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

---

Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TAL (transaldolase) was originally described in the yeast as an enzyme of the PPP (pentose phosphate pathway). However, certain organisms and mammalian tissues lack TAL, and the overall reason for its existence is unclear. Recently, deletion of Ser(171) (TALDeltaS171) was found in five patients causing inactivation, proteasome-mediated degradation and complete deficiency of TAL. In the present study, microarray and follow-up Western-blot, enzyme-activity and metabolic studies of TALDeltaS171 TD (TAL-deficient) lymphoblasts revealed co-ordinated changes in the expression of genes involved in the PPP, mitochondrial biogenesis, oxidative stress, and Ca(2+) fluxing. Sedoheptulose 7-phosphate was accumulated, whereas G6P (glucose 6-phosphate) was depleted, indicating a failure to recycle G6P for the oxidative branch of the PPP. Nucleotide analysis showed depletion of NADPH and NAD(+) and accumulation of ADP-ribose. TD cells have diminished Deltapsi(m) (mitochondrial transmembrane potential) and increased mitochondrial mass associated with increased production of nitric oxide and ATP. TAL deficiency resulted in enhanced spontaneous and H(2)O(2)-induced apoptosis. TD lymphoblasts showed increased expression of CD38, which hydrolyses NAD(+) into ADP-ribose, a trigger of Ca(2+) release from the endoplasmic reticulum that, in turn, facilitated CD20-induced apoptosis. By contrast, TD cells were resistant to CD95/Fas-induced apoptosis, owing to a dependence of caspase activity on redox-sensitive cysteine residues. Normalization of TAL activity by adeno-associated-virus-mediated gene transfer reversed the elevated CD38 expression, ATP and Ca(2+) levels, suppressed H(2)O(2)- and CD20-induced apoptosis and enhanced Fas-induced cell death. The present study identified the TAL deficiency as a modulator of mitochondrial homoeostasis, Ca(2+) fluxing and apoptosis.
...
PMID:Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing. 1849 45

Targeting death receptor-mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cancer cells are intrinsically resistant to death receptor-mediated apoptosis. In an effort to identify agents that can sensitize cancer cells to death receptor-induced apoptosis, we have identified honokiol, a natural product with anticancer activity, as shown in various preclinical studies, as an effective sensitizer of death receptor-mediated apoptosis. Honokiol alone moderately inhibited the growth of human lung cancer cells; however, when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), greater effects on decreasing cell survival and inducing apoptosis than TRAIL alone were observed, indicating that honokiol cooperates with TRAIL to enhance apoptosis. This was also true to Fas-induced apoptosis when combined with Fas ligand or an agonistic anti-Fas antibody. Among several apoptosis-associated proteins tested, cellular FLICE-inhibitory protein (c-FLIP) was the only one that was rapidly down-regulated by honokiol in all of the tested cell lines. The down-regulation of c-FLIP by honokiol could be prevented by the proteasome inhibitor MG132. Moreover, honokiol increased c-FLIP ubiquitination. These results indicate that honokiol down-regulates c-FLIP by facilitating its degradation through a ubiquitin/proteasome-mediated mechanism. Enforced expression of ectopic c-FLIP abolished the ability of honokiol to enhance TRAIL-induced apoptosis. Several honokiol derivatives, which exhibited more potent effects on down-regulation of c-FLIP than honokiol, showed better efficacy than honokiol in inhibiting the growth and enhancing TRAIL-induced apoptosis as well. Collectively, we conclude that c-FLIP down-regulation is a key event for honokiol to modulate the death receptor-induced apoptosis.
...
PMID:The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor-induced apoptosis. 1864 30

The aging process and its characterization in keratinocytes have not been studied in depth until now. We have assessed the cellular and molecular characteristics of aged epidermal keratinocytes in monolayer cultures and in skin by measuring their morphological, fluorometric and biochemical properties. Light and electron microscopy, as well as flow cytometry, revealed increase in cell size, changes in cell shape, alterations in mitochondrial structure and cytoplasmic content with aging. We showed that the expression of 16 biochemical markers was altered in aged cultured cells and in tissues, including caspases 1 and 3 and beta-galactosidase activities, immunoreactivities of p16, Ki67, 20S proteasome and effectors of the Fas-dependent apoptotic pathway. Aged cells diversity, and individual variability of aging markers, call for a multifunctional assessment of the aging phenomenon, and of its modulation by drugs. As a test case, we have measured the effects of Dead Sea minerals on keratinocyte cultures and human skin, and found that they stimulate proliferation and mitochondrial activity, decrease the expression of some aging markers, and limit apoptotic damage after UVB irradiation.
...
PMID:Aged keratinocyte phenotyping: morphology, biochemical markers and effects of Dead Sea minerals. 1876 Oct 79

This study reports that Aurora-A (Aur-A) phosphorylates Fas-associated factor-1 (FAF1) at Ser-289 and Ser-291. Forced expression of a FAF1 mutant mimicking phosphorylation at Ser-289 and Ser-291 (FAF1 DD), but not phosphorylation-deficient FAF1 (FAF1 AA), reduced Aur-A expression. However, transfection of FAF1 DD failed to reduce Aur-A expression in the presence of MG132 and MG115, indicating that this decrease is proteasome-mediated. Additionally, transfection of FAF1 DD suppressed the expression of Aur-A in ts20-BALB cells lacking E1 ubiquitin (Ub) activating enzyme activity at restrictive temperatures and also reduced the expression of Aur-A S51D, a mutant resistant to Ub-dependent degradation. Our data indicate that phosphorylated FAF1 mediates the ubiquitin-independent, proteasome-dependent degradation of Aur-A. Overexpression of FAF1 DD blocked Aur-A-induced centrosome amplification and accumulated cells in G(2)/M phase, representing cellular phenotypes consistent with the anticipated loss of Aur-A. Collectively, our findings support the negative feedback regulation of Aur-A via phosphorylation of the death-promoting protein, FAF1, and disclose the presence of molecular cross-talk between constituents of the cell cycle and cell death machinery.
...
PMID:Negative feedback regulation of Aurora-A via phosphorylation of Fas-associated factor-1. 1879 Jul 38

Ubiquitin carboxy terminal hydrolase-L1 (UCH-L1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Previous research showed that UCH-L1 was expressed in mouse retinal cells and testicular germ cells, and its function was associated with apoptosis. But it is still unclear whether UCH-L1 is concerned with apoptosis in tumor cells. In order to clarify the role of UCH-L1 in tumor cells, multi-drug resistance (MDR) human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We transfected pcDNA3.1-UCH-L1 plasmid and UCH-L1 siRNA into MCF7 and MCF7/Adr cells, respectively. Using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, western blot, Hoechst 33258 staining assay and flow cytometry, we found that over-expression of UCH-L1 in MCF7 cells induced apoptosis. On the other hand, silencing of UCH-L1 in MCF7/Adr cells led to the opposite effect. Moreover, to explore the mechanism underling these observations, we further investigated the expression of phospho-Akt and its downstream signal phospho-IkB-alpha and other signal molecules including Fas, Fas-L, Trail, DR4, DR5, Bax, cytochrome C, active caspase-3, phospho-p53, phospho-Mdm-2, Bcl-2, Bcl-xL, p21 and p27. The results indicated that the process of apoptosis triggered by UCH-L1 is, at least in part, probably through Phosphoinositide 3-kinase (PI3K)/Akt signal pathway. Our findings suggest that modulating the ubiquitination and deubiquitination pathway could be a novel method for tumor therapy.
...
PMID:Over-expression of ubiquitin carboxy terminal hydrolase-L1 induces apoptosis in breast cancer cells. 1894 67

TP-110, a new proteasome inhibitor, has previously shown potent growth inhibition in various tumor cell lines. In this study, the mechanism of TP-110-induced apoptosis is investigated in a human multiple myeloma cell line. Treatment with TP-110 for 24 h in vitro induced apoptosis in multiple myeloma cell line RPMI8226. Although the expression of Bcl-2, Bcl-xL and Bax was not affected by the treatment of TP-110, cleavage of Bid and release of cytochrome c were enhanced. Interestingly, TP-110 reduced the intrinsic inhibitor of apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases. The reduction of IAPs was observed not only by TP-110, but also by another proteasome inhibitor, MG-132. These results indicate that proteasome inhibitors reduce the level of IAPs and that the apoptosis induced by TP-110 is correlated with the level of IAPs in leukemia cell lines. Additionally, a reduction of cIAP-1 and XIAP by TP-110 contributes to the sensitization of Fas-mediated apoptosis. Taken together, the alteration of the apoptosis regulatory proteins by a proteasome inhibitor induces apoptosis in tumor cells.
...
PMID:TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells. 1941 35

The death receptor Fas (APO-1/CD95) induces apoptosis in many tissues upon cross-linking by its ligand (FasL), but a number of cancer cells exhibit resistance to such apoptosis. Indeed, resistance to apoptosis seems to be one of the hallmarks of cancer, and therefore, it is clinically important to understand the underlying mechanisms by which cancer cells acquire such resistance. In the present study, we demonstrate that Fas signaling in DU145 human prostate cancer cells leads to rapid activation of AMP-activated protein kinase (AMPK), which plays a major role in adaptive responses to ATP-depleting conditions; prostate cancer is resistant to Fas-mediated apoptosis despite high levels of Fas surface expression and no mutation in the Fas gene. We further demonstrate that inhibition of AMPK sensitizes DU145 cells to Fas-induced apoptosis via enhancement of ubiquitination and consequent proteasome degradation of the apoptosis inhibitory protein c-FLIP. These findings thus reveal a novel anticancer property of AMPK inhibition and support the synergistic application of AMPK inhibition in cancer therapy to overcome Fas resistance.
...
PMID:Down-regulation of AMP-activated protein kinase sensitizes DU145 carcinoma to Fas-induced apoptosis via c-FLIP degradation. 1947 72

In many tumor cell types, ionizing radiation or DNA-damaging anticancer drugs enhance sensitivity to death receptor-mediated apoptosis, which is of clinical interest. APO010, a form of CD95/Fas ligand is currently in a phase I trial in patients with solid tumors. To analyze the potential of combined modality treatment with APO010, we used p53-mutant Jurkat T leukemic cells, in which the mitochondrial pathway was blocked by Bcl-2 overexpression. These cells were strongly sensitized to APO010 by pretreatment with ionizing - or UV radiation, etoposide, histone deacetylase - or proteasome inhibitors. These stimuli alone did not induce apoptosis in J16-Bcl-2 cells. Sensitization could not be explained by the overruling of mitochondrial resistance imposed by Bcl-2, upregulation of CD95 membrane levels or modulation of inhibitor of apoptosis proteins. Rather, the stimuli commonly downregulated c-FLIP(L/S) protein levels, which was causally related to the sensitization: deliberate c-FLIP(L/S) downregulation by RNA interference largely overruled the capacity of the various stimuli to sensitize Jurkat-Bcl-2 cells to apoptotic execution by APO010. In p53-mutant, Bcl-2 overexpressing HCT-15 colon carcinoma cells, c-FLIP downregulation correlated with sensitization to APO010 for some, but not all stimuli. We conclude that c-FLIP downregulation represents a mechanism by which diverse anticancer regimens can facilitate tumor cell execution by CD95/Fas through the direct pathway of caspase activation.
...
PMID:Radiation and anticancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation. 1979 6

The ALP (alkyl-lysophospholipid) edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) induces apoptosis in S49 mouse lymphoma cells. A variant cell line, S49AR, made resistant to ALP, was found previously to be impaired in ALP uptake via lipid-raft-mediated endocytosis. In the present paper, we report that these cells display cross-resistance to Fas/CD95 ligation [FasL (Fas ligand)], and can be gradually resensitized by prolonged culturing in the absence of ALP. Fas and ALP activate distinct apoptotic pathways, since ALP-induced apoptosis was not abrogated by dominant-negative FADD (Fas-associated protein with death domain), cFLIP(L) [cellular FLICE (FADD-like interleukin 1beta-converting enzyme)-inhibitory protein long form] or the caspase 8 inhibitor Z-IETD-FMK (benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketone). ALP-resistant cells showed decreased Fas expression, at both the mRNA and protein levels, in a proteasome-dependent fashion. The proteasome inhibitor MG132 partially restored Fas expression and resensitized the cells to FasL, but not to ALP. Resistant cells completely lacked SM (sphingomyelin) synthesis, which seems to be a unique feature of the S49 cell system, having very low SM levels in parental cells. Lack of SM synthesis did not affect cell growth in serum-containing medium, but retarded growth under serum-free (SM-free) conditions. SM deficiency determined in part the resistance to ALP and FasL. Exogenous short-chain (C12-) SM partially restored cell-surface expression of Fas in lipid rafts and FasL sensitivity, but did not affect Fas mRNA levels or ALP sensitivity. We conclude that the acquired resistance of S49 cells to ALP is associated with down-regulated SM synthesis and Fas gene transcription and that SM in lipid rafts stabilizes Fas expression at the cell surface.
...
PMID:Fas/CD95 down-regulation in lymphoma cells through acquired alkyllysophospholipid resistance: partial role of associated sphingomyelin deficiency. 1982 85

In the treatment of colon cancer, the development of resistance to apoptosis is a major factor in resistance to therapy. New molecular approaches to overcome apoptosis resistance, such as selectively upregulating proapoptotic proteins, are needed in colon cancer therapy. In a mouse model with inactivation of the adenomatous polyposis coli (Apc) tumor suppressor gene, reflecting the pathogenesis of most human colon cancers, the gene encoding feminization-1 homolog b (Fem1b) is upregulated in intestinal epithelium following Apc inactivation. Fem1b is a proapoptotic protein that interacts with apoptosis-inducing proteins Fas, tumor necrosis factor receptor-1 (TNFR1), and apoptotic protease activating factor-1 (Apaf-1). Increasing Fem1b expression induces apoptosis of cancer cells, but effects on colon cancer cells have not been reported. Fem1b is a homolog of feminization-1 (FEM-1), a protein in Caenorhabditis elegans that is regulated by proteasomal degradation, but whether Fem1b is likewise regulated by proteasomal degradation is unknown. Herein, we found that Fem1b protein is expressed in primary human colon cancer specimens, and in malignant SW620, HCT-116, and DLD-1 colon cancer cells. Increasing Fem1b expression, by transfection of a Fem1b expression construct, induced apoptosis of these cells. We found that proteasome inhibitor treatment of SW620, HCT-116, and DLD-1 cells caused upregulation of Fem1b protein levels, associated with induction of apoptosis. Blockade of Fem1b upregulation with morpholino antisense oligonucleotide suppressed the proteasome inhibitor-induced apoptosis of these cells. In conclusion, the proapoptotic protein Fem1b is downregulated by the proteasome in malignant colon cancer cells and mediates proteasome inhibitor-induced apoptosis of these cells. Therefore, Fem1b could represent a novel molecular target to overcome apoptosis resistance in therapy of colon cancer.
...
PMID:Fem1b, a proapoptotic protein, mediates proteasome inhibitor-induced apoptosis of human colon cancer cells. 1990 42


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

---