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)

The proto-oncogene c-abl encodes a protein tyrosine kinase that is localized in the cytoplasm and the nucleus. The large carboxyl-terminal segment of c-Abl was found to contain a DNA-binding domain that was necessary for the association of c-Abl with chromatin. The DNA-binding activity of c-Abl was lost during mitosis when the carboxyl-terminal segment became phosphorylated. In vitro phosphorylation of the DNA-binding domain by cdc2 kinase abolished DNA binding. Homozygous mutant mice expressing a c-Abl tyrosine kinase without the DNA-binding domain have been reported to die of multiple defects at birth. Thus, binding of the c-Abl tyrosine kinase to DNA may be essential to its biological function.
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PMID:Cell cycle-regulated binding of c-Abl tyrosine kinase to DNA. 156 87

The cell division cycle in eukaryotes contains up to three major transition points; the conversion of quiescent cells to a stage of active proliferation, the initiation of DNA synthesis (S phase) and the induction of mitosis in cells with newly replicated genome (M phase). Within the past years two strategies, have converged to identify, genetically and biochemically a key protein kinase p34 cdc2 that governs the entry into mitosis. In the fission yeast Schizosaccharomyces pombe a number of mutants in the mitotic regulatory circuit have been isolated. A central gene in the network is cdc2 which is essential for the proper execution of mitosis. The cdc2 gene interacts with a number of other genes for correct mitotic control. The Amphibian oocyte, the oocyte from Xenopus laevis particularly, is arrested at the G2 phase of the first meiotic division; when it enters M phase, it contains a dominant regulatory factor known as MPF (M-phase or maturation promoting factor). Purified MPF is an heterodimer formed of two polypeptides p34cdc2 an homologue of the product of the gene cdc2 and p45cdc13 or cyclin an homologue of the product of the gene cdc13. Biochemical studies have revealed that p34cdc2 is a phosphotyrosine protein during the G2 phase of the cell cycle, both mitotic and meiotic. The tyrosine phosphorylation of p34cdc2 is regulated by the gradual accumulation of cyclin. At the onset of M phase, the complex p34cdc2/cyclin is activated as an histone H1 kinase, and p34cdc2 is tyrosine dephosphorylated. The mechanism of activation of p34cdc2 is negatively regulated by a form of protein phosphatase 2A. Ovulated vertebrate oocytes are arrested at metaphase of the second meiotic division (M II) under the control of the proto-oncogene c-mos a protein kinase. The exit of M II phase and the initiation of early embryonic mitotic cell cycles are physiologically induced by the spermatozoa at the time of fertilization. They requires the degradation of c-mos by a Ca2+ dependent proteolytic enzyme and the destruction of cyclin by an ubiquitin dependent pathway. The Xenopus oocyte has led to the molecular elucidation of MPF and identified links between cell cycle control, protein phosphorylation and proto-oncogenes. Despite the impresive progess of recent years, there is still much to be learned about the control of meiosis in Xenopus oocytes.
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PMID:[From ovocyte to biochemistry of the cell cycle]. 165 57

Previous studies from this laboratory have shown that purified MPF from Xenopus eggs contains cyclin B2 complexed with cdc2 kinase. The activation of MPF during oocyte maturation is known to require expression of the c-mos(xe) proto-oncogene. We show here that immunoprecipitates of either v-mos from Moloney murine sarcoma virus-transformed NIH 3T3 cells or c-mos from Xenopus eggs phosphorylate cyclin B2 in vitro. Phosphopeptide analysis reveals a pattern similar to that observed with cdc2 kinase. Moreover, ablation of c-mos(xe) from oocytes by antisense oligonucleotide injection reduces the rate of cyclin B2 phosphorylation in oocyte extracts by 40%. These results suggest that the mechanism of activation of MPF by c-mos(xe) involves phosphorylation of the cyclin component.
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PMID:The cyclin B2 component of MPF is a substrate for the c-mos(xe) proto-oncogene product. 214 May 29

The product of the c-abl proto-oncogene (c-Abl) is phosphorylated on three sites during interphase and seven additional sites during mitosis. Two interphase and all mitotic c-Abl sites are phosphorylated by cdc2 kinase isolated from either interphase or mitotic cells, with the mitotic cdc2 having an 11-fold higher activity. Inhibition of phosphatases with okadaic acid in interphase cells leads to the phosphorylation of c-Abl mitotic sites, indicating that those sites are preferentially dephosphorylated during interphase. The differential phosphorylation of c-Abl in the cell cycle is therefore determined by an equilibrium between cdc2 kinase and protein phosphatase activities. Treatment of interphase cells with okadaic acid leads to a rounded morphology similar to that observed during mitosis.
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PMID:Differential phosphorylation of c-Abl in cell cycle determined by cdc2 kinase and phosphatase activity. 218 53

The proto-oncogene c-fos is known to be an important positive regulator of cell growth and notably of the G0/G1 transition. However, we observed that v-fos or c-fos-transformed rat-1 fibroblasts paradoxically had a low growth rate as compared to control untransformed rat-1 cells. We determined that this slow growth mainly reflects an increase of the G1 phase of the cell cycle (up to fourfold). In addition, the G0 --> S progression of serum-starved fos-expressing rat-1 cells refed with serum was found to be also delayed as compared to rat-1 cells. The delayed G0 --> S progression in fos-expressing cells was accompanied by the inappropriate levels or kinetics of expression of several cell cycle-regulated genes (cyclin D1, cdc2, cdk2, cdk4 and rb). Furthermore, a clear uncoupling of the pRb hyperphosphorylation with the entry into S phase was found in these fos-expressing rat-1 cells. Interestingly, the effect of the Fos proteins on the cell cycle was independent of the fos transforming pathway, indicating that the effector genes for Fos proteins are likely to be different for each process. In conclusion, our results indicate that Fos proteins may act as negative regulators of cell growth in some cell types, independently of the fos transforming pathway.
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PMID:Fos proteins can act as negative regulators of cell growth independently of the fos transforming pathway. 763 Jun 29

Glucocorticoids inhibit transcription of the proto-oncogene c-myc in lymphoid cells of thymic origin. To determine if this effect is associated with changes in the properties of the transcription factor E2F, extracts were prepared from control and glucocorticoid-treated P1798 murine T lymphoma cells, and the macromolecular state of E2F was assessed by gel-mobility shift. Control extracts exhibit two predominant gel-mobility shift entities of which one corresponds to "free" E2F. A second entity, complex C, has properties similar to those described for the complex containing E2F, p107, cyclin A, and Cdk2. Complex C disappears after addition of dexamethasone and is replaced by complex D. The mobility of this complex and its sensitivity to SV40 T antigen suggest that complex D corresponds to an E2F-p105Rb-1 complex. Extracts from control and glucocorticoid-treated cells yield identical DNase I protection patterns on the c-myc P2 promoter. Furthermore, such extracts transcribe the c-myc P2 promoter in vitro with equal activity. The relative abundance of the E2F complexes was measured after addition of dexamethasone. Complex C disappears as cells withdraw from S phase, and complex D appears at this time. The genes encoding thymidine kinase (Tk-1) and p34cdc2 (cdc2) are regulated with kinetics similar to those observed for changes in the macromolecular state of E2F. However, regulation of c-myc expression occurs long before any change in E2F. The macromolecular state of E2F may regulate expression of genes at the G1/S boundary. However, the data are not consistent with the hypothesis that association of E2F with tumor suppressor gene products such as p107 or p105Rb-1 is relevant to glucocorticoid regulation of c-myc transcription.
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PMID:The macromolecular state of the transcription factor E2F and glucocorticoid regulation of c-myc transcription. 800 8

In eucaryotes, M-phase promoting factor (MPF) triggers meiosis in germ cells and mitosis in somatic cells. MPF is composed of two proteins of which one is homologous with the protein kinase encoded by gene cdc2 of Schizosaccharomyces pombe (p34cdc2) and the other is a cyclin whose concentration oscillates during the cell cycle. Inactivation of p34cdc2 (MPF) requires cyclin degradation, which occurs during the metaphase-anaphase transition of the M-phase. Cyclin degradation is not only associated with cell cycle progression, but is also required for this event. At the G2/M transition, p34cdc2 protein kinase is activated and catalyzes phosphorylation of numerous key proteins, thus enabling cell changes to occur. p34cdc2 undergoes multiple-site phosphorylation in a cell cycle-dependent manner. At onset of mitosis, the protein phosphatase cdc25 catalyzes dephosphorylation of the p34cdc2 kinase at the threonine 14 and tyrosine 15 sites. This event may be the rate-limiting step controlling onset of mitosis in cells of vertebrates. A second protein kinase, encoded by the proto-oncogene c-mos, acts as a cytostatic factor preventing cyclin degradation and keeping unfertilized eggs from progressing beyond the second meiotic metaphase.
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PMID:[Control of cell division in eucaryotes]. 839 83

Unfertilized frog eggs arrest at the second meiotic metaphase, due to cytostatic activity of the c-mos proto-oncogene (CSF). MAP kinase has been proposed to mediate CSF activity in suppressing cyclin degradation. Using an in vitro assay to generate CSF activity, and recombinant CL 100 phosphatase to inactivate MAP kinase, we confirm that the c-mos proto-oncogene blocks cyclin degradation through MAP kinase activation. We further show that for MAP kinase to suppress cyclin degradation, it must be activated before cyclin B-cdc2 kinase has effectively promoted cyclin degradation. Thus MAP kinase does not inactivate, but rather prevents the cyclin degradation pathway from being turned on. Using a constitutively active mutant of Ca2+/calmodulin dependent protein kinase II, which mediates the effects of Ca2+ at fertilization, we further show that the kinase can activate cyclin degradation in the presence of both MPF and the c-mos proto-oncogene without inactivating MAP kinase.
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PMID:MAP kinase does not inactivate, but rather prevents the cyclin degradation pathway from being turned on in Xenopus egg extracts. 883 8

The product of the c-mos proto-oncogene is a protein kinase that is normally expressed in germ cells and functions during oocyte maturation. It has been shown, however, that inappropriate expression of either the viral or cellular mos gene can induce neoplastic progression in somatic cells. Furthermore, v-mos-transformed NIH3T3 cells will undergo arrest of proliferation in early G1 upon serum withdrawal but are unable to appropriately down-regulate cell cycle regulatory proteins, such as cyclin and cdc2 proteins, that normally are down-regulated in quiescent, untransformed NIH3T3 cells. Since the levels of these proteins are partially transcriptionally controlled, we investigated whether there were alterations in the expression of E2F and AP-1 transcription factor complexes. Indeed, the putative G0/G1-specific p130-E2F complex that is normally observed during low serum-induced cell cycle arrest in NIH3T3 cells is not present in serum starved v-mos-transformed cells. Instead, G1-phase arrested v-mos-transformed cells stably express two E2F protein complexes that are normally observed only during S-phase in untransformed cells. The elevation of these complexes in arrested v-mos-transformed cells may be the cause of the transcriptional activation of the E2F-regulated genes cdc2, DHFR, cyclin A, and E2F1 seen in serum starved v-mos-transformed cells. In addition, there are high levels of AP-1 DNA binding activity in serum starved v-mos-transformed cells compared to very low amounts in nontransformed cells. This altered regulation of transcription factor complexes and cell cycle control proteins upon serum withdrawal may provide a mechanism for the uncontrolled cell growth associated with neoplastic transformation induced by certain proto-oncogenes.
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PMID:Deregulation of specific E2F complexes by the v-mos oncogene. 922 66

The proto-oncogene cyclin D1 and the neuron-specific cyclins p35 and p39 are expressed during brain maturation. To investigate the role of these cyclins in neuronal differentiation, we used a conditionally immortalized rat hippocampal cell line, H19-7, that expresses cyclin-dependent kinases 4 and 5 (cdk4 and -5). Cyclin D1, which activates cdk4 and binds but does not activate cdk5, was increased upon differentiation of the H19-7 cells. However, microinjection of either sense or antisense cyclin D1 cDNA or anti-cyclin D1 antibodies had no effect on morphological differentiation of the cells. On the other hand, neurite outgrowth was stimulated by expression of p35 or p39, both of which activate cdk5. A dominant-negative mutant of cdk5 blocked both p35- and p39-induced neurite extension as well as basic fibroblast growth factor (bFGF)-induced neuronal differentiation. However, of these cyclins, only antisense p39 prevented bFGF-induced neurite outgrowth. These studies indicate that cyclin D1 is neither necessary nor sufficient for morphological differentiation, that p35 is sufficient but not required, and that p39 is both necessary and sufficient for neurite outgrowth in the hippocampal cells. Taken together, these results represent the first demonstration of a specific role for p39 in neuronal differentiation, implicate the cyclin-activated kinase cdk5 in this process, and indicate that p39 is able to mediate neurite outgrowth in the presence or absence of cyclin D1.
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PMID:Role of cyclins in neuronal differentiation of immortalized hippocampal cells. 934 22


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