzyme. p34cdc2 kinase activity recovers as cells arrest in G2 and a second etoposide treatment further inhibits p34cdc2 kinase activity and prolongs G2 arrest. Exposure of asynchronous CHO cells to gamma-irradiation also inhibits p34cdc2 kinase activity within 1 h. Again this activity recovers as cells accumulate in G2. These results suggest that DNA damage in CHO cells elicits a response which results in inhibition of p34cdc2 kinase activity and, consequently, G2 arrest.
Cancer Res 1990 Jun 15
PMID:Inhibition of p34cdc2 kinase activity by etoposide or irradiation as a mechanism of G2 arrest in Chinese hamster ovary cells. 218 1

To identify cyclins specifically associated with control of melanoma cell proliferation, we now compared expression of cyclin A, reported to be a marker for hematological malignancies, with that of cyclin D and its cdk4 kinase partner. All these proteins were expressed in proliferating B16 melanoma. However, L-tyrosine which induces melanoma terminal differentiation, selectively decreased cyclin D with no comparable effect on cdk4 or cyclin A. A 2-hour exposure of the cells to the tyrosine phosphatase inhibitor, sodium vanadate, further decreased cyclin D from differentiated cells, suggesting that tyrosine phosphorylation regulates cyclin D turnover. Addition of serum to starved cells also revealed that tyrosine did not block the early cyclin D increase associated with serum stimulation, but accelerated its subsequent loss. Our data suggest that cyclin D decrease with melanoma terminal differentiation could be an alternative mode of growth arrest even in cells harbouring a mutant or transcriptionally silent cdk4 inhibitor tumor suppressor p16ink4 gene. These results also imply that cyclin D may be useful as a target and as a prognostic marker in melanoma therapy.
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PMID:Suppression of cyclin D1 but not cdk4 or cyclin A with induction of melanoma terminal differentiation. 748 22

Overexpression of c-Fos/AP-1 augments proliferation of splenic B cells stimulated with lipopolysaccharide (LPS). To elucidate mechanisms of the augmentation by c-Fos/AP-1, a cell cycle of the LPS-activated B cells from c-fos transgenic mice was analyzed. Cell cycle progression into the S phase was accelerated in the c-fos B cells. Expression of genes related to the cell cycle progression was examined in these B cells. Amount of cyclin D3 and cdk4 mRNA increased in the c-fos B cells at 6 h earlier than that in the control B cells, indicating that the kinetics of these mRNA expressions correlate with the acceleration of cell cycle progression. Furthermore, cyclin D1 and cyclin E mRNA were detected in the c-fos B cells but not in the control B cells. These results indicate that deregulated c-Fos/AP-1 modulates expression of the cyclin and the cdk gene in splenic B cells stimulated with LPS. These modulations may accelerate cell cycle progression and augment proliferation of the B cells.
Cancer Lett 1995 Jun 08
PMID:Deregulated c-Fos/AP-1 modulates expression of the cyclin and the cdk gene in splenic B cells stimulated with lipopolysaccharide. 754 12

Deletion of 9p21-22 is a common genetic alteration in dysplastic, in situ, and invasive head and neck squamous cell carcinoma (HNSCC). However, a candidate tumor suppressor gene (TSG) at this site has thus far not been identified in HNSCC. We report homozygous deletion of the recently identified multiple tumor suppressor I (MTSI)/cyclin-dependent kinase-4-inhibitor (CDKN2) gene mapped to 9p21, which encodes the p16 protein, a regulator of cyclin-dependent kinase 4, in six of 16 HNSCC cell lines. We also show absence of the CDKN2 mRNA in all cell lines with CDKN2 deletion as well as in an additional two cell lines without deletion. Overall, we have identified 9p abnormalities in 12 of 16 (75%) cell lines, at least nine of which involved CDKN2. We further demonstrate that the CDKN2 deletion in HNSCC is located within a previously described region of allelic loss between D9S171 and IFNW, which spans a 4 cM region of 9p. However, examination of 36 primary tumors revealed genetic alterations in only seven of 36 (19%) tumors. These results suggest that genetic alterations at CDKN2 are frequent in HNSCC cell lines, but the role of this gene in primary tumors is less compelling. CDKN2 does not appear to be the only TSG on 9p21 in HNSCC, and our results suggest that another region of deletion exists proximal to the IFNW locus.
Genes Chromosomes Cancer 1995 Jun
PMID:Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors. 754 12

Olomoucine (2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine) has been recently described as a competitive inhibitor (ATP-binding site) of the cell cycle regulating p34cdc2/cyclin B, p33cdk2/cyclin A and p33cdk2/cyclin E kinases, the brain p33cdk5/p35 kinase and the ERK1/MAP-kinase. The unusual specificity of this compound towards cell cycle regulating enzymes suggests that it could inhibit certain steps of the cell cycle. The cellular effects of olomoucine were investigated in a large variety of plant and animal models. This compound inhibits the G1/S transition of unicellular algae (dinoflagellate and diatom). It blocks Fucus zygote cleavage and development of Laminaria gametophytes. Stimulated Petunia mesophyl protoplasts are arrested in G1 by olomoucine. By arresting cleavage it blocks the Laminaria gametophytes. Stimulated Petunia mesophyl protoplasts are arrested in G1 by olomoucine. By arresting cleavage it blocks the development of Calanus copepod larvae. It reversibly inhibits the early cleavages of Caenorhabditis elegans embryos and those of ascidian embryos. Olomoucine inhibits the serotonin-induced prophase/metaphase transition of clam oocytes; furthermore, it triggers the the release of these oocytes from their meiotic metaphase I arrest, and induces nuclei reformation. Olomoucine slows down the prophase/metaphase transition in cleaving sea urchin embryos, but does not affect the duration of the metaphase/anaphase and anaphase/telophase transitions. It also inhibits the prophase/metaphase transition of starfish oocytes triggered by various agonists. Xenopus oocyte maturation, the in vivo and in vitro phosphorylation of elongation factor EF-1 are inhibited by olomoucine. Mouse oocyte maturation is delayed by this compound, whereas parthenogenetic release from metaphase II arrest is facilitated. Growth of a variety of human cell lines (rhabdomyosarcoma cell lines Rh1, Rh18, Rh28 and Rh30; MCF-7, KB-3-1 and their adriamycin-resistant counterparts; National Cancer Institute 60 human tumor cell lines comprising nine tumor types) is inhibited by olomoucine. Cell cycle parameter analysis of the non-small cell lung cancer cell line MR65 shows that olomoucine affects G1 and S phase transits. Olomoucine inhibits DNA synthesis in interleukin-2-stimulated T lymphocytes (CTLL-2 cells) and triggers a G1 arrest similar to interleukin-2 deprivation. Both cdc2 and cdk2 kinases (immunoprecipitated from nocodazole- and hydroxyurea-treated CTLL-2 cells, respectively) are inhibited by olomoucine. Both yeast and Drosophila embryos were insensitive to olomoucine. Taken together the results of this Noah's Ark approach show that olomoucine arrests cells both at the G1/S and the G2/M boundaries, consistent with the hypothesis of a prevalent effect on the cdk2 and cdc2 kinases, respectively.
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PMID:Cellular effects of olomoucine, an inhibitor of cyclin-dependent kinases. 754 5

Protein complexes containing cyclins and cyclin-dependent protein kinases (cdks) have been shown to be rearranged in both spontaneous and viral tumor antigen-transformed cells. We have examined G1- and S-phase cyclin/cdk complexes as a function of the neoplastic progression of human diploid fibroblasts transfected with the SV40 large T antigen. We find that the expression of cyclin D1 and its association with proliferating cell nuclear antigen (PCNA) and Waf1 remain unchanged in precrisis human fibroblasts transfected with SV40 large T antigen. However, in these same cells the association of cdk4 with cyclin D1, PCNA, and Waf1 is disrupted. Upon immortalization, cyclin D1 protein expression is decreased, and binding of both PCNA and Waf1 with the remaining cyclin D1 is reduced. In contrast, large T antigen increased the expression of cyclin A and cyclin E proteins in both precrisis and immortal cells and did not reduce the binding of PCNA or Waf1 to either cdk2 or cyclin A proteins. These results show that large T-antigen expression in human fibroblasts selectively uncouples cyclin D1 from cdk4, and subsequent immortalization of these cells results in additional changes to the cyclin D1-dependent cell cycle regulatory pathways.
Cancer Res 1995 Oct 15
PMID:Immortalization of human fibroblasts by SV40 large T antigen results in the reduction of cyclin D1 expression and subunit association with proliferating cell nuclear antigen and Waf1. 755 44


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