UNIPROT:P10415 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial cells are the initial sites of host invasion by group A Streptococcus pyogenes (GAS), and their infection of epithelial cells has been suggested to induce apoptosis. However, the mechanism responsible for bacteria-host interaction and the induction of apoptosis has not been clearly understood. We demonstrate here that human pharyngeal epithelial HEp-2 cells became apoptotic with DNA fragmentation by invasion of GAS strains JRS4 (M6+, F1+) and JRS145 (M6-, F1+ mutant of JRS4), whereas apoptotic cellular changes were not observed in SAM1 (M6+, F1- mutant) or SAM2 (M6-, F1- mutant) infected HEp-2 cells. Confocal microscopy revealed that Bax translocation to mitochondria and cytochrome c release occurred after 4 h of infection. Western blot analyses showed that the amounts of Bcl-2 and Bcl-xL were decreased in the mitochondria of infected cells. In addition, we demonstrated that the release of nuclear histone from infected cells was prevented by the addition of caspase-9 inhibitor (Ac-LEHD-CHO). We conclude that the internalization of GAS in epithelial cells is necessary and sufficient for the induction of apoptosis, which is initiated by mitochondrial dysfunction, and the mechanism of GAS-induced apoptosis is clearly different from that induced by other intracellular invasive bacteria, e.g. Shigella and Salmonella species.
...
PMID:Cytochrome c-mediated caspase-9 activation triggers apoptosis in Streptococcus pyogenes-infected epithelial cells. 1142 82

In the past ten years a wealth of fundamental knowledge delineating the molecular mechanism(s) of apoptosis has emerged, and can now be exploited to identify novel apoptotic modulators for the treatment of cancer. Two distinct yet complimentary classes of non-genotoxic agonists that can selectively kill tumor cells are discussed; agents that target 'classical' and 'atypical' apoptotic signaling pathways. The goal of agents targeting classical apoptosis and survival pathways is to directly modulate key apoptotic regulators such as Bcl-2, Akt/PKB, and p53. The aim of agents targeting atypical apoptotic pathways is to target signaling cascades whose inhibition remains non-lethal in normal cells, yet is suicidal in tumor cells. Such compounds presently under development include inhibitors of heat shock protein 90, histone deacetylases and HMG-CoA reductase. Both classes of apoptotic modulators have merit and identification of additional agonists of this nature will provide the many diverse cytotoxic agents that are required to combat the many diseases we call cancer.
...
PMID:Apoptosis modulators as cancer therapeutics. 1156 48

Growth retardation is a complication often associated with corticosteroid therapy. Corticosteroids are frequently used in the treatment of children with chronic renal failure. To examine the effects of corticosteroids on the growth plate cartilage in renal failure, selected markers of chondrocyte function and phenotype were evaluated in the proximal tibia of subtotally nephrectomized rats treated with corticosteroid. Serum parathyroid hormone (PTH), urea nitrogen, and creatinine levels were higher in the nephrectomized animals. Weight gain was less in the corticosteroid-treated animals; however, linear growth and tibial length did not differ among the groups after 10 days of corticosteroid therapy. The total width of the growth plate and the width of the proliferative zone were much smaller in corticosteroid-treated nephrectomized (Nx-MP) animals. Type II collagen mRNA expression was lower in animals treated with corticosteroids, and proliferating-cell nuclear antigen staining, histone-4, and insulin-like growth factor-1 (IGF-1)-receptor mRNA expression were further decreased in the Nx-MP group. There was an increase in TUNEL-positive cells in the corticosteroid-treated rats with normal renal function (intact-MP), associated with an increase in Bax and a decrease in Bcl-2 protein expression. In the Nx-MP group, both Bax and Bcl-2 protein staining was much less frequent, and TUNEL-positive cells were lower in number compared with the intact-MP group. Vascular endothelial growth factor expression in the hypertrophic chondrocytes was lower in corticosteroid-treated animals. There was less gelatinase B/matrix metalloproteinase-9 expression in the Nx-MP group, which was not associated with a decrease in tartrate-resistant acid phosphatase (TRAP) staining in the chondro-osseous junction. Inhibition of chondrocyte proliferation, diminishing of apoptosis, and lower angiogenic activity may contribute to the alterations in growth plate architecture and the significant reduction in growth plate width in rats with renal failure receiving corticosteroid therapy.
...
PMID:Alterations in the growth plate cartilage of rats with renal failure receiving corticosteroid therapy. 1199 6

The aim of this study was to clarify the mechanism(s) of an inhibitory effect of cerivastatin on cultured rat vascular smooth muscle cell (VSMC) growth. After being starved, cultured VSMCs were stimulated by 5% fetal bovine serum with either various concentrations of cerivastatin or 10-4 M of mevalonate. Cerivastatin dose-dependently decreased the values of [3H]-thymidine incorporation and cell numbers and the level of phosphorylated extracellular signal-regulated protein kinase 1/2. It also suppressed the level of proliferative cell nuclear antigen in a dose-dependent manner. These reductions were abolished by the addition of mevalonate. Similarly, the level of phosphorylated p38 was also decreased by cerivastatin. In contrast, cerivastatin dose-dependently activated the phosphorylation of both c-jun NH2-terminal protein kinase and activating transcription factor-2, and these activations were abolished by the addition of mevalonate. The levels of phosphorylated Akt and p70 S6 kinase as well as those of Bcl-2 were dose-dependently reduced by cerivastatin, and these reductions were abolished by the addition of mevalonate. Cerivastatin could dose-dependently elevate the levels of CPP32/caspase-3 activity and cytoplasmic histone-associated DNA fragments in VSMCs without causing cytotoxicity. These results indicate that cerivastatin suppresses cell survival and activates the apoptotic cellular signaling in VSMCs, suggesting that it could be effective for preventing the progression of restenosis after angioplasty.
...
PMID:Mechanisms of inhibitory effects of cerivastatin on rat vascular smooth muscle cell growth. 1213 57

Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.
...
PMID:Molecular sequelae of histone deacetylase inhibition in human malignant B cells. 1253 99

The human retinoic acid receptor beta (RARbeta) has three isoforms (beta1, beta2, and beta4), which play important, distinct roles in mediating the effects of retinoic acid on cell growth and apoptosis. Whereas RARbeta2 is a potent inhibitor of breast cancer cell proliferation, RARbeta4 can act as a dominant-negative repressor of RARbeta2-mediated growth suppression. In this study we investigated the effects of all-trans-retinoic acid (ATRA) on two clones derived from the breast cancer cell line MDA-MB-435: a non-metastatic clone (NM-2C5) and a metastatic clone (M-4A4). ATRA treatment of the NM-2C5 cells resulted in growth inhibition and apoptosis, whereas the M-4A4 cells were resistant to ATRA. Analyses of the expression of RARbeta isoforms revealed that the sensitive NM-2C5 clone expressed only RARbeta2, whereas the resistant M-4A4 cells expressed both RARbeta2 and RARbeta4 mRNA and protein. ATRA treatment increased RARbeta2 mRNA level in NM-2C5 cells, whereas the same treatment of the M-4A4 cells resulted in an increase in RARbeta4 and a decrease in RARbeta2 mRNA. ATRA treatment of NM-2C5 cells increased the protein levels of the histone acetyl transferases p300 and CBP, suppressed the level of histone deacetylase and increased the level of acetylated histone H4. ATRA also decreased Bcl-2 and increased Bax and decreased VEGF. In contrast, the same treatment of the M-4A4 cells resulted in opposite effects. These results suggest that the effects of ATRA on the growth of the metastatic and non-metastatic breast cancer cell lines depend on the expression of RARbeta isoforms and that the expression of RARbeta4 may contribute to metastatic properties.
...
PMID:Differential effects of retinoic acid on the growth of isogenic metastatic and non-metastatic breast cancer cell lines and their association with distinct expression of retinoic acid receptor beta isoforms 2 and 4. 1257 17

We studied effects of methylpyridinium ion (MPP(+)) on apoptosis, cell death and regulation of Bcl-2-family proteins in SH-SY5Y neuroblastoma cells. MPP(+) increased intracellular accumulation of DNA-histone complexes as a measure of apoptosis and decreased intracellular calcein fluorescence as a measure of cell death. If ATP synthesis was supported, MPP(+) caused apoptosis in rho(0) cells devoid of electron transport function. Caspase inhibition blocked apoptosis but not cell death caused by MPP(+). MPP(+) increased levels of Bax, Bcl-2 and Bcl-X(L) proteins approximately 2-fold over 24 hr, with Bax increases occurring first; Bax did not increase in rho(0) cells. The Bax increase, but not that of Bcl-2 or Bcl-X(L), was dependent on nitric oxide (NO) and seemed post-transcriptional. DAF-FM imaging revealed increased mitochondrial NO within hours of exposure to MPP(+). Western blots showed a constitutive approximately 130 kD protein that stained for NOS-2, consistent with reports of mitochondrial nitric oxide synthase (mtNOS). MPP(+) caused a NO-dependent release of cytochrome C into cytoplasm. MPP(+) increases mitochondrial NO levels and causes a NO-dependent increase in Bax protein, providing a mechanism for NOS-and Bax-dependency of MPTP neurotoxicity in vivo and implicating locally produced NO as a signaling molecule used by mitochondria to manipulate cell death cascades.
...
PMID:Interactions among nitric oxide and Bcl-family proteins after MPP+ exposure of SH-SY5Y neural cells I: MPP+ increases mitochondrial NO and Bax protein. 1264 81

Depsipeptide is in clinical trials for chronic lymphocytic leukemia (CLL) on the basis of earlier observations demonstrating selective in vitro activity in CLL. We sought to determine the relationship of histone H3 and H4 acetylation, inhibition of histone deacetylase, and apoptosis observed in CLL cells to justify a pharmacodynamic end point in these clinical trials. We demonstrate that in vitro depsipeptide induces histone H3 and H4 acetylation and histone deacetylase enzyme inhibition at concentrations corresponding to the LC50 (concentration producing 50% cell death) for cultured CLL cells (0.038 microM depsipeptide). The changes in histone acetylation are lysine specific, involving H4 K5, H4 K12, and H3 K9, and to a lesser extent H4 K8, but not H4 K16 or H3 K14. Depsipeptide-induced apoptosis is caspase dependent, selectively involving the tumor necrosis factor (TNF) receptor (extrinsic pathway) initiating caspase 8 and effector caspase 3. Activation of caspase 8 was accompanied by the down-regulation of cellular FLICE-inhibitory protein (c-FLIP, I-FLICE) without evidence of Fas (CD95) up-regulation. Changes in other apoptotic proteins, including Bcl-2, Bax, Mcl-1, and X-linked inhibitor of apoptosis (XIAP), were not observed. Our results demonstrate a relationship between target enzyme inhibition of histone deacetylase, histone H3 and H4 acetylation, and apoptosis involving the TNF-receptor pathway of apoptosis that is not used by other therapeutic agents in CLL. These data suggest use of histone H3 and H4 acetylation, inhibition of histone deacetylase, and down-regulation of FLIP as pharmacodynamic end points for further evaluation of this drug in patients.
...
PMID:Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. 1264 37

Hepatic stellate cells (HSCs) play a central role in the development of hepatic fibrosis. Recent evidence has revealed that HSCs also play a role in its resolution, where HSC apoptosis was determined. Moreover, induction of HSC apoptosis caused a reduction of experimental hepatic fibrosis in rats. Thus knowing the mechanism of HSC apoptosis might be important to clarify the pathophysiology and establish the therapeutic strategy for hepatic fibrosis. In HSCs, Rho and Rho kinase are known to regulate contraction, migration, and proliferation with modulation of cell morphology. Controversy exists as to the participation of Rho and Rho kinase on cell survival, and little is known regarding this matter in HSCs. In this study, we directed our focus on the role of the Rho pathway in the regulation of HSC survival. C3, an inhibitor of Rho, increased histone-associated DNA fragmentation and caspase 3 activity with enhanced condensation of nuclear chromatin in rat cultured HSCs. Moreover, Y-27632, an inhibitor of Rho kinase, had the same effects, suggesting that inhibition of the Rho/Rho kinase pathway causes HSC apoptosis. On the other hand, lysophosphatidic acid, which stimulates the Rho/Rho kinase pathway, decreased histone-associated DNA fragmentation in HSCs. Inhibition of the Rho/Rho kinase pathway did not affect p53, Bcl-2, or Bax levels in HSCs. Thus we concluded that the Rho/Rho kinase pathway may play a role in the regulation of HSC survival.
...
PMID:Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. 1282 36

Chronic graft-versus-host disease (cGVHD) is a severe and frequent complication of allogenic bone marrow transplantation which is often treated with extracorporeal photochemotherapy (ECP) with a positive clinical outcome in patients resistant to conventional protocols. The mechanism of action of ECP has not been fully elucidated, although several authors have reported that it is able to induce apoptosis. Using samples obtained from ten cGVHD patients, we sought to determine whether lymphocytes treated with ECP underwent apoptosis and, above all, the mechanisms involved. Lymphocytes at four stages were isolated: immediately before ECP, from the last buffy coat collected, after UV irradiation prior to reinfusion, and the day after ECP. When cultured for 48 h, lymphocytes treated with ECP underwent accelerated apoptosis (tested as annexin V binding cells and as intracellular histone-associated DNA fragments) in comparison with lymphocytes from the other samples. This enhanced programmed cell death could not be prevented by IL-2. Immediately after isolation, there was no difference in Bcl-2 or bax expression among the four different samples, or in Fas and FasL mRNA. However, when cultured, lymphocytes treated with ECP showed a rapid downregulation of Bcl-2, an upregulation of bax with an increased bax/Bcl-2 ratio, a decrease in bcl-2 mRNA and an increase in Fas. No changes were detectable in lymphocytes from the other samples. IL-2 and TNF-alpha production was not significantly different among lymphocytes from the four samples. In conclusion, in patients affected by cGVHD, ECP induced apoptosis of lymphocytes with the involvement of both the Fas/FasL system and the Bcl-2 protein family.
...
PMID:ECP-treated lymphocytes of chronic graft-versus-host disease patients undergo apoptosis which involves both the Fas/FasL system and the Bcl-2 protein family. 1288 27

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