Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adenovirus E1A protein interferes with regulators of apoptosis and growth by physically interacting with cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein and the coactivator proteins p300/CBP (where CBP is the CREB-binding protein). The p300/CBP proteins occupy a pivotal role in regulating mitogenic signaling and apoptosis. The mechanisms by which cell cycle control genes are directly regulated by p300 remain to be determined. The cyclin D1 gene, which is overexpressed in many different tumor types, encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates PRB. In the present study E1A12S inhibited the cyclin D1 promoter via the amino-terminal p300/CBP binding domain in human choriocarcinoma JEG-3 cells. p300 induced cyclin D1 protein abundance, and p300, but not CBP, induced the cyclin D1 promoter. cyclin D1 or p300 overexpression inhibited apoptosis in JEG-3 cells. The CH3 region of p300, which was required for induction of cyclin D1, was also required for the inhibition of apoptosis. p300 activated the cyclin D1 promoter through an activator protein-1 (AP-1) site at -954 and was identified within a DNA-bound complex with c-Jun at the AP-1 site. Apoptosis rates of embryonic fibroblasts derived from mice homozygously deleted of the cyclin D1 gene (cyclin D1(-/-)) were increased compared with wild type control on several distinct matrices. p300 inhibited apoptosis in cyclin D1(+/+) fibroblasts but increased apoptosis in cyclin D1(-/-) cells. The anti-apoptotic function of cyclin D1, demonstrated by sub-G(1) analysis and annexin V staining, may contribute to its cellular transforming and cooperative oncogenic properties.
 ...
PMID:Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis. 1056 90

An inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, lovastatin, induces growth arrest and cell death in a wide variety of malignant cells in vitro. We analyzed the effect of lovastatin on myeloid leukemic cell lines. Lovastatin significantly inhibited the proliferation of 7 cell lines among 11 myeloid leukemic cell lines in a dose-dependent manner. In order to address the mechanism of antileukemic effect of lovastatin, cell cycle analysis was attempted in HL-60 cells, showing that lovastatin induced G1 arrest in HL-60 cells following 72 h of drug exposure (1.5 microM, 5 microM and 10 microM) in a dose-dependent manner. Analysis of G1 regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase (CDK) 2, CDK4, CDK6 and cyclin E were decreased after treatment with lovastatin (10 microM) in a time-dependent manner, but not cyclin D1. In addition, lovastatin increased the protein level of the cyclin-dependent kinase inhibitor (CDKI), p27, and markedly enhanced the binding of p27 with CDK2 and CDK4 more than CDK6 after 24 h exposure. At higher doses of lovastatin (50 mM, 100 mM, 200 mM), a significant apoptosis was observed as evidenced by FACS analysis with annexin V staining, which was associated with downregulation of Bcl-2 protein. These results suggest that lovastatin inhibits the proliferation of myeloid leukemic cells via G1 arrest in association with p27 induction and is an effective inducer of apoptosis in HL-60 cells.
 ...
PMID:Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest and apoptosis. 1065 2

We investigated the in vitro effect of As2O3 on proliferation, cell cycle regulation, and apoptosis in human myeloma cell lines. As2O3 significantly inhibited the proliferation of all of eight myeloma cell lines examined in a dose-dependent manner with IC50 of approximately 1-2 microM. DNA flow cytometric analysis indicated that As2O3 (2 microM) induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of As2O3, we examined the effect of As2O3 on cell cycle-related proteins in MC/CAR cells in which both G1 and G2-M phases were arrested. Western blot analysis demonstrated that treatment with As2O3 (2 microM) for 72 h did not change the steady-state levels of CDK2, CDK4, cyclin D1, cyclin E, and cyclin B1 but decreased the levels of CDK6, cdc2, and cyclin A. The mRNA and protein levels of CDKI, p21 were increased by treatment with As2O3, but those of p27 were not. In addition, As2O3 markedly enhanced the binding of p21 with CDK6, cdc2, cyclin E, and cyclin A compared with untreated control cells. Furthermore, the activity of CDK6-associated kinase was reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by the up-regulation of cdc2 phosphorylation (cdc2-Tyr15 phosphorylation) resulting from reduction of cdc25B and cdc25C phosphatases. As2O3 also induced apoptosis in MC/CAR cells as evidenced by flow cytometric detection of sub-G1 DNA content and annexin V binding assay. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondrial transmembrane potential (delta psi(m)), and an increase of caspase-3 activity. These results suggest that As2O3 inhibits the proliferation of myeloma cells, especially MC/CAR cells, via cell cycle arrest in association with induction of p21 and apoptosis.
 ...
PMID:Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. 1085 Apr 58

Past research indicated that methylseleninic acid (MSA) is an excellent tool for investigating the cancer chemopreventive action of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in the MCF10AT1 and MCF10AT3B premalignant human breast cells. After exposure to MSA, both cell lines exhibited a dose- and time-dependent growth-inhibitory response as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. Further characterization of cellular and molecular changes was carried out only with the MCF10AT1 cells. Flow cytometry analysis showed that MSA blocked cell cycle progression at the G(0)-G(1) phase. Induction of apoptosis was also observed with the use of either the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) or the annexin V binding method. cDNA microarray analyses with cell cycle- and apoptosis-targeted arrays were then applied to profile the gene expression changes mediating these two cellular events. The analyses were conducted at 6 and 12 h of MSA treatment using synchronized cells. The expression signals of 30 genes were found to be significantly altered by MSA. These genes fall into three categories: cell cycle checkpoint controllers (e.g., cyclins, cdcs, cdks, E2F family proteins, and serine/threonine kinases), apoptosis regulatory genes (e.g., Apo-3, c-jun, and cdk5/cyclin D1), and signaling molecules [e.g., mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3'-kinase (PI3k) cascade genes]. The expression changes of 15 genes were selected for verification by Western or semiquantitative reverse transcription-PCR analyses. An agreement rate of 60% (9 of 15) was obtained from these confirmation experiments. On the basis of the above findings, tentative signaling pathways mediating the outcome of selenium-induced cell cycle arrest and apoptosis are proposed. The present study thus demonstrated the feasibility of applying cDNA microarray technology in delineating the mechanisms of the action of selenium and in pinpointing molecular targets as potential biomarkers for evaluating the efficacy of selenium intervention.
 ...
PMID:Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. 1183 May 24

Human and simian immunodeficiency virus (HIV and SIV, respectively) infections are characterized by gradual depletion of CD4+ T cells. The underlying mechanisms of CD4+ T-cell depletion and HIV and SIV persistence are not fully determined. The Nef protein is expressed early in infection and is necessary for pathogenesis. Nef can cause T-cell activation and downmodulates cell surface signaling molecules. However, the effect of Nef on the cell cycle has not been well characterized. To determine the role of Nef in the cell cycle, we investigated whether the SIV Nef protein can modulate cell proliferation and apoptosis in CD4+ Jurkat T cells. We developed a CD4+ Jurkat T-cell line that stably expresses SIV Nef under the control of an inducible promoter. Alterations in cell proliferation were determined by flow cytometry using stable intracytoplasmic fluorescent dye 5- and 6-carboxyfluorescein diacetate succinimidyl ester and bromodeoxyuridine incorporation. Apoptotic cell death was measured by annexin V and propidium iodide staining. Our results demonstrated that SIV Nef inhibited Fas-induced apoptosis in these cells and that the mechanism involved upregulation of the Bcl-2 protein. SIV Nef suppressed CD4+ T-cell proliferation by inhibiting the progression of cells into S phase of the cell cycle. Suppression involved an upregulation of cyclin-dependent kinase inhibitors p21 and p27 and the downregulation of cyclin D1 and cyclin A. In summary, inhibition of apoptosis by Nef can lead to persistence of infected cells and can support viral replication. In addition, a Nef-mediated delay in cell cycle progression may contribute to CD4+ T-cell anergy/depletion seen in HIV and SIV disease.
 ...
PMID:Simian immunodeficiency virus Nef protein delays the progression of CD4+ T cells through G1/S phase of the cell cycle. 1190 98

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we investigated the antiproliferative effect of monensin on human myeloma cell lines. Monensin significantly inhibited the proliferation of myeloma cell lines examined with IC50 of about 1 micro M. Cell cycle analysis indicated that monensin induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of this drug on cell cycle-related proteins in NCI-H929 cells. Monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A, cyclin B1, cyclin D1 and cyclin E proteins but did not alter CDK4 protein. While p21 was increased by monensin, p27 was not. In addition, monensin markedly enhanced the binding of p21 with CDK6 and cdc2. Furthermore, the activities of CDK2- and CDK6-associated kinases were reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by reduction of cdc25C phosphatase. Also, monensin induced apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondria transmembrane potential (Deltapsim) and an increase of caspase-3 activity. In addition, monensin caused the up-regulation of ERK and p38 kinase activities. Taken together, these results have demonstrated for the first time that monensin potently inhibited the proliferation of human myeloma cell lines, especially NCI-H929 cells, via cell cycle arrest in association with p21 and apoptosis.
 ...
PMID:Monensin-mediated growth inhibition in NCI-H929 myeloma cells via cell cycle arrest and apoptosis. 1279 94

The receptor activator of NF-kappaB ligand (RANKL), a recently identified member of the tumor necrosis factor (TNF) superfamily, has been shown to induce osteoclastogenesis and dendritic cell survival. Most members of the TNF superfamily suppress cell proliferation and induce apoptosis, but whether RANKL does so is not known. We demonstrate that treatment of monocyte RAW 264.7 cells with RANKL induces dose-dependent growth inhibition (IC50 = 10 ng/ml) as determined by dye uptake and [3H]thymidine incorporation methods. Suppression of RANKL-induced NF-kappaB activation by dominant-negative IkappaBalpha or by the NEMO-peptide had no effect on RANKL-induced cell growth inhibition. Inhibition of RANKL-induced JNK activation, however, abolished the RANKL-induced apoptosis. Suppression of interaction of RANK with TRAF6 by TRAF6-binding peptide abrogated the anti-proliferative effects of RANKL, suggesting the critical role of TRAF6. Flow cytometric analysis of cells treated with RANKL showed accumulation of cells in G0/G1 phase of the cell cycle, and this accumulation correlated with a decline in the levels of cyclin D1, cyclin D3, and cyclin E and an increase in cyclin-dependent kinase inhibitor p27 (Kip). Flow cytometric analysis showed the presence of annexin V-positive cells in cultures treated with RANKL. RANKL-induced apoptosis was further confirmed using calcein AM/ethidium homodimer-1 dye and cleavage of poly(ADP-ribose) polymerase (PARP), procaspase 3, and procaspase 9; benzyloxycarbonyl-VAD, the pancaspase inhibitor, suppressed the PARP cleavage. Thus, overall, our studies indicate that RANKL can inhibit cell proliferation and induce apoptosis through a TRAF-6-dependent but NF-kappaB-independent mechanism.
 ...
PMID:Evidence that receptor activator of nuclear factor (NF)-kappaB ligand can suppress cell proliferation and induce apoptosis through activation of a NF-kappaB-independent and TRAF6-dependent mechanism. 1464 59

Radiolabeled annexin V may provide an early indication of the success or failure of anticancer therapy on a patient-by-patient basis as an in vivo marker of tumor cell killing. An important question that remains is when, after initiation of treatment, should annexin V imaging be performed. To address this issue, we obtained simultaneous in vivo measurements of tumor burden and uptake of radiolabeled annexin V in the syngeneic orthotopic murine BCL1 lymphoma model using in vivo bioluminescence imaging (BLI) and small animal single-photon emission computed tomography (SPECT). BCL1 cells labeled for fluorescence and bioluminescence assays (BCL1-gfp/luc) were injected into mice at a dose that leads to progressive disease within two to three weeks. Tumor response was followed by BLI and SPECT before and after treatment with a single dose of 10 mg/kg doxorubicin. Biodistribution analyses revealed a biphasic increase of annexin V uptake within the tumor-bearing tissues of mice. An early peak occurring before actual tumor cells loss was observed between 1 and 5 hr after treatment, and a second longer sustained rise from 9 to 24 hr after therapy, which heralds the onset of tumor cell loss as confirmed by BLI. Multimodality imaging revealed the temporal patterns of tumor cell loss and annexin V uptake revealing a better understanding of the timing of radiolabeled annexin V uptake for its development as a marker of therapeutic efficacy.
 ...
PMID:Multi-modality imaging identifies key times for annexin V imaging as an early predictor of therapeutic outcome. 1514 7

Glycogen synthase kinase (GSK)-3beta is a constitutively active, proline-directed serine/threonine kinase that controls growth modulation and tumorigenesis through multiple intracellular signaling pathways. How GSK-3beta regulates signaling pathways induced by cytokines such as tumor necrosis factor (TNF) is poorly understood. In this study, we used fibroblasts derived from GSK-3beta gene-deleted mice to understand the role of this kinase in TNF signaling. TNF induced NF-kappaB activation as measured by DNA binding in wild-type mouse embryonic fibroblasts, but deletion of GSK-3beta abolished this activation. This inhibition was due to suppression of IkappaBalpha kinase activation and IkappaBalpha phosphorylation, ubiquitination, and degradation. TNF-induced NF-kappaB reporter gene transcription was also suppressed in GSK-3beta gene-deleted cells. NF-kappaB activation induced by lipopolysaccharide, interleukin-1beta, or cigarette smoke condensate was completely suppressed in GSK-3beta(-/-) cells. Deletion of GSK-3beta also abolished TNF-induced c-Jun N-terminal kinase and p44/p42 mitogen-activated kinase activation. Most surprisingly, TNF-induced Akt activation also required the presence of GSK-3beta. TNF induced expression of the NF-kappaB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP 1, IAP 2, Bcl-x(L), Bfl-1/A1, TRAF1, and FLIP in wild-type mouse embryonic fibroblasts but not in GSK-3beta(-/-) cells, and this correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, annexin V staining, and caspase activation. Overall, our results indicate that GSK-3beta plays a critical role in TNF signaling and in the signaling of other inflammatory stimuli and that its suppression can be exploited as a potential target to inhibit angiogenesis, proliferation, and survival of tumor cells.
 ...
PMID:Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. 1525 41

Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.
 ...
PMID:Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. 1525 36


1 2 3 4 5 6 7 8 9 10 Next >>