Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have presently determined the effect of inhibition of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) on the occurrence of apoptosis in insulin-producing cells. The ADP-ribosylation activities of intact cells were decreased by incubation of RINm5F cells for 16 h with the PARP inhibitors nicotinamide (NA) (20-50 mM) or 3-aminobenzamide (3-ABA) (10 mM). Exposure to 20-50 mM NA or 10 mM 3-ABA both resulted in massive apoptosis in RINm5F cells. A 24 h exposure to 50 mM nicotinamide induced apoptosis in fetal but not adult rat islet cells. In addition, exposure of RINm5F cells to 50 mM NA for 12-24 h induced the appearance of the 85 kDa proteolytic PARP fragment, indicating activation of the ICE-like protease caspase-3. Incubation with 20-50 mM NA did not induce any consistent effects upon transcription factor NF-kappaB activity, demonstrating that this pathway is not involved in induction of apoptosis by NA. It is concluded that in insulin-producing cells with a high mitotic rate, inhibition of ADP-ribosylation--and consequently of auto-modification and release of PARP bound to DNA strand breaks--leads to activation of programmed cell death.
Mol Cell Endocrinol 1998 Apr 30
PMID:Nicotinamide-induced apoptosis in insulin producing cells is associated with cleavage of poly(ADP-ribose) polymerase. 970 78

The requirement for caspases (ICE-like proteases) were investigated in mediating apoptosis of WEHI7.2 mouse lymphoma cells in response to two death inducers with different mechanisms of action, the glucocorticoid hormone dexamethasone (DX) and the calcium-ATPase inhibitor thapsigargin (TG). Apoptosis induction by these agents followed different kinetics, and was closely correlated with in vivo activation of caspase-3 (CPP32/Yama/Apopain) and cleavage of the caspase target protein poly(ADP-ribose) polymerase (PARP). Caspase activation and PARP cleavage were inhibited by Bcl-2 overexpression. Cell extracts from DX- and TG-treated cells cleaved the in vitro synthesized baculovirus p35 ICE-like protease target, producing 25 and 10 kDa fragments. p35 cleavage was inhibited by mutating the active site aspartic acid to alanine, and by a panel of protease inhibitors that inhibit caspase-3-like proteases, including iodoacetamide, N-ethylmaleimide, and Ac-DEVD-cho. Treatment of cells in vivo with two cell permeant peptide fluoromethylketone inhibitors of caspase activity, Z-VAD-fmk and Z-DEVD-fmk, inhibited DX- and TG-induced apoptotic nuclear changes and maintained plasma membrane integrity, whereas the cathepsin inhibitor, Z-FA-fmk, and two calpain inhibitors failed to inhibit apoptosis. An unexpected observation was that due to the delayed time course of DX-induced apoptosis, optimal preservation of plasma membrane integrity was achieved by adding caspase inhibitors beginning 8 h after DX addition. In summary, the findings indicate that two diverse apoptosis-inducing signals converge into a common Bcl-2-regulated pathway that leads to caspase activation and apoptosis.
Mol Cell Endocrinol 1998 Apr 30
PMID:Apoptosis induction by the glucocorticoid hormone dexamethasone and the calcium-ATPase inhibitor thapsigargin involves Bc1-2 regulated caspase activation. 970 90

Mice exposed to 100% O2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.
Am J Respir Cell Mol Biol 1998 Oct
PMID:Oxygen toxicity in mouse lung: pathways to cell death. 976 53

Apoptosis, the process of programmed cell death, involves activation of caspase proteases cascade that remains under the regulatory control of nitric oxide. In this study, we investigated the activity of a key apoptotic protease, caspase-3, and the expression of nitric oxide synthase-2 (NOS-2) associated with buccal epithelial cells apoptosis induced by chronic ethanol diet. The assays revealed that a 7.9-fold enhancement in buccal epithelial cells apoptosis, observed in the alcohol diet group, was accompanied by a 37.6-fold increase in caspase-3 activity and a 10.1-fold increase in NOS-2. Furthermore, the expression of NOS-2 showed a positive correlation (r = 0.92) with the extent of changes induced in caspase-3 activity. These results implicate caspase-3 in the process of alcohol-induced epithelial cells apoptosis, and point towards participation of NOS-2 in the amplification of the cell death signaling cascade.
Biochem Mol Biol Int 1998 Sep
PMID:Activation of apoptotic caspase-3 and nitric oxide synthase-2 in buccal mucosa with chronic alcohol ingestion. 976 19

The exact mechanisms of action of antiresorptive bisphosphonate drugs remain unclear, although they may inhibit bone resorption by mechanisms that can lead to osteoclast apoptosis. These drugs also cause apoptosis in J774 macrophages, probably as a consequence of inhibition of protein prenylation. However, the molecular pathways that lead to apoptosis are not known. In some cells, apoptosis induced by statins (other inhibitors of protein prenylation) is dependent on protein synthesis. The aim of this study was to further characterize the kinetics and biochemical features of bisphosphonate-induced apoptosis, including the dependence on protein synthesis. Alendronate-induced apoptosis in J774 cells occurred after approximately 16 hr of treatment, although shorter exposures to the drug followed by incubation in bisphosphonate-free medium also committed cells to apoptosis. The appearance of apoptotic cells was associated with the appearance of caspase-3-like activity. Apoptosis induced by bisphosphonate or mevastatin was found to be dependent on protein synthesis because cycloheximide inhibited chromatin condensation, DNA fragmentation and activation of caspase-3-like protease or proteases. Protein synthesis was required for events that lead to commitment to apoptosis but not for the execution phase because cycloheximide did not prevent apoptosis when added >/=15 hr after the start of alendronate treatment. Furthermore, staurosporine-induced caspase-3-like activity and apoptosis in J774 cells could not be prevented by cycloheximide. These observations demonstrate that activation of caspase-3-like proteases and inhibition of commitment to apoptosis by cycloheximide are common features of apoptotic cell death induced by inhibitors of protein prenylation such as bisphosphonates.
Mol Pharmacol 1998 Oct
PMID:Protein synthesis is required for caspase activation and induction of apoptosis by bisphosphonate drugs. 976 5

The caspases have been shown to be key components of programmed cell death (PCD) in various cell types, including neurons. Caspase-3 (CPP32) is the predominant caspase that appears to be involved in cell death in several systems. In embryonic motoneuron cultures, caspase-3 activity increases beginning at 20 h following deprivation of trophic support, as determined by the cleavage of its specific substrates. Inhibition of caspase-3 by peptide inhibitors prevents the PCD of motoneurons following trophic factor deprivation in vitro, as well as in vivo. We also investigated the cleavage of poly(ADP-ribose) polymerase (PARP) in motoneurons after trophic factor withdrawal. No PARP cleavage was detected in either viable or dying cells. These data suggest that some components of the cell death machinery such as the involvement of caspases may be conserved in different cell types undergoing PCD, whereas the activation and specific substrates of the caspases may differ from one cell type to another.
Mol Cell Neurosci 1998 Oct
PMID:Involvement of specific caspases in motoneuron cell death in vivo and in vitro following trophic factor deprivation. 979 Jul 36

Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 microM TSA and 1-10 mM butyrate for 1-2 days. Both of these inhibitors induced a prominent neuronal apoptosis characterized by morphological changes as well as by the activation of caspase-3 protease and subsequent cleavage of poly(ADP-ribose) polymerase, one of the caspase-3 targets. Caspase-3 activities reached the highest level on the second day after treatment, higher in the proliferating neuroblastoma cells than in the cerebellar granule neurons. Caspase-3 activation and morphological changes were prevented by cycloheximide treatment. Histone deacetylase inhibitors increased the DNA-binding activities of AP1, CREB and NF-kappaB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells.
Brain Res Mol Brain Res 1998 Oct 30
PMID:Neuronal apoptosis induced by histone deacetylase inhibitors. 979 19

Treatment of human neuroblastoma SH-SY5Y cells with 1 mM 1-methyl-4-phenylpyridinium (MPP+) for 3 days induced production of reactive oxygen species (ROS), followed by caspase-3 activation, cleavage of poly(ADP-ribose) polymerase (PARP), and apoptotic cell death with DNA fragmentation and characteristic morphological changes (condensed chromatin and fragmented nuclei). Simultaneous treatment with 1 mM talipexole slightly inhibited the MPP+-induced ROS production and apoptotic cell death. In contrast, pretreatment with 1 mM talipexole for 4 days markedly protected the cells against MPP+-induced apoptosis. However, this protective effect might not be mediated by dopamine receptors. The talipexole pretreatment induced an increase in antiapoptotic Bcl-2 protein level but had no effect on levels of proapoptotic Bax, Bak, and Bad. It also inhibited MPP+-induced ROS production, p53 expression, and cleavages of caspase-3 and PARP. Similarly, pramipexole pretreatment increased Bcl-2 and inhibited MPP+-induced apoptosis. Although pretreatment with bromocriptine also had a protective effect against MPP+-induced apoptosis, it had no effect on the protein levels of Bcl-2 family members. On the other hand, N6,2'-O-dibutyryl cAMP or calphostin C induced a decreased Bcl-2 level and enhanced MPP+-induced cell death. These results suggest that talipexole has dual actions: (1) it directly scavenges ROS, affording slight protection against MPP+-induced apoptosis, and (2) it induces Bcl-2 expression, thereby affording more potent protection, if it is administrated before MPP+. Pramipexole has similar effects, whereas bromocriptine seems to exhibit the former but not the latter effect.
Mol Pharmacol 1998 Dec
PMID:Protective effects of the antiparkinsonian drugs talipexole and pramipexole against 1-methyl-4-phenylpyridinium-induced apoptotic death in human neuroblastoma SH-SY5Y cells. 985 33

The mechanism by which radiation induces human peripheral T cell apoptosis is not known. We examined sequential changes in post-irradiated peripheral blood mononuclear cells (PBMC(S)) taken from normal volunteers, by using flow-cytometer and an anti-CD3 monoclonal antibody, annexin V, propidium iodide, anti-Fas antibody, and anti-Fas ligand antibody. After 5 or 10 Gy of irradiation with a 60Co radiation therapy unit, most of the human peripheral T cells showed positivity against annexin V in 15 h, and positivity against propidium iodide in 23 h after irradiation. On a microscopy-video system, approximately 80% of mononuclear cells revealed apoptotic changes in 24 h after irradiation. Because of its proposed role in activation-induced cytotoxicity, we also examined the Fas (CD95/Apo-1) pathway in killing T cells by irradiation. Irradiated PBMC, displayed no increase in surface Fas expression and caspase-3 activity relative to non-irradiated cells. In addition, the anti-Fas ligand failed to eliminate the apoptotic death of PBMC, after irradiation. These results suggest that irradiation induces direct apoptosis of T cells by a Fas-independent mechanism.
Int J Mol Med 1998 Oct
PMID:Radiation kills human peripheral T cells by a Fas-independent mechanism. 985 24

A molecular structural relationship of thyroid hormones to methyl-3,5-diiodo-4-(4'-methoxy-phenoxy) benzoate (DIME) and 1-[3,5-diiodo-4-(4'-methoxyphenoxy)-phenyl]-ethanone) (DIPE) and to apoptosis-mediated metamorphogenic mechanisms is postulated. DIME disrupts microtubule assembly already in anaphase, preparing cells for G2/M block, chromosome aggregation and caspase-3 mediated apoptosis. Cooperative action of DIME and vincristine, defining mutually exclusive cellular sites, identifies microtubules as primary drug targets followed by downstream cellular consequences, leading to cell death. Absence of in vivo toxicity of DIME appears to be related to impermeability to DIME of normal cells, but not of tumor cells in vivo. Normal tissue cells hydrolyze DIME but most tumor cells, except lung cancer cells, do not. DIPE, being resistant to enzymatic hydrolysis, is equally effective in all tumor cells.
Int J Mol Med 1998 Nov
PMID:Molecular pharmacology of methyl-3,5-diiodo-4 (4'methoxyphenoxy) benzoate (DIME) and its non-hydrolyzible ethanone analog (DIPE) (Review). 985 56


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