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)

The product of the cell cycle control gene cdc2 is required in yeast for transition through both G1 and G2 control points of the cell cycle. The homologous protein in higher eukaryotes has been shown to be a component of the mitosis promoting factor complex and may thus regulate entry through the G2 control point into mitosis. It is suggested from the work presented here that, as in yeast, the human CDC2Hs gene product (p34CDC2Hs) may also play a role in cell cycle control in the G1(G0) phase of the cell cycle. Interferon-alpha inhibits the growth of the human B-cell line Daudi in the G1(G0) phase of the cell cycle and prevents cells from entering S-phase. Culturing the cells with interferon-alpha inhibits the phosphorylation of p34CDC2Hs and causes the down-regulation of CDC2Hs mRNA. Phorbol ester also inhibits the Daudi cell cycle in G1(G0) and causes the inhibition of p34CDC2Hs phosphorylation and a reduction of CDC2Hs mRNA. These studies provide insights into the process of growth control and the cytostatic mechanism of interferon-alpha.
 ...
PMID:Regulation of the product of a possible human cell cycle control gene CDC2Hs in B-cells by alpha-interferon and phorbol ester. 266 71

We previously reported that combined treatment with tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha) showed a synergistic antitumor effect via regulation of cell cycle progression in the S phase. Here, we investigated the effect of the combined treatment with TNF-alpha and IFN-alpha on cell cycle regulating protein in RPMI 4788 cells. Treatment with TNF-alpha or IFN-alpha alone showed no effect on these proteins, however, the combined treatment showed suppression of cyclin A protein and its associated kinase activity. Furthermore, although the combined treatment inhibited Cdk2 kinase activity, the amount of Cdk2 protein was not affected. These results suggested that TNF-alpha and IFN-alpha work together to suppress cyclin A and Cdk2 kinase activity and to inhibit cell cycle progression in the S phase.
 ...
PMID:Cyclin A and Cdk2 kinase activity are suppressed by combined treatment with tumor necrosis factor-alpha and interferon-alpha. 765 28

E2F is a heterodimeric transcription factor that controls transcription of several growth-regulatory genes including cdc2. To investigate the mechanism of interferon-alpha (IFN-alpha)-mediated growth suppression of hematopoietic cells, we examined the effect of IFN-alpha on the expression and function of E2F using IFN-sensitive Daudi cells. Down-regulation of E2F-1, a subunit of E2F, was observed after 8 h of culture with IFN-alpha; expression of E2F-4, another subunit of E2F, and DP-1, a heterodimeric partner of E2F, was unaffected. Gel shift assays revealed that the DNA binding activity of free E2F, which is composed of E2F-1 and E2F-4, was inhibited by IFN-alpha. In contrast, IFN-alpha did not affect the DNA binding ability of E2F-1 and E2F-4 in a complex with retinoblastoma (RB) susceptibility gene family proteins including pRB, p107, and p130. IFN-alpha could induce dephosphorylation of pRB, thereby turning active E2F-pRB complexes into transcriptional repressors. Transient chloramphenicol acetyltransferase assays revealed that the activity of the E2F-dependent cdc2 promoter was suppressed by IFN-alpha. These results suggest that the antiproliferative action of IFN-alpha is mediated through the modulation of E2F activity in two different ways: down-regulation of transcriptionally active free E2F and conversion of E2F-pRB complexes into transcriptional repressors.
 ...
PMID:Modulation of E2F activity is linked to interferon-induced growth suppression of hematopoietic cells. 913 87

The mechanism of cell cycle arrest induced by interferon-alpha (IFN-alpha) was analysed using a mouse macrophage cell line, BAC1.2F5A. IFN-alpha added in media before mid-G1 prohibited cells from entering S phase. The blockage of G1/S transition was associated with diminuition of both cyclin D1/cdk4- and cyclin E/cdk2-associated kinase activities. G1 cyclin-associated kinase activities were down-regulated quickly after the addition of IFN-alpha. Cells treated with IFN-alpha contained excess amounts of cdk inhibitors which down-regulated G1 cyclin/cdk-associated kinase activities in the proliferating cells and this action was counteracted by exogenously-supplied recombinant cyclin D2/cdk4 complexes. In parallel, accumulation of p19Ink4D and p21Cip1, and their attachment to cdks were up-regulated quickly after the addition of IFN-alpha. Expression of p19Ink4D and p21Cip1 was potentiated transcriptionally. We concluded that increased attachment of up-regulated cdk inhibitors including p19Ink4D and p21Cip1 to G1 cyclin/cdk complexes contributed to diminuition of G1 cyclin/cdk-associated kinase activities and resulting G1 phase arrest during the early phase of treatment with IFN-alpha.
 ...
PMID:Interferon-alpha-induced G1 phase arrest through up-regulated expression of CDK inhibitors, p19Ink4D and p21Cip1 in mouse macrophages. 957 88

The potential antiproliferative effects of interferon-alpha (IFN-alpha) in the treatment of hepatocellular carcinoma (HCC) are controversial, and the growth inhibitory mechanisms remain poorly understood. Therefore, the current study was designed to delineate the molecular mechanisms responsible for direct antiproliferative actions of IFN-alpha in HCC cells. IFN-alpha receptor expression and signal transduction were examined by RT-PCR, immunoprecipitation, Western analysis, and transient transactivation assays. Effects of IFN-alpha on cell growth and cell-cycle distribution were evaluated based on cell numbers and flow cytometry. Composition and activity of cyclin-dependent kinase complexes were determined by immunoblotting and histone-H1-kinase assays. Expression of IFN-alpha receptors was found in all 3 HCC cell lines. IFN-alpha binding initiated phosphorylation of Jak1 and Tyk2 kinases leading to Stat1/Stat2 activation, nuclear translocation, and transactivation of an ISRE-luciferase reporter gene construct. IFN-alpha treatment resulted in a time- and dose-dependent reduction of proliferation. Cell cycle analysis of G1-synchronized, IFN-alpha-treated HCC cells revealed a substantial delay in S-phase progression but no alteration of G1/S-phase transition or evidence of apoptotic cell death. Reflecting the time course of S-phase accumulation, cell cycle-dependent induction of Cyclin A and Cyclin B was impaired, resulting in reduced activity of Cdk2 and Cdc2 kinases. Furthermore, Cdc25C was selectively down-regulated. IFN-alpha treatment inhibits growth of HCC cells by specifically delaying S-phase progression, most likely because of inhibition of Cyclin A induction, resulting in decreased activity of the associated Cdk2 and Cdc2 kinases.
 ...
PMID:Interferon-alpha delays S-phase progression in human hepatocellular carcinoma cells via inhibition of specific cyclin-dependent kinases. 1117 36