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)

Mcl-1 (myeloid cell leukaemia-1) is a Bcl-2 family member with short-term pro-survival functions but whose other functions, demonstrated by embryonic lethality of knockout mice, do not involve apoptosis. In the present study, we show a cell-cycle-regulatory role of Mcl-1 involving a shortened form of the Mcl-1 polypeptide, primarily localized to the nucleus, which we call snMcl-1. snMcl-1 interacts with the cell-cycle-regulatory protein Cdk1 (cyclin-dependent kinase 1; also known as cdc2) in the nucleus, and Cdk1 bound to snMcl-1 was found to have a lower kinase activity. The interaction with Cdk1 occurs in the absence of its cyclin partners and is enhanced on treatment of cells with G2/M blocking agents, but not by G1/S blocking. The snMcl-1 polypeptide is present during S and G2 phases and is negligible in G1. Overexpression of human Mcl-1 in a murine myeloid progenitor cell line resulted in a lower rate of proliferation. Furthermore, Mcl-1-overexpressing cells had lower total Cdk1 kinase activity compared with parental cells, in both anti-Cdk1 and anti-cyclin B1 immunoprecipitates. The latter results suggest that binding to snMcl-1 alters the ability of Cdk1 to bind its conventional partner, cyclin B1. Given the important role of Cdk1 in progression through G2 and M phases, it is probable that the inhibition of Cdk1 activity accounts for the inhibitory effect of Mcl-1 on cell growth.
 ...
PMID:A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth by interaction with Cdk1. 1555 78

In diabetes, peripheral nerves suffer deficient neurotrophic support-a situation which resembles axotomy. This raises the question: does inappropriate establishment of an axotomised neuronal phenotype contribute to diabetic neuropathy, and in extremis, does this provoke apoptosis? We hybridized reverse-transcribed RNA, from the dorsal root ganglia (DRG) of 8-week streptozotocin (STZ)-induced diabetic rats, to Affymetrix Rat Genome U34A chips and scanned the array for expression of (a) genes that are upregulated by axotomy, (b) proapoptotic and (c) anti-apoptotic genes. Expression of the axotomy-responsive genes coding for growth-associated protein 43 (GAP-43), galanin, neuropeptide Y (NPY), pre-pro-vasoactive intestinal polypeptide (pre-pro-VIP), neuronal nitric oxide synthase (nNOS), protease nexin 1, heat-shock protein 27 (HSP 27) and myosin light chain kinase II (MLCK II) was unaffected in ganglia from diabetic rats compared to controls; thus, no axotomised phenotype was established. The expression of the majority of proapoptotic genes in the DRG was also unaltered (bax, bad, bid, bok, c-Jun, p38, TNFR1, caspase 3 and NOS2). Similarly there was no change in expression of the majority of antiapoptotic genes (bcl2, bcl-xL, bcl-w, NfkappaB). These alterations in gene expression make it clear that neither axotomy nor apoptotic phenotypes are established in neurones in this model of diabetes.
 ...
PMID:Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes. 1558 61

An Escherichia coli plasmid vector for the high-level expression of hydrophobic membrane proteins is described. The plasmid, pBCL, directs the expression of a target polypeptide fused to the C terminus of a mutant form of the anti-apoptotic Bcl-2 family protein, Bcl-XL, where the hydrophobic C terminus has been deleted, and Met residues have been mutated to Leu to facilitate CNBr cleavage after a single Met inserted at the beginning of the target sequence. Fusion protein expression is in inclusion bodies, simplifying the protein purification steps. Here we report the high-level production of PLM, a membrane protein that is a member of the FXYD family of tissue-specific and physiological-state-specific auxiliary subunits of the Na,K-ATPase, expressed abundantly in heart and skeletal muscle. We demonstrate that milligram quantities of pure, isotopically labeled protein can be obtained easily and in little time with this system.
 ...
PMID:Bcl-XL as a fusion protein for the high-level expression of membrane-associated proteins. 1574 45

N-glycosylation in the endoplasmic reticulum is an essential protein modification and highly conserved in evolution from yeast to man. Defects of N-glycosylation in humans lead to congenital disorders. The pivotal step of this pathway is the transfer of the evolutionarily conserved lipid-linked core-oligosaccharide to the nascent polypeptide chain, catalysed by the oligosaccharyltransferase. One of its nine subunits, Ost2, has homology to DAD1, originally characterized in hamster cells as a defender against apoptotic death. Here we show that ost mutants, such as ost2 and wbp1-1, display morphological and biochemical features of apoptosis upon induction of the glycosylation defect. We observe nuclear condensation, DNA fragmentation as well as externalization of phosphatidylserine. We also demonstrate induction of caspase-like activity, both determined by flow cytometric analysis and in cell-free extracts. Similarly, the N-glycosylation inhibitor tunicamycin in combination with elevated temperature is able to challenge the apoptotic cascade. Heterologous expression of anti-apoptotic human Bcl-2 diminishes caspase activation, improves survival of cells and suppresses the temperature-sensitive growth defect of wbp1-1. Furthermore, accumulation of reactive oxygen species occurs in response to defective glycosylation. As deletion of the metacaspase YCA1 does not seem to abrogate glycosylation-induced apoptosis, we postulate a different proteolytic process to be involved in this death pathway.
 ...
PMID:Defects in N-glycosylation induce apoptosis in yeast. 1642 Mar 50

Cardiotoxin III (CTX III) is a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom. This is the first report on the mechanism of the anticancer effect of CTX III in human colorectal cancer Colo205 cells. 2. Cardiotoxin III-induced Colo205 cell apoptosis was confirmed by DNA fragmentation (DNA ladder and sub-G1 formation) with an IC(50) of 4 mg/mL at 48 h. 3. Further mechanistic analysis demonstrate that CTX III induced the loss of mitochondrial membrane potential (Dym), cytochrome c release from mitochondria into the cytosol and activation of capase-9, caspase 3, as well as markedly enhancing the expression of Bax, but not Bcl-2, protein in the cells. Moreover, the CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. 4. However, CTX III did not generate the formation of reactive oxygen species and anti-oxidants, including N-acetylcysteine, and catalase could not block CTX III-induced apoptosis in the Colo205 cells. 5. Taken together, these results suggest that CTX III may induce apoptosis through a mitochondrial- and caspase-dependent mechanism and alteration of Bax/Bcl-2 ratio in human colorectal Colo205 cancer cells.
 ...
PMID:Mechanisms of cardiotoxin lll-induced apoptosis in human colorectal cancer colo205 cells. 1648 59

Previously, we reported that SV40 T/t-common polypeptide, which contains the NH(2)-terminal common domain of SV40 large T and small t antigens, can repress HER2/neu (also known as erbB-2) expression and consequently suppress the tumorigenic potential of the HER2/neu-overexpressing ovarian carcinoma cells. Here we report that T/t-common could specifically induce apoptosis in HER2/neu-overexpressing human cancer cell lines but not in nontransformed cell lines and HER2/neu low-expressing human cancer cell lines. The ability of T/t-common to induce apoptosis in HER2/neu-overexpressing cancer cells was derived from its ability to inhibit HER2/neu because reexpression of a large amount of HER2/neu could block apoptosis induced by T/t-common. T/t-common expression in HER2/neu-overexpressing SK-OV-3 cancer cells led to down-regulation of Bcl-2 and Bcl-X(L), and overexpression of Bcl-2 could inhibit the ability of T/t-common to induce apoptosis in these cells. Therefore, the apoptosis-inducing activity of T/t-common is related to its ability to inhibit Bcl-2 expression in HER2/neu-overexpressing cancer cells. Consistent with the apoptosis-inducing activity of T/t-common, we found that T/t-common could specifically inhibit the soft-agarose colony-forming ability of the HER2/neu-overexpressing human cancer cell lines but not that of the HER2/neu low-expressing human cancer cell lines. Finally, we showed that T/t-common could specifically sensitize HER2/neu-overexpressing human cancer cell lines, but not HER2/neu low-expressing human cancer cell lines, to chemotherapeutic agent etoposide. Together, these data suggest that T/t-common alone or in combination with chemotherapy may provide a new approach for treatment of cancers that overexpress HER2/neu.
 ...
PMID:SV40 T/t-common polypeptide specifically induces apoptosis in human cancer cells that overexpress HER2/neu. 1674 Jul 24

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III-induced K562 cell apoptosis was confirmed by DNA fragmentation (DNA ladder, sub-G1 formation) and phosphatidylserine (PS) externalization with an IC(50) value of 1.7 microg/ml at 48 h. A mechanistic analysis demonstrated that CTX III-induced apoptotic cell death was accompanied by up-regulation of both Bax and endonuclease G (Endo G), and downregulation of Bcl-X(L). CTX III had no effect on the levels of Bcl-2, Bid, XIAP survivin, and AIF proteins. CTX III treatment caused loss of the mitochondrial membrane potential (DeltaPsim), release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and -3. CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK. However, CTX III did not generate reactive oxygen species (ROS) and antioxidants, including N-acetylcysteine and catalase, did not block CTX III-induced apoptosis in K562 cells. Modulation of Bax, Bcl-XL, and the Endo G proteins, release of mitochondrial cytochome c, and activation of caspase-3 and -9 all are involved in the CTX III-triggered apoptotic process in human leukemia K562 cells.
 ...
PMID:Up-regulation of Bax and endonuclease G, and down-modulation of Bcl-XL involved in cardiotoxin III-induced apoptosis in K562 cells. 1695 23

In this work we have studied how dietary fat affects aging-related changes in a number of factors that regulate rat hepatic apoptosis. Animals were fed lifelong with two experimental diets containing either virgin olive oil or sunflower oil as dietary fat. Caspases of the intrinsic and extrinsic pathways of apoptosis, Bcl-2 and Bax polypeptide levels, and plasma membrane neutral sphingomyelinase activity were determined at 6, 12, and 24 months of age. Caspase-8/10 activity (a marker of the extrinsic pathway) was not affected by either aging or dietary fat, but activities of both caspase-9 (a marker of the intrinsic pathway) and caspase-3 (an executioner caspase) were significantly depressed in liver from animals fed on a sunflower oil-based diet. These decreases were not observed in animals fed with a diet based on virgin olive oil, which also resulted in significantly lower Bcl-2/Bax ratios. On the other hand, in comparison with sunflower, dietary olive oil decreased oxidative stress in liver from aged rats, resulting in lower levels of membrane hydroperoxides and higher coenzyme Q levels in plasma membrane. Plasma membrane Mg(2+)-dependent neutral sphingomyelinase was strongly activated in aged rats fed on the sunflower oil diet, but no aging-related increase was observed in animals fed on the olive oil diet. Our results support that dietary oil can alter significantly the susceptibility of hepatocytes to different apoptotic stimuli by altering both pro- and anti-apoptotic mediators, which reinforces the importance of the diet in aging studies. Because virgin olive oil may increase susceptibility of hepatocytes to apoptosis induced through the intrinsic pathway under conditions of decreased oxidative stress, our results may have important implications to understand the potential beneficial effects of that edible oil against liver carcinogenesis during aging.
 ...
PMID:Differential regulation of hepatic apoptotic pathways by dietary olive and sunflower oils in the aging rat. 1704 86

HGF is a multifunctional polypeptide with mitogenic, motogenic and morphogenic effects. These effects are mediated by c-met, a specific receptor of HGF and a member of the receptor tyrosine kinase superfamily, virtually expressed in every type of kidney cell. HGF has a central role during embryogenesis since it stimulates epithelial differentiation of metanephric mesenchymal cells and induces branching tubules, as experiments in epithelial cells cultures demonstrated. Several studies have shown also that HGF accelerates the recovery from toxic-ischemic acute renal failure. This effect seems to be mediated by the inhibition of programmed cell death and an increased cell survival. HGF inhibits apoptosis by upregulating the protooncogene Bcl-2 and downregulating Bax. Since HGF can modulate extracellular matrix turnover, authors suggest its beneficial role in tissue remodelling and particularly in chronic renal diseases. Several studies reported a key role for HGF in reducing interstitial fibrosis and glomerular sclerosis, both in in vivo and in vitro models. This protective effect is secondary to HGF antagonizing the profibrotic action of TGF-beta. HGF modulates the balance between synthesis and degradation of extracellular matrix, increasing the expression of metalloproteases and reducing the production of their specific inhibitors TIMPs. Furthermore HGF suppresses the effect of TGF-beta by blocking the axis TGF-beta/Smad. Last, the antifibrotic effect of HGF might be modulated by the proliferative status of target cells. To sum up, the supplementation of exogenous HGF or the induction of endogenous HGF expression may provide an effective therapeutic strategy for combating chronic renal diseases.
 ...
PMID:[Hepatocyte growth factor and kidney]. 1706 38

We examined in vitro sensitivity of B-CLL cells exposed to cladribine, mafosfamide, mitoxantrone and combinations ofcladribine with mafosfamide and/or mitoxantrone. The results revealed that each applied treatment of leukemic cells, besides having a cytotoxic effect, affected the events associated with apoptosis. All drugs used alone, and cladribine combinations with mafosfamide and/or mitoxantrone induced DNA fragmentation and the changes in expression/proteolysis level of caspase-3, caspase-9 precursors, PARP-1, lamin B, Bax and Bcl-2; however, each to a different degree. The exposure of leukemic cells to both cladribine combinations induced stronger effects. Moreover, the data showed that the expression of regulatory antiapoptotic protein Bcl-2 generally decreased in drug-treated B-CLL cells, whereas proapoptotic polypeptide Bax increased, resulting in enhancement of Bax-Bcl-2 ratios in comparison with untreated cells. Drug-treatment of the studied cells induced the translocation of Bax protein from the cytosol to the cellular pellet, containing mitochondria, where this polypeptide indicated the capacity for oligomerization. These observations suggest that the examined drugs are able to induce apoptosis of B-CLL cells via the mitochondria pathway.
 ...
PMID:In vitro sensitivity of B-cell chronic lymphocytic leukemia to cladribine and its combinations with mafosfamide and/or mitoxantrone. 1708 66


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