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)

Retinoids are promising agents for the prevention and treatment of several human malignancies including lung cancer. In this study, the effect of retinoic acid (RA) on cell growth and the mechanism of growth modulation were examined in human lung squamous carcinoma CH27 cells. Here we report that RA mediated the dose- and time-dependent growth arrest in G1 phase, accompanied by the up-regulation of p27(Kip1) and the down-regulation of the cyclin-dependent kinase 3 (Cdk3) and p21(CIP1/Waf1) proteins. Furthermore, RA-induced growth arrest of CH27 cells was also associated with increased retinoic acid receptor beta (RARbeta) and reduced c-Myc expression. However, RA had no effect on the levels of cyclins A, D1, D3, E, or H, or on Cdk2, Cdk4, Cdk5, CDk6, Cdk7, p16(Ink4A), p15(Ink4B), p53, or pRb proteins in CH27 cells. Evaluation of the kinase activity of cyclin-Cdk complexes showed that RA increases p27(Kip1) expression in CH27 cells leading to markedly reduced cyclin A/Cdk2 kinase activity and slightly reduced cyclin E/Cdk2 kinase activity, with no effect on cyclin D/Cdk4 and cyclin D/Cdk6 activities. Moreover, coincident with the decrease in kinase activity was a drastic increase in cyclin A-bound p27(Kip1). These results suggest that increases in the levels of p27(Kip1) and its binding to cyclin A, as well as reduction of Cdk3 protein expression, are strong candidates for the cell cycle regulator that prevents the entry into the S phase in RA-treated CH27 cells, with prolongation of G1 phase and inhibition of DNA synthesis.
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PMID:Retinoic acid-mediated G1 arrest is associated with induction of p27(Kip1) and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells. 1089 83

p27(Kip1) (p27) is a member of the universal cyclin-dependent kinase inhibitor (CDKI) family and a putative tumor suppressor gene. In several tumors including lung cancer, decreased expression of p27 is associated with poor prognosis. These observations suggest a potential role for p27 as a new gene therapy target. In this study, we constructed adenovirus expressing human p27 (ad-p27) and investigated its antitumor effects on human lung cancer cell lines. Upon transduction of several human lung cancer cells with ad-p27, a high level of p27 expression, with a decrease in cdk2 and an increase in cyclin E were observed. These changes resulted in G1/S arrest. Transduction of human lung cancer cell lines with ad-p27 showed in vitro growth inhibition and a marked suppression of colony formation upon soft agar clonogenic assay. Direct intratumoral injection of ad-p27 induced the growth suppression of established lung tumors in nude mice. From these observations, gene therapy using ad-p27 seems to offer a potential basis for the development of new cancer gene therapy modality and a useful tool to investigate the mechanisms of cell cycle control.
Lung Cancer
PMID:Adenovirus expressing p27(Kip1) induces growth arrest of lung cancer cell lines and suppresses the growth of established lung cancer xenografts. 1116 93

Cyclin E is an important regulator of entry into the S phase of the cell cycle. p27/Kip1 (p27) binds to cyclin E/Cdk2 complex and negatively regulates cell proliferation. We immunohistochemically examined the expression of cyclin E and p27 in 98 cases of resected lung adenocarcinoma to evaluate the prognostic significance of cyclin E and p27. Cyclin E was expressed in 16 cases (16%), and p27 was expressed in 41 cases (42%). Using Kaplan-Meier survival analysis, patients with cyclin E positive (P=0.0017) and p27 negative (P=0.011), both individually and in combination (P<0.0001), had a worse prognosis. We also analyzed the relationship of these findings to clinicopathological parameters, which revealed that cyclin E-positive, p27-negative cases had a higher Ki67 expression (P=0.012) and a higher rate of lymph node metastasis (P=0.0078) than other groups. Our results suggested that cyclin E over expression, in association with p27 reduction in particular, may potentially be a poor prognostic factor in lung adenocarcinoma patients. However, to verify the prognostic significance of these factors, a multivariate analysis of a larger number of patients should be undertaken.
Lung Cancer 2001 Oct
PMID:High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients. 1155 14

The Myc gene family which includes c-Myc, N-Myc and L-Myc, are transcription factors that play a role in cell proliferation, apoptosis and in the development of human tumors. Myc amplification and overexpression has been detected in lung cancer of different histologic subtypes. Although the mechanism of Myc action is not yet fully understood, Myc has been proposed to play a role in growth control and cell cycle progression by stimulating and repressing the expression of key cell cycle regulators. This review will focus on the role of Myc in stimulating the G1/S transition of the cell cycle by regulating the levels and activity of cyclins, cyclin dependent kinases (cdk), cdk inhibitors and the pRb-binding transcription factor E2F. It is proposed that both the overexpression of Myc and the deregulation of the pRB/E2F pathway promotes the G1 to S transition in parallel by activating cyclinE/cdk2 complexes in lung cancer cells.
Lung Cancer 2001 Dec
PMID:Myc oncogene: a key component in cell cycle regulation and its implication for lung cancer. 1172 Jul 40

Arsenic trioxide (As(2)O(3)) has been found to induce apoptosis in leukemia cell lines and clinical remissions in patients with acute promyelocytic leukemia. In this study, we investigated the cytotoxic effect and mechanisms of action of As(2)O(3) in human tumor cell lines. As(2)O(3) caused inhibition of cell growth (IC(50) range, 3-14 microM) in a variety of human solid tumor cell lines, including four human non-small-cell lung cancer cell lines (H460, H322, H520, H661), two ovarian cancer cell lines (SK-OV-03, A2780), cervical cancer HeLa, and breast carcinoma MCF-7, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry analysis showed that As(2)O(3) treatment resulted in a time-dependent accumulation of cells in the G(2)/M phase. We observed, using Wright-Giemsa and 4',6-diamidine-2-phenylindole-dihydrochloride staining, that As(2)O(3) blocked the cell cycle in mitosis. In vitro examination revealed that As(2)O(3) markedly promoted tubulin polymerization without affecting GTP binding to beta-tubulin. Immunocytochemical and EM studies of treated MCF-7 cells showed that As(2)O(3) treatment caused changes in the cellular microtubule network and formation of polymerized microtubules. Similar to most anti-tubulin agents, As(2)O(3) treatment induced up-regulation of the cyclin B1 levels and activation of p34(cdc2)/cyclinB1 kinase, as well as Bcl-2 phosphorylation. Furthermore, activation of caspase-3 and -7 and cleavage of poly(ADP-ribose) polymerase and beta-catenin occurred only in As(2)O(3)-induced mitotic cells, not in interphase cells, suggesting that As(2)O(3)-induced mitotic arrest may be a requirement for the activation of apoptotic pathways. In addition, As(2)O(3) exhibited similar inhibitory effects against parental MCF-7, P-glycoprotein-overexpressing MCF-7/doxorubicin cells, and multidrug resistance protein (MRP)-expressing MCF-7/etoposide cells (resistance indices, 2.3 and 1.9, respectively). Similarly, As(2)O(3) had similar inhibitory effect against parental ovarian carcinoma A2780 cells and tubulin mutation paclitaxel-resistant cell lines PTx10 and PTx22 (resistance indices, 0.86 and 0.93, respectively), suggesting that its effect on tubulin polymerization and G(2)/M phase arrest is distinct from that of paclitaxel. Taken together, our data demonstrate that As(2)O(3) has a paclitaxel-like effect, markedly promotes tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. In addition, As(2)O(3) is a poor substrate for transport by P-glycoprotein and MRP, and non-cross-resistant with paclitaxel resistant cell lines due to tubulin mutation, suggesting that As(2)O(3) may be useful for treatment of human solid tumors, particularly in patients with paclitaxel resistance.
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PMID:Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. 1218 29

Genetic mechanisms underlying origin and progression of lung cancer are still poorly understood, despite the numerous studies which identified many genomic alterations. Using polymorphic microsatellites, allelic imbalances have been frequently found at loci such as 3p, 5q, 8p, 9p and 9q, 11p and 11q, and 17q without either histologic specificity or prognosis value. We report allelotyping results in 54 cases (50 smokers) of primary lung adenocarcinoma (50 men/4 women) resected at one institution. To perform this study, a panel of seven microsatellites were chosen upon their likely involvement in lung cancer or in the cell cycle. A highly sensitive method was designed using fluorescent PCR coupled with quantification on an automated DNA sequencer. We report that at least one allelic imbalance was observed in 87% of adenocarcinoma. Alterations at 17q23 tended to be associated with early stage tumors (I and II) and longer survivals (P = 0.05 and P = 0.06, respectively). Furthermore, concomitant alterations were found at 9p21 and at either 9q34 or 3p24 loci (P = 0.003 and P = 0.004, respectively). The presence of genes coding for TGF-beta receptors I and II at these loci suggests that the TGF-beta/CDK inhibitor P16/P15 signaling pathway might be involved in lung adenocarcinoma development.
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PMID:Association of genetic defects in primary resected lung adenocarcinoma revealed by targeted allelic imbalance analysis. 1235 84

The genetic components of the RB:CDK:cyclin:p16 tumor suppressor pathway undergo mutational and epigenetic alterations in a wide range of human cancers and serve as critical targets for inactivation by the transforming oncoproteins of several DNA tumor viruses. Lung cancer has been a useful model system for these studies as it was the first tumor to demonstrate an important role for RB in the genesis of a common adult malignancy and was also the first human cancer to demonstrate genetic evidence for a multi-component RB:p16 tumor suppressor pathway. Lung tumorigenesis, however, is a complex disease process that requires longstanding carcinogen exposure in order to acquire somatic alterations at many distinct genetic loci. Understanding the multifunctional properties of RB to regulate cell proliferation, differentiation, and apoptosis and how they relate to the sequential accumulation of other clonal gene defects will be essential in order to understand the specific patterns of gene inactivation observed in different subtypes of lung cancer and to fulfill the promise of 'molecular target' therapeutics.
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PMID:RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. 1236 73

Uteroglobin is a secretory protein synthesized by most epithelia, including the respiratory tract. It has strong anti-inflammatory properties that appear to be related to the inhibition of phospholipase A2. Recent experimental evidence indicates that uteroglobin has an inhibitory effect on the proliferation and invasion of cancer cells. We investigated the effects of the adenovirus-uteroglobin (ad-UG) transduction on the growth of lung cancer cell lines, which did not express the uteroglobin gene. Upon transduction of ad-UG, the rate of cell growth and the ability to produce colonies in soft agar were evaluated. Cell cycle analysis, Western blot for cell cycle-related proteins and annexin V staining for apoptosis were carried out to see if they were associated with the changes in cell growth. All the tested lung cancer cell lines did not express the uteroglobin gene. The growth rates, and colony-forming ability of transformed cells, were significantly inhibited by the induction of uteroglobin gene expression. The DNA histogram showed that the cell fraction of the G2/M phase was increased, and this G2/M phase arrest was related to a decrease of cdk1 and cyclin A. However, a fraction of apoptotic cells were same as the control. From these results, uteroglobin is thought to have an inhibitory effect on the growth of lung cancer cells. This suggests a potential role for uteroglobin in gene therapy for lung cancer.
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PMID:Inhibitory effect of adenovirus-uteroglobin transduction on the growth of lung cancer cell lines. 1267 1

Methylxantine derivative, caffeine, is known to prevent the p53-dependent apoptosis pathway via inhibition of ATM (ataxia telangiectasia mutated) kinase, which activates p53 by phosphorylation of the Ser-15 residue. In contrast, it has been reported that caffeine induces p53-mediated apoptosis through Bax protein in non-small-cell lung cancer cells. Therefore, the effects of caffeine on cellular growth in malignant cells are controversial. We investigated the effects of caffeine on cell proliferation, cell cycle progression, and induction of apoptosis in NB4 promyelocytic leukemia cells containing wild-type p53. Caffeine suppressed the cellular growth of NB4 cells in a dose- and time-dependent manner. Caffeine induced G(2)/M phase cell cycle arrest in NB4 cells in association with the induction of phosphorylation at the Ser-15 residue of p53 and induction of tyrosine phosphorylation of cdc2. Expression of Bax protein was increased in NB4 cells after treatment with caffeine. Interestingly, the antisense oligonucleotides for p53 significantly reduced p53 expression and caffeine-induced G(2)/M phase cell cycle arrest in NB4 cells. These results suggest that caffeine induces cell cycle arrest and apoptosis in association with activation of p53 by a novel pathway to phosphorylate the Ser-15 residue and induction of phosphorylation of cdc 2 in leukemic cells with normal p53.
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PMID:Caffeine induces G2/M arrest and apoptosis via a novel p53-dependent pathway in NB4 promyelocytic leukemia cells. 1281 20

In normal lung epithelial cells, cellular division is an ordered, tightly regulated process involving multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity. In contrast, neoplastic lung cells develop the ability to bypass several of these checkpoints, particularly at the G1/S and G2/M boundaries. We used genomic profiling to compare gene expression levels in early stage lung adenocarcinomas and non-neoplastic pulmonary tissue in order to comprehensively identify alterations in the process of cell cycling. RNA extracted from node negative, poorly differentiated lung adenocarcinomas (15 patients) and non-neoplastic pulmonary tissue (5 patients) was hybridized to oligonu-cleotide microarray filters containing 44,363 genes. Ontological classification was used to extract genes involved with cell cycle progression. Further analysis discovered a subset of differentially expressed genes for further study. Of the 624 cell cycle genes on the microarray filters, 40 genes were predicted to be differentially expressed in lung adeno-carcinomas. Alterations in several genes (i.e., cyclin B1, cyclin D1, p21, MDM2) are consistent with published data in the literature. We also identified 19 novel genes that have neither been described in non-small cell lung cancer (i.e., cdc2, cullin 4A, ZAC, p57, DP-1, GADD45, PISSLRE, cdc20) nor in any other tumors (i.e., cyclin F, cullin 5, p34). These results identified several potential cell cycle genes altered in lung cancer.
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PMID:Alterations in cell cycle genes in early stage lung adenocarcinoma identified by expression profiling. 1287 70


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