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)

Human cytomegalovirus (HCMV) has many strategies to survive the attack of the host. HCMV infection of host cells induces cellular activation and disturbance of the cell cycle. It is possible that HCMV modulates the behavior of certain cancer cells that are susceptible to HCMV infection. This study was performed to identify the possible mechanism of resistance to apoptotic stimuli in some cancer cell lines by HCMV infection. HCMV-infected cancer cells showed resistance to apoptosis induced by the topoisomerase II inhibitor etoposide. UMG1-2, which constitutively expresses HCMV immediate-early protein-1 (IE1), had resistance to apoptosis induced by etoposide as compared with the parental cell line U373MG. Measurement of caspases activity with fluorogenic substrates in etoposide-treated U373MG and UMG1-2 cells and the direct activation of caspase-3 with peptides containing arginine-glycine-aspartate in U373MG and UMG1-2 cells revealed that the inhibition level of apoptosis by HCMV IE1 would be upstream of caspase-3 in the caspase cascade pathway. Cellular expression of Cdk2 was increased in UMG1- 2 after etoposide treatment while the expression of E2F-1 in UMG1-2 was decreased as compared with that in U373MG. The Cdk2 inhibitor, roscovitine, decreased the resistance to apoptosis on etoposide-treated UMG1-2. These results suggest that aberrant HCMV infection confers resistance to anticancer drugs on some cancer cells and protects cells from apoptosis, possibly due to the deregulation of cyclin-dependent kinase by HCMV immediate-early protein.
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PMID:Human cytomegalovirus (HCMV) IE1 plays role in resistance to apoptosis with etoposide in cancer cell line by Cdk2 accumulation. 1469 46

The expression of G1-phase cell-cycle regulators is commonly deregulated in human malignancies. In the present study, we investigate components of the retinoblastoma (RB) pathway in normal salivary glands (NSG) and in salivary gland tumours (SGT). Samples of NSG, pleomorphic adenoma (PA), adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC), epithelial-myoepithelial carcinoma (EMC), malignant myoepithelioma (MEM), carcinoma ex pleomorphic adenoma (CEPA), and polymorphous, low-grade adenocarcinoma (PLGA) were examined immunohistochemically using antibodies to cyclin D1, cyclin-dependent kinase 4 (CDK-4), retinoblastoma protein (pRb), CDK inhibitor p16 and transcription factor E2F-1. In normal salivary glands, cyclin D1 and cdk-4 were not expressed in any case while p16 was positively expressed. pRb was abundant and E2F-1 moderately expressed. In tumors, cdk-4 was overexpressed in half of the cases. Most tumour cases showed decreased pRb immunoexpression compared to normal salivary glands. In contrast, expression of p16 and E2F-1 increased. pRb expression was absent in three cases of PA, two of EMC and one of CEPA. One case of MEM and one of PLGA showed no E2F-1 expression. Statistical analyses revealed positive correlations between cyclin D1 and cdk-4, cyclin D1 and E2F-1, cdk-4 and E2F-1, and p16 and E2F-1. The benign and malignant tumours expressed retinoblastoma pathway proteins differently form the normal salivary gland. Our findings suggest that, pRb pathway deregulation in salivary gland neoplasms is unrelated to their biological behaviour.
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PMID:Immunohistochemical expression of retinoblastoma pathway proteins in normal salivary glands and in salivary gland tumours. 1474 65

In order to test the hypothesis that alteration of cell cycle proteins are involved in the neuronal damage caused by human immunodeficiency virus (HIV), the authors have been studying the effect of chemokines on the CDK/Rb/E2F-1 pathway--which is involved in neuronal apoptosis and differentiation. First, they have asked whether CXCR4, the specific receptor for the chemokine SDF-1 and X4-using gp120s, can regulate Rb and E2F-1 activity in cultures of differentiated rat neurons. Although CCR3 and CCR5 are known to mediate infection of microglia by HIV-1, recent evidence indicate that CXCR4 also play important roles in HIV-induced neuronal injury, and dual-tropic isolates that use CXCR4 to infect macrophages have recently been reported. The authors have focused on two specific brain areas in which CXCR4 is physiologically relevant, i.e., the cerebellum and the hippocampus. So far, the data indicate that changes in the nuclear and cytosolic levels of Rb, which result in the functional loss of this protein, are associated with apoptosis in these neurons, and that SDF-1alpha and gp120IIIB affect this pathway. A summary of the findings are presented.
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PMID:Regulation of cell cycle proteins by chemokine receptors: A novel pathway in human immunodeficiency virus neuropathogenesis? 1498 48

The p53 tumor suppressor gene product plays an important role in the regulation of apoptosis. Transforming growth factor beta1 (TGF-beta1)-induced apoptosis in hepatic cells is associated with reduced expression of the retinoblastoma protein (pRb) and subsequent E2F-1-activated expression of apoptosis-related genes. In this study, we explored the potential role of p53 in TGF-beta1-induced apoptosis. HuH-7 human hepatoma cells were either synchronized in G1, S and G2/M phases, or treated with 1 nM TGF-beta1. The results indicated that greater than 90% of the TGF-beta1-treated cells were arrested in G1 phase of the cell cycle. This was associated with enhanced p53 dephosphorylation and p21(Cip1/Waf1) expression, which coincided with decreased Cdk2, Cdk4, and cyclin E expression, compared with synchronized G1 cells. In addition, p53 dephosphorylation coincided with caspase-3 activation, and translocation of p21(Cip1/Waf1) and p27(Kip1) into the cytoplasm, all of which were suppressed by caspase inhibition of TGF-beta1-induced apoptosis. Finally, phosphatase inhibition and pRb overexpression partially inhibited p53-mediated apoptosis. In conclusion, the results demonstrated that TGF-beta1-induced p53 dephosphorylation is associated with caspase-3 activation, and cytosolic translocation of p21(Cip1/Waf1) and p27(Kip1), resulting in decreased expression of Cdks and cyclins. Further, p53 appears to mediate TGF-beta1-induced apoptosis downstream of the pRb/E2F-1 pathway.
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PMID:p53 dephosphorylation and p21(Cip1/Waf1) translocation correlate with caspase-3 activation in TGF-beta1-induced apoptosis of HuH-7 cells. 1500 18

Cell cycle aberrations occurring at the G(1)/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1beta inhibits insulin-like growth factor (IGF)-I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this juxtamembrane cross-talk between cytokine and growth factor receptors to downstream cell cycle machinery. IL-1beta reduces the ability of IGF-I to activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not the mammalian target of rapamycin or mitogen-activated protein kinase pathways, is required for IGF-I to hyperphosphorylate retinoblastoma and to cause accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt activation and cell cycle progression, IL-1beta has no effect. IL-1beta induces p21(Cip1/Waf1), which may contribute to its inhibition of IGF-I-activated Cdk2. Collectively, these data establish a novel mechanism by which prolonged Akt phosphorylation serves as a convergent target for both IGF-I and IL-1beta; stimulation by growth factors such as IGF-I promotes G(1)-S phase progression, whereas IL-1beta antagonizes IGF-I-induced Akt phosphorylation to induce cytostasis. In this manner, Akt serves as a critical bridge that links proximal receptor signaling events to more distal cell cycle machinery.
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PMID:IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells. 1518 2

As previously demonstrated, the synthetic bile acid derivatives mediate anti-proliferative properties in a variety of human cancer cells. In the present study, the effects of the synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1030 and HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of HT-29 human colon cancer cells were investigated. Whereas UDCA and CDCA had no effect on the growth of cells in the concentration ranges we have tested, HS-1199 and HS-1200 completely inhibited cell proliferation, while HS-1030 and HS-1183 showed weak inhibitory activities. Simultaneous estimation of cell cycle parameters and apoptosis by flow cytometry showed that the synthetic bile acid derivatives produced the arrest of cell cycle progression at the G1 phase and ensuing increase of sub-G1 fraction, which resulted in the induction of apoptosis. The induction of apoptosis was confirmed by observation of cleavages of poly(ADP-ribose) polymerase and DNA fragmentation. Furthermore, Western blot analysis showed decreased expression levels of cyclin D1, cyclin E, cyclin A, Cdk2, Cdk4, and Cdk6 proteins. In addition, the synthetic bile acid derivatives markedly induced the level of Cdk inhibitor, p21WAF1/CIP1, in a p53-independent manner. Furthermore, the exposure of cells to the synthetic bile acid derivatives resulted in a decrease in the level of pRb and enhanced binding between pRb and E2F-1. Based on these data, these synthetic bile acid derivatives may serve as potential lead compounds in the treatment of colon cancer.
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PMID:Synthetic bile acid derivatives inhibit cell proliferation and induce apoptosis in HT-29 human colon cancer cells. 1520 11

Flavopiridol is the first potent inhibitor of cyclin-dependent kinases (cdks) to reach clinical trial. In the majority of solid tumor cell lines and xenografts, flavopiridol induces cell cycle arrest and tumor growth inhibition. This is reflected in clinical outcomes: across multiple Phase II trials there are subsets of patients with prolonged stable disease, although few responses have been observed. Flavopiridol displays sequence-dependent cytotoxic synergy with chemotherapy agents. These effects are most marked when chemotherapy precedes flavopiridol. In the case of DNA-damaging agents that impose S-phase delay, flavopiridol-mediated cdk inhibition disrupts the phosphorylation of E2F-1, leading to inappropriate persistence of its activity, inducing apoptotic pathways. This mechanism has been exploited in a Phase I trial of sequential gemcitabine and flavopiridol that has produced promising results. Flavopiridol is also synergistic with taxanes. Inhibition of cyclin B-cdk1 by flavopiridol accelerates exit from an abnormal mitosis associated with taxane-induced cell death and reduces the phosphorylation of survivin, preventing its stabilization and the cellular protection it affords after taxane exposure. The sequential combination of docetaxel and flavopiridol has been investigated in a Phase I trial in patients with advanced non-small cell lung cancer, and a randomized Phase II study is under way. Initial schedules of flavopiridol used prolonged continuous infusions that produced nanomolar levels of drug thought to be capable of achieving cdk inhibition based on results in tumor cell lines. Recently, it has been discovered that micromolar concentrations are likely to be more effective, and shorter infusions that achieve a higher C(max) have now been adopted. Loading followed by maintenance infusions are also under development, designed to achieve sustained micromolar drug levels. Clinical trials remain complicated by the absence of pharmacodynamic end points to confirm target inhibition.
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PMID:Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. 1521 73

Prostate cancer (PCA) is the leading cause of cancer mortality among older men in Western countries. Epidemiological studies have shown correlation between a lower risk of PCA and a higher consumption of antioxidants. However, the mechanism by which antioxidants exert their effects is still unknown. In the present study, we explored the signaling mechanism through which unique natural antioxidant derived from spinach extract (NAO) exerts their beneficial effects in the chemoprevention of PCA using human PC3 cells. Probing into the effect of NAO and its derived polyphenols on cell-cycle G1 arrest, we found that they cause cell-cycle prolongation. NAO and its two derived purified components exhibited a significant increase in the level of p21cip1 expression after 36 h of starvation, followed by 18 h of treatment with NAO in the presence of serum. In addition, under similar conditions, the expressed level of Cyclin A and CDK-2 in the PC3 cells was significantly reduced after treatment with NAO or its purified components. Immunoblot analysis demonstrated a significant increase in the hypophosphorylated form of pRb and a decrease in ppRb. NAO and its purified derived components were found to downregulate the protein expression of another member of the pRb family, p107, as well as that of E2F-1. These results suggest that NAO-induced G1 delay and cell cycle prolongation are caused by downregulation of the protein expression of ppRb and E2F in the human PCA cell line PC3.
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PMID:Unique natural antioxidants (NAOs) and derived purified components inhibit cell cycle progression by downregulation of ppRb and E2F in human PC3 prostate cancer cells. 1532 71

We have previously shown that expression of the transcription factor HES-1 is required for the growth-inhibitory effect of all-trans retinoic acid on MCF-7 cells. In this study, we have used T47D cells with tetracyclin-regulated expression of wild-type or a dominant-negative form of HES-1. Expression of HES-1 in T47D cells inhibited G1/S-phase transition and activation of Cdk2 elicited by estrogen. Estrogen treatment of T47D cells caused increased expression of E2F-1, and this expression was inhibited by cotreatment with all-trans retinoic acid. We show that the effect is mediated through HES-1, which directly downregulates E2F-1 expression through a CACGAG-site within the E2F-1 promoter. Furthermore, proliferation caused by heregulin-beta1 treatment of T47D cells was inhibited by all-trans retinoic acid and this effect was mediated by HES-1. Interestingly, heregulin-beta1-mediated upregulation of E2F-1 expression was directly inhibited by HES-1 through the same CACGAG-site as seen with estrogen-stimulated induction. In addition, we found that two important downstream target genes of estrogen and heregulin-beta1 that are regulated through E2F-1, cyclin E and NPAT, were both regulated in a similar fashion by all-trans retinoic acid, and these effects were antagonized by dominant-negative HES-1. These findings establish that HES-1 inhibits both estrogen- and heregulin-beta1-stimulated growth of breast cancer cells, and further suggest that growth inhibition induced in these cells by all-trans retinoic acid occurs via HES-1-mediated downregulation of E2F-1 expression.
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PMID:HES-1 inhibits 17beta-estradiol and heregulin-beta1-mediated upregulation of E2F-1. 1546 35

Hepatocyte growth factor (HGF) induces growth stimulation of a variety of cell types, but it also induces growth inhibition of several types of tumor cell lines. We previously investigated the intracellular signaling pathway involved in the antiproliferative effect of HGF on the human hepatocellular carcinoma cell line HepG2. The results suggested that the HGF-induced proliferation inhibition is caused by cell cycle arrest, which results from the retinoblastoma tumor suppressor gene product pRb being maintained in its active hypophosphorylated form via a high-intensity ERK signal. In this study, we examined the molecular mechanism of the HGF-induced cell cycle arrest in HepG2 cells. Cyclin A/Cdk2 complexes phosphorylated serine residues on pRb crucial for the G1 to S phase transition in proliferating HepG2 cells, and HGF treatment inhibited the phosphorylation. The expression of cyclin A was decreased and the expression of a Cdk inhibitor p21(Cip1) was increased in HGF-treated HepG2 cells, and these changes were prevented by pretreatment with a low concentration of a MEK inhibitor. These results suggest that the decrease in cyclin A expression and increase in p21(Cip1) expression through a high-intensity ERK signal by HGF lead to suppression of the phosphorylation of pRb by Cdk2, which contributes to the cell cycle arrest at G1 in HepG2 cells by HGF. Furthermore, the expression of E2F-1, a member of the E2F transcription factor family, was decreased in HGF-treated HepG2 cells, suggesting that the decrease in E2F-1 expression may also contribute to the cell cycle arrest at G1.
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PMID:Involvement of down-regulation of Cdk2 activity in hepatocyte growth factor-induced cell cycle arrest at G1 in the human hepatocellular carcinoma cell line HepG2. 1563 11


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