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)

Genetic studies using fission yeast (Schizosaccharomyces pombe) have identified a gene, cdc2, whose product (p34cdc2) is a protein kinase required for traversal of both the G1 and G2 cell cycle control points. Genetic complementation has been used to demonstrate that p34cdc2 homologues are functionally and structurally conserved in distantly related eukaryotes, and p34cdc2-related proteins are components of both maturation-promoting factor (MPF) and the M phase (growth-associated) histone H1 kinase. The p34cdc2 homologues of multicellular eukaryotes undergo potentially regulatory phosphorylation changes through the cell cycle. Phosphorylation on serine during late G1 is accompanied by a significant increase in p34cdc2 kinase activity which, by analogy with fission yeast, may betray a function related to control over entry into S phase. Phosphorylation on threonine and tyrosine in G2 precedes dephosphorylation of these residues during kinase hyperactivation and entry into mitosis. In addition, long-term control of expression of mammalian p34cdc2 homologues is likely to be exerted at the transcriptional level. These observations provide the framework of a universal model for the control of eukaryotic cell proliferation, in which the p34cdc2 protein kinase integrates multiple cues to signal the initiation of S phase and, subsequently, mitosis.
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PMID:Controls of cell proliferation in yeast and animals. 219 66

cdc2 is a catalytic subunit of a protein kinase complex, called the M-phase promoting factor, that induces entry into mitosis and is universal among eukaryotes. In HeLa cells, cdc2 is shown to be the most abundant phosphotyrosine-containing protein and its phosphotyrosine content is subject to cell-cycle regulation. One site of cdc2 tyrosine phosphorylation in vivo is selectively phosphorylated by pp60c-src in vitro.
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PMID:Human cdc2 protein kinase is a major cell-cycle regulated tyrosine kinase substrate. 246 72

It has been demonstrated that the Xenopus homolog of the fission yeast cdc2 protein is a component of M phase promoting factor (MPF). We show that the Xenopus cdc2 protein is phosphorylated on tyrosine in vivo, and that this tyrosine phosphorylation varies markedly with the stage of the cell cycle. Tyrosine phosphorylation is high during interphase (in Xenopus oocytes and activated eggs) but absent during M phase (in unfertilized eggs). In vitro activation of pre-MPF from Xenopus oocytes results in tyrosine dephosphorylation of the cdc2 protein and switching-on of its kinase activity. The product of the fission yeast suc1 gene (p13), which inhibits the entry into mitosis in Xenopus extracts, completely blocks tyrosine dephosphorylation and kinase activation. However, p13 has no effect on the activated form of the cdc2 kinase. These findings suggest that p13 controls the activation of the cdc2 kinase, and that tyrosine dephosphorylation is an important step in this process.
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PMID:Fission yeast p13 blocks mitotic activation and tyrosine dephosphorylation of the Xenopus cdc2 protein kinase. 247 38

Tyrosine phosphorylation of cdc2 is regulated in the cell cycle of mouse 3T3 fibroblasts. Phosphotyrosine in cdc2 is detectable at the onset of DNA synthesis and becomes maximal in the G2 phase of the cell cycle. Quantitative tyrosine dephosphorylation of cdc2 occurs during entry into mitosis and no phosphotyrosine is detected during the G1 phase of the cell cycle. While increasing tyrosine phosphorylation of cdc2 correlates with the formation of a cdc2/p62 complex, the tyrosine phosphorylated cdc2 is inactive as a histone H1 kinase. cdc2 is fully dephosphorylated in its most active mitotic form, yet specific tyrosine dephosphorylation of interphase cdc2 in vitro is insufficient to activate the kinase. In vivo inhibition of tyrosine dephosphorylation by exposure of cells to a phosphatase inhibitor is associated with G2 arrest, which is reversible upon the removal of the phosphatase inhibitor. Tyrosine dephosphorylation of cdc2 may be one of a number of obligatory steps in the mitotic activation of the kinase.
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PMID:Reversible tyrosine phosphorylation of cdc2: dephosphorylation accompanies activation during entry into mitosis. 247 39

The physiological roles, precise locations, and relevant targets of the 60 kD protein-tyrosine kinase encoded by viral and cellular src genes p60src are not known, despite intensive study. We describe recent work that bears upon these unresolved problems: (i) p60c-src is phosphorylated during mitosis on threonine and serine residues by the protein kinase encoded by the mammalian homologue of cdc2, suggesting that c-src may contribute to the phenotype of mitotic cells; (ii) multiple regions in the amino-terminal portion of p60src are required for its proper intracellular localization--a short signal for myristylation and signals for association with cytoplasmic granules and with perinuclear and plasma membranes; and (iii) regions (called SH3 and SH2) upstream of the kinase domain modulate the behavior of p60src in complex ways, with some mutations in SH2 rendering p60 host-dependent for transformation. The latter mutants may prove to be powerful tools for identifying proteins that modify or serve as targets for src-encoded protein-tyrosine kinases.
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PMID:Function, location, and regulation of the src protein-tyrosine kinase. 248 25

In response to genotoxic stress, cell cycle progression can be arrested at certain checkpoints which serve to maintain genomic integrity. We have investigated the mechanism of ultraviolet B (UVB) irradiation-induced cell cycle arrest in normal human keratinocytes and in the HaCaT keratinocyte cell line which carries mutant p53 tumour suppressor protein. While only normal keratinocytes showed a delay in G1 following sublethal UVB irradiation both cell types exhibited prolonged G2 arrest attributable to rapid inhibition of cyclin B-associated cdc2 kinase activity. This inhibition coincided with increased tyrosine phosphorylation of cdc2 and was reversed by the cdc25C phosphatase in vitro. The data indicate that UVB-induced G2 arrest in mammalian cells is mediated by inhibitory tyrosine phosphorylation of cdc2 and acts as a defense mechanism against DNA damage irrespective of the cells' p53 status.
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PMID:Ultraviolet B irradiation-induced G2 cell cycle arrest in human keratinocytes by inhibitory phosphorylation of the cdc2 cell cycle kinase. 747 36

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

Intercellular adhesion molecules (ICAM)-1 and -3 coexist on T lymphocytes and are counter-receptors for the integrin LFA-1. Signaling through ICAM-3 stimulates a number of T cell functions and involves phosphorylation of Fyn, Lck, CD45, and other proteins. In contrast, this type of specific signaling event has not been described for signaling through ICAM-1. Here, tyrosine phosphorylation of cellular proteins was examined after cross-linking of ICAM-1. Tyrosine phosphorylation of the 34-kDa cdc2 protein kinase was induced transiently after stimulation of the leukemic T cell line, Molt-3, or peripheral blood T cells. Stimulation through ICAM-1 had no effect on constitutive presence of cdc2 or phosphorylation of cdc2 on threonine. cdc2 kinase activity was constitutive in peripheral blood T cells, and transient inhibition of kinase activity after ICAM-1 stimulation correlated kinetically with phosphorylation of cdc2 on tyrosine.
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PMID:Cross-linking of ICAM-1 on T cells induces transient tyrosine phosphorylation and inactivation of cdc2 kinase. 749 27

The cdc2-activator cdc25C was immunoprecipitated from HeLa cell extracts and assayed as tyrosine phosphatase (PTP) using tyrosine-phosphorylated myelin basic protein. The PTP activity was 12-fold higher in immunocomplexes from mitotic (nocodazole-arrested) than from asynchronous cells. This difference is due to enzyme activation, since the same amount of cdc25C was immunodetected in both conditions. However, mitotic cdc25C had M(r) 59,000, while a 56,000-59,000 doublet was detected in immunocomplexes from asynchronous cells. The PTP activity of mitotic cdc25C was decreased by treatment with Phosphatase-2A catalytic subunit (but not with Phosphatase-1), with re-appearance of the 56,000 polypeptide. cdc25C was also found associated with cdc2-p13-Sepharose complex and its PTP activity was 7-fold higher in samples from mitotic than from asynchronous cells. cdc25C and cdc2 co-migrated during gel filtration and the higher activity of mitotic cdc25C was retained through gel filtration.
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PMID:Activation of the cdc25C phosphatase in mitotic HeLa cells. 750 71

An increase in tyrosine phosphorylation of two hepatic S9 proteins migrating at 34 and 33 kDa that cross-reacted with anti-PSTAIR antibody on immunoblots was seen 24 h after administration of a single dose of 0.25, 0.5, 1 or 2 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg to C57BL/6J female mice. Two hepatic S9 proteins migrating at 34 and 33 kDa that cross-reacted with anti-cdc2 C-terminus antibody on immunoblots were observed in corn oil control mice; increased expression of these proteins was seen with increasing doses of TCDD. A maximal increase in expression of 3-times the control was observed at 1 and 2 micrograms TCDD/kg for both p34 and p33. The stimulation of enhanced tyrosylphosphorylation and expression of cyclin dependent kinases p34cdc2 and p3cdk2 by TCDD is consistent with a mechanism of action of TCDD toxicity associated with stimulation of cellular proliferation.
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PMID:Acute 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure results in enhanced tyrosylphosphorylation and expression of murine hepatic cyclin dependent kinases. 750 35


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