Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential role of caveolin-1 in apoptosis remains controversial. Here, we investigate whether caveolin-1 expression is proapoptotic or antiapoptotic using a well-defined antisense approach. We show that NIH/3T3 cells harboring antisense caveolin-1 are resistant to staurosporine-induced apoptosis, as assessed using cell morphology, DNA content, caspase 3 activation, and focal adhesion kinase cleavage. Importantly, sensitivity to apoptosis is recovered when caveolin-1 levels are restored. Conversely, recombinant stable expression of caveolin-1 in T24 bladder carcinoma cells sensitizes these cells to caspase 3 activation. Consistent with the observations using NIH/3T3 cells, downregulation of caveolin-1 in T24 cells substantially diminishes caspase 3-like activity. Loss of sensitivity to apoptotic stimulation is recovered by inhibition of the phosphatidylinositol 3-kinase pathway using LY-294002, suggesting a possible mechanism for the sensitizing effect of caveolin-1. Thus our results suggest that caveolin-1 may act as a coupling or sensitizing factor in signaling apoptotic cell death in both fibroblastic (NIH/3T3) and epithelial (T24) cells.
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PMID:Caveolin-1 expression sensitizes fibroblastic and epithelial cells to apoptotic stimulation. 1124 99

We recently demonstrated that functional inactivation of H-Ras results in significant reduction in interleukin 1 beta (IL-1 beta)-mediated effects on isolated beta cells. Since palmitoylation of Ras has been implicated in its membrane targeting, we examined the contributory roles of palmitoylation of Ras in IL-1 beta-induced nitric oxide (NO) release and subsequent activation of caspases. Preincubation of HIT-T15 or INS-1 cells with cerulenin (CER, 134 microM; 3 hr), an inhibitor of protein palmitoylation, significantly reduced (-95%) IL-1 beta-induced NO release from these cells. 2-Bromopalmitate, a structurally distinct inhibitor of protein palmitoylation, but not 2-hydroxymyristic acid, an inhibitor of protein myristoylation, also reduced (-67%) IL-1 beta-induced NO release from HIT cells. IL-induced inducible nitric oxide synthase gene expression was markedly attenuated by CER. Further, CER markedly reduced incorporation of [3H]palmitate into H-Ras and caused significant accumulation of Ras in the cytosolic fraction. CER-treatment also prevented IL-1 beta-induced activation of caspase 3 in these cells. Moreover, N-monomethyl-L-arginine, a known inhibitor of inducible nitric oxide synthase, markedly inhibited IL-induced activation of caspase 3, thus establishing a link between IL-induced NO release and caspase 3 activation. Depletion of membrane-bound cholesterol using methyl-beta-cyclodextrin, which also disrupts caveolar organization within the plasma membrane, abolished IL-1 beta-induced NO release suggesting that IL-1 beta-mediated Ras-dependent signaling in these cells involves the intermediacy of caveolae and their key constituents (e.g. caveolin-1) in isolated beta cells. Confocal light microscopic evidence indicated significant colocalization of Ras with caveolin-1. Taken together, our data provide the first evidence to indicate that palmitoylation of Ras is essential for IL-1 beta-induced cytotoxic effects on the islet beta cell.
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PMID:Novel roles for palmitoylation of Ras in IL-1 beta-induced nitric oxide release and caspase 3 activation in insulin-secreting beta cells. 1456 79

Precision-cut rat lung slices have been employed in combination with an extensive immunohistochemistry of paraffin-embedded slices for monitoring of early pathohistological changes after exposure to CdCl(2)/TGF-beta(1). Three days of CdCl(2) exposure in combination with TGF-beta(1) seem to be sufficient to induce lung injury with alterations similar to changes observed in early lung fibrogenesis: (1) extracellular matrix accumulation and myofibroblast transdifferentiation (Sirius red staining, collagen type IV, alpha-smooth muscle actin), (2) type I cell injury with loss of type I cell antigens (T1alpha antigen, aquaporin-5, RAGE), (3) increased apoptosis of pulmonary cells (active caspase-3, vimentin cleavage product V1 of caspase-9), and (4) activation of microvascular endothelial cells (podocalyxin, caveolin-1). Western blot analysis confirmed the increasing amount of alpha-smooth muscle actin, the loss of T1alpha antigen, and the increase in caveolin-1 immunoreactivity. The explant culture using CdCl(2)/TGF-beta(1) provides a suitable tool for the study of other factors involved in pulmonary pathology including transcription factors, cytokines, and other metabolites involved in early stages of fibrogenesis.
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PMID:Early signs of lung fibrosis after in vitro treatment of rat lung slices with CdCl2 and TGF-beta1. 1475 65

Although progesterone (P4) has been implicated to offer protection against ovarian cancer (OCa), little is known of its mechanism of action. The goal of this study was to identify P4-regulated genes that have anti-OCa action. Three immortalized nontumorigenic human ovarian surface epithelial (HOSE) cell lines and three OCa (OVCA) cell lines were subjected to 5 days of P4 treatment. Transcriptional profiling with a cDNA microarray containing approximately 2400 known genes was used to identify genes (1) whose expression was consistently downregulated in OVCA cell lines compared to HOSE cell lines, and (2) whose expression was restored in OCa cell lines by P4 treatment. From the candidates selected, activating transcription factor-3 (ATF-3), caveolin-1, deleted in liver cancer-1 (DLC-1), and nonmetastatic clone 23 (NM23-H2) were chosen for post hoc functional studies based on their previously reported action as tumor suppressors or apoptosis inducers. Semiquantitative RT-PCR analyses confirmed loss of or reduced transcription of these genes in OVCA cells when compared to HOSE cells and their upregulation following P4 treatment. Hormonal specificity was demonstrated by blockade experiments with a progestin antagonist RU 38486. Ectopic expression of caveolin-1, DLC-1, and NM23-H2 caused growth inhibition in OVCA cell cultures, but not in HOSE cell cultures, while forced expression of ATF-3 suppressed growth in both. Overexpression of AFT-3 also enhanced caspase-3 activity in both HOSE and OVCA cells, whereas ectopic expression of caveolin-1 and DLC-1 only activated this enzyme in OCa cells. In contrast, NM23-H2 overexpression was ineffective in activating caspase-3. Overexpression of any of the four genes in OCa cells reduced soft-agar colony formation and cell invasiveness. Taken together, we have identified four new P4-regulated, antitumor genes for OCa. However, their modes of action differ significantly; ATF-3 primarily functions as an apoptosis inducer, NM23-H2 as a suppressor of cell motility, and caveolin-1 and DLC-1 exhibiting features of classical tumor suppressors. To the best of our knowledge, except for NM23-H2, this is the first report linking P4 to the regulation of these tumor suppressor/proapoptotic genes, which could serve as future therapeutic targets.
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PMID:Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. 1567 52

1 Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, participates in the regulation of endothelial function through mechanisms that are not fully elucidated. This study examined the impact of ET-1 on oxidative stress, apoptosis and cell proliferation in human umbilical vein endothelial cells (HUVEC). HUVECs were challenged for 24 h with ET-1 (10 pM-10 nM) in the absence or presence of the ET(B) receptor antagonist BQ788 (1 microM) or the NADPH oxidase inhibitor apocynin (1 microM). Reactive oxygen species (ROS) were detected using chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated with 4',6'-diamidino-2'-phenylindoladihydrochloride staining and by the caspase-3 assay. Cell proliferation was measured by a colorimetric assay. Expression of NADPH oxidase, Akt, pAkt, Bcl-2, Bax, IkappaB, caveolin-1 and eNOS was evaluated by Western blot analysis. 2 ET-1 significantly enhanced ROS generation and cell proliferation following 24-h incubation, both of which were prevented by BQ788 or apocynin, consistent with the ability of ET-1 to directly upregulate NADPH oxidase. ET-1 itself did not affect apoptosis but attenuated homocysteine-induced apoptosis through an ET(B) receptor-mediated mechanism. Western blot analysis indicated that ET-1 alleviated homocysteine (Hcy)-induced apoptosis, likely acting by antagonizing the Hcy-induced decreases in Akt, pAkt, pAkt-to-Akt, Bcl-2-to-Bax ratios and increases in Bax and caveolin-1 expression. Furthermore, ET-1 downregulated expression of caveolin-1 and eNOS, which was attenuated by BQ788 or apocynin. 3 In summary, our results suggest that ET-1 affects oxidative stress, proliferation and apoptosis possibly through ET(B), NADPH oxidase, Akt, Bax and caveolin-1-mediated mechanisms.
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PMID:Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ETB receptor, NADPH oxidase and caveolin-1. 1576

Bradykinin is an important modulator of endothelial cell function and has also a powerful cardioprotective effect. Here we report that treatment of severely pulmonary hypertensive rats (that recapitulate several of the physiological and pathological characteristics of the human pulmonary vascular disease, including dramatic right ventricular hypertrophy, pericardial effusion and death) with a newly synthesized long-acting bradykinin B2 receptor agonist B9972 caused reduction of the pulmonary artery pressure (PAP=51+/-2.0 versus 68+/-2.8 of untreated animals) and of right ventricular hypertrophy (Rv/Lv+S=0.55+/-0.02 versus 0.73+/-0.03 of untreated rats) and activation of Akt. Long-term stimulation with B9972 in our animal model of SPH resulted in decreased expression of the B2 receptor in lung vasculature. Treatment with B9972 decreased the number of plexiform lesions in the lungs by inducing cell apoptosis in the obliterated vessels and by restoring caveolin-1 expression. B9972 also promoted eNOS activation. In vitro B9972 caused activation of caspase-3 as well as Erk and induction of prostacyclin production in rat pulmonary microvascular EC. Taken together our data suggest that a stable bradykinin B2 agonist B9972 demonstrates the capacity to reduce severe pulmonary hypertension, right ventricular hypertrophy and induce apoptosis of hyperproliferative cells in pre-capillary pulmonary arterioles.
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PMID:Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy. 1587 94

Gene expression was measured during t10c12-CLA-induced body fat reduction in a polygenic obese line of mice. Adult mice (n = 185) were allotted to a 2 x 2 factorial experiment consisting of either nonobese (ICR-control) or obese (M16-selected) mice fed a 7% fat, purified diet containing either 1% linoleic acid (LA) or 1% t10c12-CLA. Body weight (BW) by day 14 was 12% lower in CLA- compared with LA-fed mice (P < 0.0001). By day 14, t10c12-CLA reduced weights of epididymal, mesenteric, and brown adipose tissues, as a percentage of BW, in both lines by 30, 27, and 58%, respectively, and increased liver weight/BW by 34% (P < 0.0001). Total RNA was isolated and pooled (4 pools per tissue per day) from epididymal adipose (days 5 and 14) of the obese mice to analyze gene expression profiles using Agilent mouse oligo microarray slides representing > 20,000 genes. Numbers of genes differentially expressed by greater than or equal to twofold in epididymal adipose (days 5 and 14) were 29 and 125, respectively. It was concluded that, in adipose tissue, CLA increased expression of uncoupling proteins (1 and 2), carnitine palmitoyltransferase system, tumor necrosis factor-alpha (P < 0.05), and caspase-3 but decreased expression of peroxisome proliferator-activated receptor-gamma, glucose transporter-4, perilipin, caveolin-1, adiponectin, resistin, and Bcl-2 (P < 0.01). In conclusion, this experiment has revealed candidate genes that will be useful in elucidating mechanisms of adipose delipidation.
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PMID:Functional genomic characterization of delipidation elicited by trans-10, cis-12-conjugated linoleic acid (t10c12-CLA) in a polygenic obese line of mice. 1588 70

A decreased apoptotic response toward noxious stress is an issuing characteristic of the aging phenotype. Hydrogen peroxide or staurosporine induced apoptosis readily in young cells but not in senescent cells. We showed that focal adhesion kinase (FAK) expression and its phosphorylation at Tyr397, autophosphorylation site for focal adhesion formation, and Tyr577, Src-dependent phosphorylation site, were both increased in senescent cells. Moreover, FAK was inactivated proteolytically by apoptotic stimuli in young cells, but not in senescent cells. In addition, senescent cells whose FAK expression was downregulated by siRNA showed the increased level of apoptosis by staurosporine treatment via caspase-3 activation but not by hydrogen peroxide treatment. Interestingly dephosphorylation at Tyr577 of FAK by PP2 treatment, Src-family kinase inhibitor, induced the apoptosis by staurosporine in senescent cells but dephosphorylation at Tyr397 by downregulation of caveolin-1 was not affected. These data suggest that FAK might differently regulate apoptosis and focal adhesion formation through site-specific tyrosine phosphorylation in senescent cells.
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PMID:Role of Src-specific phosphorylation site on focal adhesion kinase for senescence-associated apoptosis resistance. 1652 41

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
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PMID:Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. 1669 53

The cellular functions regulated by 17beta-estradiol (E2) start after the hormone binds to its receptors (i.e., ERalpha and ERbeta). These act as ligand-dependent transcription factor transactivating target genes. In addition, E2 induces non-genomic actions, whose activation is triggered by a fraction of the ERs localized at the plasma membrane. Palmitoylation allows ERalpha to localize at the plasma membrane, to associate with caveolin-1, and, upon E2 stimulation, to activate rapid signals relevant for cell proliferation. The existence of a mechanism, which allows ERbeta localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ERbeta to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ERbeta or in HeLa cells transiently transfected with ERbeta or ERalpha expression vectors. As for ERalpha, palmitoylation is necessary for ERbeta localization at the plasma membrane and its association with caveolin-1 but, in contrast to ERalpha, the E2 binding increases ERbeta association with caveolin-1 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ERbeta-E2 complex to activate p38 impairing the receptor-dependent activation of downstream proapoptotic cascade (i.e., caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage). Consequently, palmitoylation must be considered to be a molecular device for ERbeta, which allows these receptors to interact with the plasma membrane and to regulate E2-induced non-genomic functions relevant to the anti-proliferative effect of this hormone.
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PMID:Role of ERbeta palmitoylation in the inhibition of human colon cancer cell proliferation. 1739 84


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