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)

Interferon (IFN) modulates the expression of several genes and some of them are considered to be responsible for the inhibition of cellular growth. However, the alterations of cell cycle-regulating genes produced by IFN still remain unclear. Accordingly, we studied the expression of cell cycle-regulating genes during IFN-induced growth arrest. Cell cycle synchronized and unsynchronized Daudi Burkitt lymphoma cells were treated with IFN. Both the cell cycle distribution and the expression of cell cycle-regulating genes (cdk2, cdc2, cyclins A, B, C, D3, cdc25, and wee 1) were studied by flow cytometry and by Northern blot hybridization or the reverse-transcription polymerase chain reaction, respectively. Treated cells passed through the first G1 phase and gradually accumulated in the following G1 phase. Expression of cyclins A, B, and D3 oscillated along with the cell cycle progression in control cells, and the alterations of cyclin B expression were especially prominent. Both cdc2 and cdk2 also showed changes, but these were not so distinct as observed with cyclin B. Expression of cdc25 and wee1 was little affected by cell cycle progression. In IFN-treated cells, expression of cyclins A and B were down-regulated, while that of cyclin C was not. Cyclin D3 expression was also down-regulated at 48 h, followed by an increase at 72 h. Expression of both cdc2 and cdk2 was down-regulated, especially that of the later. Wee1 expression was down-regulated by IFN but, the expression of cdc25 remained stable. These findings suggest that the modulation of cell cycle-regulating genes, particular by cyclin A and cdk2, plays an important role in IFN-induced cellular growth arrest.
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PMID:Changes of cell cycle-regulating genes in interferon-treated Daudi cells. 753 Dec 77

The c-myc gene encodes a sequence-specific DNA binding protein that activates transcription of cellular genes. Transcription activation by Myc proteins is regulated by phosphorylation of serine and threonine residues within the transactivation domain and by complex formation with the retinoblastoma-related protein p107. In Burkitt's lymphoma, missense mutations within the c-Myc transactivation domain have been found with high frequency. It has been reported that mutant c-Myc proteins derived from Burkitt's lymphoma cell lines are resistant to inhibition by p107, thus providing a rationale for the increased oncogenic activity of these mutant c-Myc proteins. It has been suggested that these mutant c-Myc proteins resist down-modulation by p107 because they lack cyclin A-cdk2-dependent phosphorylation. Here, we have examined three different Burkitt's lymphoma mutant c-Myc proteins found in primary Burkitt's lymphomas and one mutant c-Myc protein detected in a Burkitt's lymphoma cell line. All four have an unaltered ability to activate transcription and are sensitive to inhibition of transactivation by p107. Furthermore, we provide evidence that down-modulation of c-Myc transactivation by p107 does not require phosphorylation of the c-Myc transactivation domain by cyclin A-cdk2. Our data indicate that escape from p107-induced suppression is not a general consequence of all Burkitt's lymphoma-associated c-Myc mutations, suggesting that other mechanisms exist to deregulate c-Myc function.
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PMID:Functional analysis of Burkitt's lymphoma mutant c-Myc proteins. 862 9

Alpha interferon is a potent growth inhibitor of Daudi Burkitt's lymphoma cells. We show here that alpha-interferon signaling interacted simultaneously with several components of the basic cell cycle machinery, causing cells to enter into a state that had many features characteristic of the G0 state. Within a few hours after alpha-interferon treatment, cyclin D3 mRNA and protein levels dropped to undetectable levels and, in parallel, the activities of cyclin A- and cyclin E-associated kinases were significantly reduced. The latter resulted from the rapid alpha-interferon-mediated elimination of cdc25A, a phosphatase that is required for antagonism of negative tyrosine phosphorylation of cdk2 in cyclin-cdk complexes. This regulation represents a novel mechanism through which an external inhibitory cytokine interacts with the cell cycle machinery. At later time points after alpha-interferon treatment, the levels of the 55-kDa slowly migrating hyperphosphorylated form of cyclin E and of cyclin A were also reduced. The antiproliferative effects were reversible, and cultures from which alpha interferon was removed reentered S phase after a lag that typically corresponded to approximately two doubling times. During this lag period, the expression of cyclin D3 and cyclin A, as well as of the cdc25A phosphatase, continued to be switched off, in spite of the removal of alpha interferon from the cell surface. In contrast, c-myc, which represents another downstream target gene that is subjected to negative regulation by alpha interferon, was relieved from suppression much earlier, concomitant with the decay in early signaling of the cytokine. The delayed pattern of cyclin reexpression provides evidence that alpha-interferon signaling imposes a G0-like state on this system.
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PMID:Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest. 866 11

Type I interferons (IFN), such as IFN-alpha, are potent antiproliferative and antitumor agents. IFN-tau, originally identified as a pregnancy recognition hormone, is a type I IFN that is related to IFN-alpha. We examine here the mechanism of the antiproliferative effects of IFN-alpha and IFN-tau in terms of their effects on intracellular events that regulate the cell cycle. Both IFN inhibited proliferation of the human Burkitt lymphoma cell line, Daudi, causing accumulation of cells in the G1 phase of the cell cycle. IFN-alpha was more effective than IFN-tau in this regard. Both IFN were found to inhibit the kinase activity of the cyclin-dependent kinase cdk2 in a manner that correlated with their relative abilities to cause cells to accumulate in the G1 phase of the cell cycle. Further, IFN treatment did not affect the expression of cdk2 protein, suggesting that the IFN modulated cdk2 activity through a cdk inhibitor. Consistent with this conclusion, both IFN induced the expression of the cyclin-dependent kinase inhibitor protein p21. The levels of p21 induced also correlated with the relative abilities of the IFN to inhibit cdk2 activity and to arrest cell growth in the G1 phase of the cell cycle. Moreover, following IFN treatment, increased levels of p21 were found complexed with cdk2, consistent with its role in the inhibition of cdk2 activity. These data suggest that p21-mediated inhibition of cdk2 activity plays an important role in the antiproliferative activity of type I IFN. The findings highlight interesting similarities between these cytokines and the products of tumor suppressor genes, such as p53, and may indicate a mechanism for the antitumor effects of the type I IFN.
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PMID:A role for the cyclin-dependent kinase inhibitor p21 in the G1 cell cycle arrest mediated by the type I interferons. 904 66

Cellular proliferation is regulated by several kinasic complexes associating cyclins and their catalytic subunits cyclin-dependent kinases (CDKs). In order to gain insight into the mechanisms underlying proliferation in non-Hodgkin's lymphoma (NHL), we examined the expression of certain cell cycle regulatory proteins normally expressed in lymphoid cells, cyclins A, B, D3 and E and cdk1, 2, 4, and 6. In 70 patients presenting a previously untreated lymphoma, cyclins and CDKs were studied by Western blotting and quantified by densitometry. Flow cytometry study of DNA content was carried out for all patients in order to study cell proliferation and level of ploidy. The results were analysed according to the histological types, the immunological phenotypes of the lymphomas and the outcome of the patients. Cdkl and cyclin A were correlated with the percentage of cells in S and S+G2/M phases, and significantly different according to the grade of malignancy, with the lowest expression in low-, and the highest in high-grade NHL according to the Working Formulation. In B-NHLs, cdk1, cyclin A, as well as cdk2, cyclin D3 and E expression was higher in the aneuploid than in the euploid group. Our results point to some particularities of cell cycle regulation in two lymphoma sub-types: 1) a low expression of cyclin D3 and cdk6 in mantle cell lymphomas and 2) a discrepancy between the high proliferative activity and the level of protein expression in Burkitt's lymphomas. CDK1 and cyclin A showed a significant prognostic value for achievement of complete remission (Cdk 1) and for both disease free (cyclin A) and overall survival (cyclin A and cdk1): low protein level was associated with the best prognosis in B-NHLs. Our results show that differential cell cycle regulating protein expression may be associated with different biological and clinical behaviour of NHLs and confirm the usefulness of the study of cell cycle regulation as a tool for understanding lymphoid malignancies.
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PMID:CDK1 and cyclin A expression is linked to cell proliferation and associated with prognosis in non-Hodgkin's lymphomas. 1051 72

Olomoucine, a purine derivative, inhibits multiple cyclin-dependent kinases that play important roles in regulating the G1/S and G2/M transitions of the cell cycle. In this study we investigated the cellular effects of olomoucine in two human Burkitt's lymphoma cell lines, WMN (containing wild-type p53) and CA46 (containing mutant p53), and found that in consistency with its ability to block the activity of cyclin E/Cdk2 and cyclin B1/Cdc2 kinases, olomoucine caused cell cycle arrest at both G1/S and G2/S boundaries. Moreover, cell cycle arrest occurred equally well in these two cell lines bearing different p53 gene status, suggesting that p53 was not responsible for the cell cycle arrest by olomoucine. A similar p53-independent fashion was also observed in the cytotoxic potency and apoptosis induction of olomoucine, in contrast to ionizing radiation which caused more cytotoxic activity and apoptosis in the WMN cell line bearing wild-type p53 compared with CA46 cells bearing mutant p53. Such p53-independent cytotoxicity of olomoucine was also confirmed in other human Burkitt's lymphoma and lymphoid cell lines containing wild-type and mutant p53. Therefore, our results give an impetus to continued research into olomoucine that might be a very useful chemotherapeutic strategy in the treatment of patients with mutant p53 tumors, at least in lymphoma patients.
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PMID:Cellular effects of olomoucine in human lymphoma cells differing in p53 function. 1056 74

Lack of detectable expression of p27kip1 cyclin dependent kinase inhibitor has previously been correlated with high degree of malignancy in human breast, colorectal, gastric and small cell lung carcinomas. Here we demonstrate that an inverse correlation between p27kip1 expression and tumour malignancy also exists in most types of human B cell lymphomas examined. A clear exception was Burkitt's lymphoma (BL), a highly malignant tumour which often expresses high levels of p27kip1. Analysis of p27kip1 derived from Burkitt's lymphoma cell lines expressing high levels of p27kip1, BL40 and BL41, in a cyclin E/cdk2 kinase inhibition assay demonstrated that p27kip1 is not permanently inactivated since heat treatment can restore the inhibitory activity of p27kip1. However, p27kip1 expressed in these two cell lines is largely sequestered in inactive complexes and we have no evidence that c-myc or Epstein-Barr virus are responsible for the sequestration of p27kip1 in these two cell lines although c-myc and EBV are two oncogenic agents often associated with Burkitt's lymphomas. Interestingly, we observed that high level p27kip1 expression often correlated with cyclin D3 overexpression both in vivo and in BL cell lines. The majority of p27kip1 in BL40 cells was complexed with cyclin D3 indicating that overexpressed cyclin D3 may at least be part of the sequestering activity for the inhibitory function of p27kip1. Furthermore, cyclinD3/cdk4 complex could sequester p27kip1 in a cyclin E/cdk2 kinase assay in vitro. Finally, we show that cyclin D3 transfected into an inducible p27kip1 cell line could overcome the G1 arrest mediated by p27kip1. These results argue that in addition to down-regulation of p27kip1 expression, some tumour cells can sequester and tolerate the antiproliferative function of p27kip1. They also suggest a novel role for the overexpression of D-type cyclins as one pathway allowing tumour cells to overcome the antiproliferative function of p27kip1.
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PMID:Antiproliferative function of p27kip1 is frequently inhibited in highly malignant Burkitt's lymphoma cells. 1059 39

Using 2-dimensional gel electrophoresis (2D-gel) analysis, we show here that cell-cycle entry is associated with a significant increase in p27(kip1) phosphorylation in human primary B cells. A similar pattern of increase in p27(kip1) phosphorylation was also seen in 2 fast-growing tumor cell lines, Burkitt lymphoma cell line BL40 and breast carcinoma cell line Cal51, where inactive p27(kip1) is expressed at high levels. Detailed analysis revealed for the first time that different cyclins and cyclin-dependent kinases (cdk's) interact with distinct posttranslationally modified isoforms of p27(kip1) in vivo. Cyclin E but not cyclin A selectively interacts with phosphorylated p27(kip1) isoforms, while cyclin D1 and D2 favor unphosphorylated p27(kip1) isoforms in vivo. Interestingly, cyclin D3 and cdk4 selectively interact with phosphorylated p27(kip1) in BL40 cells. Among all D-type cyclin/cdk4 and cdk6 complexes, cyclin D3/cdk4 is most active in sequestering the inhibitory activity of p27(kip1) in vitro in a cyclinE/cdk2 kinase assay. This novel feature of the binding specificity of p27(kip1) to cyclins and cdk's in vivo is interpreted in the context of overexpression of cyclin D3 in the presence of high levels of p27(kip1) in human B-cell lymphomas with adverse clinical outcome.
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PMID:Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo. 1566 20

Silurus asotus (catfish) egg lectin (SAL) has potent affinity to Gal alpha-linked carbohydrate chains of not only glycoproteins but also glycosphingolipids such as globotriaosylceramide (Gb3). SAL selectively bound to Gb3 localized in glycosphingolipid-enriched microdomain (GEM) of Gb3-expressing (Gb3(+)) Burkitt's lymphoma cells. Since treatment of Gb3(+) cells with SAL caused an increase in externalization of phosphatidylserine via activation of P-glycoprotein, and apoptotic volume decrease via activation of G-protein activated K(+) channel-1, SAL may function as an inducer of early apoptotic signal; however, neither caspase-8 and -3 activation nor DNA fragmentation was observed. We therefore investigated whether cell proliferation and viability were altered in SAL-treated Raji cells. SAL caused reduction of Raji cell proliferation without cytotoxicity. Although SAL did not induce apoptotic cell death to Gb3-expressing cells, it functionally behaved as a regulator of cell proliferation. SAL activated the suppression system of cell proliferation, such as down-regulation of c-myc and cdk4, and up-regulation of p21 and p27, inducing G1 arrest of the cell cycle, and consequently inhibited cell proliferation of Raji cells. Therefore, we conclude that SAL leads the cells to early apoptotic status but not late apoptotic (necrotic) status via binding to Gb3 existing in GEM, and that this binding is a prerequisite condition to induce cell cycle stop signal.
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PMID:[Regulation of globotriaosylceramide (Gb3)-mediated signal transduction by rhamnose-binding lectin]. 1740 83

Inhibition of c-MYC has been considered as a potential therapy for lymphoma treatment. We explored a lentiviral vector-mediated small interfering RNA (siRNA) expression vector to stably reduce c-MYC expression in B cell line Jijoye cells and investigated the effects of c-MYC downregulation on cell growth, cell cycle, and apoptosis in vitro. The expression of c-MYC mRNA and protein levels were inhibited significantly by c-MYC siRNA. The c-MYC downregulation resulted in the inhibition of cell proliferation and cell cycle arrest at G2/M phase, which was associated with decreased expression of cyclin B and cyclin-dependent kinase 1 (CDK1) and increased expression of CDK inhibitor p21 proteins. In addition, downregulation of c-MYC induced cell apoptosis characterized by DNA fragmentation and caspase-3 activation. Taken together, these results suggest that lentiviral vector-mediated siRNA for c-MYC may be a promising approach for targeting c-MYC in the treatment of Burkitt lymphoma.
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PMID:Lentiviral vector-mediated siRNA knockdown of c-MYC: cell growth inhibition and cell cycle arrest at G2/M phase in Jijoye cells. 2365 34


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