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

Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesions. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to induce apoptosis in a variety of tumor cell lines. To evaluate whether these agents also induce apoptosis of VSMCs, cultured rat VSMCs were treated with increasing doses of atorvastatin in the presence of FBS as a survival factor. The presence of apoptosis was evaluated by morphological criteria, annexin V binding, and DNA fragmentation and quantified as the proportion of hypodiploid cells by flow cytometry. Atorvastatin induced apoptosis in a dose-dependent manner, an effect also seen with simvastatin and lovastatin, but not with the hydrophilic drug pravastatin. The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterols was >95% and was fully reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate but not by isopentenyl adenosine, ubiquinone, or squalene, suggesting a role for prenylated proteins in the regulation of VSMC apoptosis. To further assess the role of protein prenylation, VSMCs were exposed to the prenyl transferase inhibitors perillic acid and manumycin A. Both agents induced VSMC apoptosis as evaluated by the above-mentioned criteria. Finally, VSMC treatment with lipophilic statins was associated with decreased prenylation of p21-Rho B, further supporting the role of protein prenylation inhibition in statin-induced VSMC apoptosis. The present data suggest that interference with protein prenylation by HMG-CoA reductase inhibitors or other agents may provide new strategies for the prevention of neointimal thickening.
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PMID:3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. 973 71

In addition to its inhibitory activity against viral DNA polymerases and reverse transcriptase, the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) also markedly inhibits the replicative cellular DNA polymerases alpha, delta, and epsilon. We have previously shown that PMEA is a strong inducer of differentiation in several in vitro tumor cell models and has marked antitumor potential in vivo. To elucidate the molecular mechanism of the differentiation-inducing activity of PMEA, we have now investigated the effects of the drug on cell proliferation and differentiation, cell cycle regulation, and oncogene expression in the human erythroleukemia K562 cell line. Terminal, irreversible erythroid differentiation of PMEA-treated K562 cells was evidenced by hemoglobin production, increased expression of glycophorin A on the K562 cell membrane, and induction of acetylcholinesterase activity. After exposure to PMEA, K562 cell cultures displayed a marked retardation of S-phase progression, leading to a severe perturbation of the normal cell cycle distribution pattern. Whereas no substantial changes in c-myc mRNA levels and p21, PCNA, cdc2, and CDK2 protein levels were noted in PMEA-treated K562 cells, there was a marked accumulation of cyclin A and, most strikingly, cyclins E and B1. A similar picture of cell cycle deregulation was also observed in PMEA-exposed human myeloid THP-1 cells. However, in contrast to the strong differentiation-inducing activity of PMEA in K562 cells, the drug completely failed to induce monocytic maturation of human myeloid THP-1 cells. On the contrary, THP-1 cells underwent apoptotic cell death in the presence of PMEA, as demonstrated by prelytic, intracellular DNA fragmentation and the binding of annexin V to the cell surface. We hypothesize that, depending on the nature of the tumor cell line, PMEA triggers a process of either differentiation or apoptosis by the uncoupling of normally integrated cell cycle processes through inhibition of DNA replication during the S phase.
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PMID:9-(2-Phosphonylmethoxyethyl)adenine induces tumor cell differentiation or cell death by blocking cell cycle progression through the S phase. 1039 5

Cytoplasmic caudal tags of maturing spermatids condense and are detached from the spermatidal cells just before the spermatids are released as spermatozoa. The detached cytoplasmic masses are termed "residual bodies." Features of residual bodies seem to be compatible with those of apoptosis and, just as occurs with apoptotic bodies, residual bodies are phagocytosed by Sertoli cells. Since in vitro studies have demonstrated that nucleus and cytoplasm apoptosis events can be independent phenomena, we reasoned that apoptosis pathways might be restricted to the caudal tag of the maturing spermatids in order to originate residual bodies. Consistent with this idea, here we showed that annexin V specifically bound the membranes of isolated residual bodies and that expression levels of caspase-1, c-jun, p53, and p21 were specifically increased in these cytoplasmic compartments. Electron microscopy of cytoplasmic lobes and residual bodies confirmed that their ultrastructural features were those of apoptosis. These data indicate that the mechanism responsible for the formation of residual bodies is similar to that for apoptotic bodies; and the study presents evidence, for the first time, that apoptotic signaling molecules can be restricted to a cytoplasmic compartment and proceed in the presence of a healthy nucleus.
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PMID:Apoptosis is physiologically restricted to a specialized cytoplasmic compartment in rat spermatids. 1057 1

Papillary serous endometrial carcinoma is an aggressive tumor characterized by late-stage presentation, i.p. spread, and poor prognosis. It is histologically similar to serous papillary carcinoma of the ovary. Preclinical studies have shown that adenovirus-mediated expression of p53 in ovarian cancer cell lines causes growth inhibition and apoptosis in vitro and in vivo. Such studies provide the rationale for Phase I Adp53 gene therapy clinical trials in ovarian cancer. In the present study, we compared the efficacy of adenoviral vectors containing p53 (Adp53) or p21 (Adp21) in a papillary serous endometrial tumor cell line (SPEC-2) that contains mutated p53. Growth assays revealed that both Adp53 and Adp21 were efficacious in decreasing cell proliferation as assessed by anchorage-dependent and anchorage-independent growth assays. However, as compared with Adp53, the effects of Adp21 tended to be more transient and less marked. Strikingly, Adp21, but not Adp53, induced a G1 arrest in SPEC-2 endometrial adenocarcinoma cells. In contrast, as assessed by induction of hypodiploid peaks, free DNA ends detected by a terminal deoxynucleotidyl transferase-based assay, and annexin V positivity, p53 was more effective than p21 in inducing cell death by apoptosis. Compatible with the more efficient induction of apoptosis, Adp53, but not Adp21, induced a marked increase in expression of the preapoptotic molecule BAX without a concomitant change in expression of the antiapoptotic mediator Bcl-2. The differential effects of Adp53 and Adp21 on cell cycle progression and apoptosis may be related to the reversibility of p21-induced cell cycle arrest and the irreversibility of p53-induced apoptosis. Thus, at least in the papillary serous endometrial carcinoma cell line SPEC-2, Adp53 may be more effective than Adp21 as a gene therapeutic. Nevertheless, these preclinical studies suggest that papillary serous endometrial carcinoma is a potential target for p53- or p21-mediated gene therapy.
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PMID:Adenovirus-mediated expression of p53 or p21 in a papillary serous endometrial carcinoma cell line (SPEC-2) results in both growth inhibition and apoptotic cell death: potential application of gene therapy to endometrial cancer. 1065 59

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.
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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

Inflammation is characterized by an excess of cell proliferation often leading to fibrosis and sclerosis with subsequent loss of organ function. We hypothesized that these features may be ameliorated by induction of cell cycle arrest and apoptosis as result of therapy with matrix metalloproteinase (MMP) inhibitors. In our study, mesangial cells and experimental mesangial proliferative glomerulonephritis provided the model of inflammation. First, we investigated the effect of the MMP inhibitor BB-1101 in anti-Thy1.1 nephritis. The numbers of apoptotic glomerular cells in nephritic rats increased about 4 and 6 times as a result of BB-1101 therapy, observed 11 and 14 days after induction of disease, respectively. Subsequently, rat mesangial cells were exposed to an MMP inhibitor in vitro. Fluorescence-activated cell sorter analyses of cells exposed to RO111-3456 demonstrated a dose-dependent cell cycle arrest in the G(0)/G(1) phase associated with increased expression of statin. The cell cycle arrest was followed by apoptosis as investigated by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) biotin nick-end labeling (TUNEL) and acridine orange/ethidium bromide stainings, as well as by annexin V binding. The induction of p53, p21, and bax, but not the Fas/FasL pathway appeared to play an important pathogenetic role. In summary, MMP inhibitors induce cell cycle arrest followed by apoptosis in mesangial cells. These features help to explain the anti-inflammatory effects of these compounds, such as reduction of mesangial cell proliferation and attenuation of extracellular matrix accumulation. In conclusion, induction of cell cycle arrest with subsequent apoptosis may offer new perspectives in the therapy of inflammation even beyond kidney diseases.
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PMID:Matrix metalloproteinase inhibitors cause cell cycle arrest and apoptosis in glomerular mesangial cells. 1125 28

Cyclin-dependent kinases (cdk's) have recently been suggested to regulate human immunodeficiency virus type 1 (HIV-1) transcription. Previously, we have shown that expression of one cdk inhibitor, p21/Waf1, is abrogated in HIV-1 latently infected cells. Based on this result, we investigated the transcription of HIV-1 in the presence of chemical drugs that specifically inhibited cdk activity and functionally mimicked p21/Waf1 activity. HIV-1 production in virally integrated lymphocytic and monocytic cell lines, such as ACH(2), 8E5, and U1, as well as activated peripheral blood mononuclear cells infected with syncytium-inducing (SI) or non-syncytium-inducing (NSI) HIV-1 strains, were all inhibited by Roscovitine, a purine derivative that reversibly competes for the ATP binding site present in cdk's. The decrease in viral progeny in the HIV-1-infected cells was correlated with a decrease in the transcription of HIV-1 RNAs in cells treated with Roscovitine and not with the non-cdk general cell cycle inhibitors, such as hydroxyurea (G(1)/S blocker) or nocodazole (M-phase blocker). Cyclin A- and E-associated histone H1 kinases, as well as cdk 7 and 9 activities, were all inhibited in the presence of Roscovitine. The 50% inhibitory concentration of Roscovitine on cdk's 9 and 7 was determined to be approximately 0.6 microM. Roscovitine could selectively sensitize HIV-1-infected cells to apoptosis at concentrations that did not impede the growth and proliferation of uninfected cells. Apoptosis induced by Roscovitine was found in both latent and activated infected cells, as evident by Annexin V staining and the cleavage of the PARP protein by caspase-3. More importantly, contrary to many apoptosis-inducing agents, where the apoptosis of HIV-1-infected cells accompanies production and release of infectious HIV-1 viral particles, Roscovitine treatment selectively killed HIV-1-infected cells without virion release. Collectively, our data suggest that cdk's are required for efficient HIV-1 transcription and, therefore, we propose specific cdk inhibitors as potential antiviral agents in the treatment of AIDS.
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PMID:Inhibition of human immunodeficiency virus type 1 transcription by chemical cyclin-dependent kinase inhibitors. 1146 99

The present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensitivity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the MN-1 cell line containing wild-type p53 (wt-p53) and the MDD2 line, containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to the cytotoxic effects of vinblastine and paclitaxel than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after exposure to TBA. Both cell lines arrested at G(2)/M after drug treatment. However exposure of MN1 cells to TBA resulted in a stronger variation in mitochondrial membrane potential, associated with cleavage of PARP, and more apoptosis, as measured by annexin V expression. After exposure to vinblastine, Raf 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Addition of flavopiridol to vinblastine- and paclitaxel-treated cells reversed the MDD2-resistant phenotype by inducing G(1)cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influences their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade.
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PMID:Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity. 1155 44

HPMPC (cidofovir, CDV) is an acyclic nucleoside phosphonate (ANP) with broad-spectrum activity against DNA viruses, including human papillomavirus (HPV). HPMPC has proved to be effective in the treatment of HPV-associated disease in several clinical investigations. In vitro, treatment of HPV-positive cells (compared with normal primary human keratinocytes) with HPMPC has resulted in a concentration- and time-dependent inhibition of cell proliferation. We have now evaluated the mechanism by which this compound induces cell death. Different parameters of apoptosis, that is, (i) induction of CPP32 (caspase-3) protease activity, (ii) translocation of phosphatidylserine (PS) from the inner part of the plasma membrane to the outer layer, (iii) disintegration of the nuclear matrix protein (NMP), (iv) DNA fragmentation, (v) number of cells in apoptotic phase following cell cycle analysis, showed that the mechanism of cell death following treatment with CDV is based on apoptosis. Annexin V staining showed that induction of apoptosis in HPV-positive cells was correlated with a decrease in the percentage of viable cells, while no significant changes in the percentages of living cells were noted in primary human keratinocytes (PHK) cell cultures. Furthermore, a remarkable accumulation of HPMPC-treated cells in the S phase of the cell cycle was observed. Apoptosis induction and S phase arrest were concentration and time dependent. Induction of apoptosis in HPV-positive cells by HPMPC was associated with accumulation of the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitor p21/WAF-1. As HPMPC has proved to induce apoptosis, in a time- and concentration-dependent manner, in a number of HPV-positive cell lines, the regression of papillomatous lesions observed with HPMPC in patients may be due, at least in part, to the induction of apoptosis.
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PMID:Induction of apoptosis by cidofovir in human papillomavirus (HPV)-positive cells. 1169 18

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.
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PMID:Simian immunodeficiency virus Nef protein delays the progression of CD4+ T cells through G1/S phase of the cell cycle. 1190 98


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