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

Although evasion of apoptosis is thought to be required for the development of cancer, it is unclear which cell death pathways are evaded. We previously identified a novel epithelial cell death pathway that works in normal cells but is inactivated in tumor cells, implying that it may be targeted during tumor development. The pathway can be activated by the Fas-associated death domain (FADD) of the adaptor protein but is distinct from the known mechanism of FADD-induced apoptosis through caspase-8. Here, we show that a physiological signal (tumor necrosis factor-related apoptosis-inducing ligand) can kill normal epithelial cells through the endogenous FADD protein by using the novel FADD death domain pathway, which activates both apoptosis and autophagy. We also show that selective resistance to this pathway occurs when primary epithelial cells are immortalized and that this occurs through a mechanism that is independent of known events (telomerase activity, and loss of function of p53, Rb, INK4a, and ARF) that are associated with immortalization. These data identify a novel cell death pathway that combines apoptosis and autophagy and that is selectively inactivated at the earliest stages of epithelial cancer development.
Mol Biol Cell 2005 Mar
PMID:Selective inactivation of a Fas-associated death domain protein (FADD)-dependent apoptosis and autophagy pathway in immortal epithelial cells. 1563 90

Niemann-Pick disease type C (NP-C) is an autosomal recessive neurovisceral storage disease with neurodegeneration caused by mutations in either the NPC-1 or NPC-2 gene. The murine ortholog of NPC-1 is mutated in BALB/c npc(nih) and this mutant mouse shows equally conspicuous neurodegeneration and loss of neurons. However, the molecular mechanisms causing neurodegeneration in NP-C remain elusive. Here, we report the presence of apoptotic cells detected by both TUNEL staining and electron microscopy in the cerebrum and cerebellum of human patients and the mouse model. Moreover, we found that with progression of the disease process leading to neuronal cell death, an up-regulation of genes involved in the TNF-alpha death pathway caspase-8, FADD, TNFRp55, TRADD, and RIP-by an RNA protection assay. Furthermore, RT-PCR showed that TNF-alpha mRNA expression level also increased up to 30-50-fold in the cerebellum of 7- and 9-week-old NP-C mice compared with wild-type mice. Elevated expression of TNF-alpha was detected in both neurons and astrocytes with TNF-alpha-expressing astrocytes distributed in the affected brain regions. Collectively, our results suggest that the cell death in the brain of NP-C disease occurs through apoptosis and it is mediated by the TNF receptor superfamily pathway.
Mol Genet Metab 2005 Jan
PMID:Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease. 1563 90

Cancer cells frequently possess defects in the genetic and biochemical pathways of apoptosis. Members of the Bcl-2 family play pivotal roles in regulating apoptosis and possess at least one of four Bcl-2 homology (BH) domains, designated BH1 to BH4. The BH3 domain is the only one conserved in proapoptotic BH3-only proteins and plays an important role in protein-protein interactions in apoptosis by regulating homodimerization and heterodimerization of the Bcl-2 family members. To date, 10 BH3-only proapoptotic proteins have been identified and characterized in the human genome. The completion of the Human Genome Project and the availability of various public databases and sequence analysis algorithms allowed us to use the bioinformatic database-mining approach to identify one novel BH3-only protein, apolipoprotein L6 (ApoL6). The full-length cDNA of ApoL6 was identified, cloned, and functionally expressed in p53-null colorectal cancer cells (DLD-1). We found that overexpression of wild-type ApoL6 induced mitochondria-mediated apoptosis in DLD-1 cells characterized by release of cytochrome c and Smac/DIABLO from mitochondria and activation of caspase-9, whereas ApoL6 BH3 domain deletion allele did not. In addition, overexpression of ApoL6 also induced activation of caspase-8. Furthermore, we showed that adenovirus harboring the full-length cDNA of ApoL6 induced marked apoptosis in a variety of cancer cell types, and ApoL6 recruited and interacted with lipid/fatty acid components during the induction of apoptosis. To our knowledge, this is the first example that intracellular overproduction of an apolipoprotein induces marked apoptosis.
Mol Cancer Res 2005 Jan
PMID:Apolipoprotein l6, a novel proapoptotic Bcl-2 homology 3-only protein, induces mitochondria-mediated apoptosis in cancer cells. 1567 Dec 46

In a previous study, we showed that G3139, an antisense phosphorothioate oligonucleotide that down-regulates the expression of Bcl-2 protein, did not cause chemosensitization of 518A2 melanoma cells. In this work, we show that G3139, and the 2-base mismatch, G4126, can initiate apoptosis in this and other melanoma cell lines as shown by increased cell surface Annexin V expression, typical nuclear phenotypic changes as assessed by 4',6-diamidino-2-phenylindole staining, activation of caspase-3 (but not caspase-8) and Bid, appearance of DEVDase (but not IETDase) activity, and cleavage of poly(ADP-ribose)-polymerase 1. Depolarization of the mitochondrial membrane occurs as a relatively late event. All of these processes seem to be substantially, but perhaps not totally, Bcl-2 independent as shown by experiments employing an anti-Bcl-2 small interfering RNA, which as shown previously down-regulated Bcl-2 protein expression but did not produce apoptosis or chemosensitization in melanoma cells. In fact, these G3139-induced molecular events were not dramatically altered in cells that forcibly overexpressed high levels of Bcl-2 protein. Addition of irreversible caspase inhibitors (e.g., the pan-caspase inhibitor zVAD-fmk) to G3139-treated cells almost completely blocked cytotoxicity. Examination of the time course of the appearance of caspase-3 and cleaved poly(ADP-ribose)-polymerase 1 showed that this could be correlated with the release of cytochrome c from the mitochondria, an event that begins only approximately 4 hours after the end of the oligonucleotide/LipofectAMINE 2000 5-hour transfection period. Thus, both G3139 and cytotoxic chemotherapy activate the intrinsic pathway of apoptosis in these cells, although Bcl-2 expression does not seem to contribute strongly to chemoresistance. These findings suggest that the attainment of G3139-induced chemosensitization in these cells will be difficult.
Mol Cancer Ther 2005 Feb
PMID:Phosphorothioate oligodeoxynucleotides and G3139 induce apoptosis in 518A2 melanoma cells. 1571 1

The APC tumor suppressor is found in nonproliferating epithelial cells of the colonic crypts and is mutated in most colorectal tumors. To understand the function of APC in normal epithelium and how its loss leads to tumor formation, we tested whether APC is a mediator of apoptosis using an in vitro assay that monitors caspase-3-mediated cleavage of lamin B protein or a colorimetric substrate in a cell-free Xenopus egg extract. Recombinant APC protein accelerates apoptosis-associated caspase activity independently of ongoing transcription and protein synthesis. Conversely, the addition of mutant APC and immunodepletion of Xenopus APC decelerates apoptosis-associated caspase activity. Acceleration of apoptosis by APC is abolished by the caspase-8 inhibitor Z-IETD-FMK, demonstrating that caspase-8 is an essential component of APC-mediated apoptosis. These results suggest that the induction of apoptosis may be one role of APC in tumor suppression and that this mechanism is independent of beta-catenin-mediated effects on transcription.
Mol Cancer Res 2005 Feb
PMID:The APC tumor suppressor promotes transcription-independent apoptosis in vitro. 1575 74

The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate-induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.
Mol Cancer Ther 2005 Mar
PMID:Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells. 1576 47

Although signaling by death receptors involves the recruitment of common components into their death-inducing signaling complexes (DISCs), apoptosis susceptibility of various tumor cells to each individual receptor differs quite dramatically. Recently it was shown that, besides caspase-8, caspase-10 is also recruited to the DISCs, but its function in death receptor signaling remains unknown. Here we show that expression of caspase-10 sensitizes MCF-7 breast carcinoma cells to TRAIL- but not tumor necrosis factor (TNF)-induced apoptosis. This sensitization is most obvious at low TRAIL concentrations or when apoptosis is assessed at early time points. Caspase-10-mediated sensitization for TRAIL-induced apoptosis appears to be dependent on caspase-3, as expression of caspase-10 in MCF-7/casp-3 cells but not in caspase-3-deficient MCF-7 cells overcomes TRAIL resistance. Interestingly, neutralization of TRAIL receptor 2 (TRAIL-R2), but not TRAIL-R1, impaired apoptosis in a caspase-10-dependent manner, indicating that caspase-10 enhances TRAIL-R2-induced cell death. Furthermore, whereas processing of caspase-10 was delayed in TNF-treated cells, TRAIL triggered a very rapid activation of caspase-10 and -3. Therefore, we propose a model in which caspase-10 is a crucial component during TRAIL-mediated apoptosis that in addition actively requires caspase-3. This might be especially important in systems where only low TRAIL concentrations are supplied that are not sufficient for the fast recruitment of caspase-8 to the DISC.
Mol Cell Biol 2005 Apr
PMID:Caspase-10 sensitizes breast carcinoma cells to TRAIL-induced but not tumor necrosis factor-induced apoptosis in a caspase-3-dependent manner. 1576 84

Tumor microenvironment, which is characterized by hypoxia, low-glucose concentrations, high-lactate concentrations, low-extracellular pH, can alter the therapeutic response in tumors. In this study, we investigated whether hypoxia affects TRAIL-induced apoptotic death. When human prostate adenocarcinoma DU-145 cells were treated with 50 ng/mL TRAIL or hypoxia for 4 h, the survival was 45.7 and 32.5%, respectively. The combination of TRAIL and hypoxia synergistically increased cell death. Similar results were observed in human prostate adenocarcinoma LNCaP cells. Western blot analysis showed that the hypoxia augmented TRAIL-induced PARP cleavage as well as the activation of caspase-8 and caspase-3, but not caspase-9. Unlike hypoxia, low glucose promoted caspase-9 activation during TRAIL treatment. These results suggest that hypoxia or low glucose-augmented TRAIL cytotoxicity is mediated through the mitochondria-independent pathway or -dependent pathway, respectively.
Mol Cell Biochem 2005 Feb
PMID:Hypoxia and low glucose differentially augments TRAIL-induced apoptotic death. 1579 57

Photodynamic therapy using 5-aminolevulinic acid-induced protoporphyrin IX synthesis as a photosensitizing reagent is an encouraging modality for cancer treatment. Understanding the mechanism of tumor phototoxicity is important to provide a basis for combinatory therapy regimens. A normal cell line (UROtsa, urothelial) and two tumor cell lines (RT4, urothelial; HT29, colonic) were treated with cell line-specific LD50 doses of light after exposure to 5-aminolevulinic acid (100 microg/mL), and harvested for RNA extraction 0, 10, and 30 minutes after irradiation. The RNA was hybridized to the metg001A Affymetrix GeneChip containing 2,800 genes, focusing on cancer-related and growth regulatory targets. Comparing the gene expression profiles between the different samples, 40 genes (e.g., SOD2, LUC7A, CASP8, and DUSP1) were identified as significantly altered in comparison with the control samples, and grouped according to their gene ontology. We selected caspase-8 (CASP8) and dual specificity phosphatase 1 (DUSP1) for further validation of the array findings, and compared their expression with the expression of the immediate early gene FOS by quantitative reverse transcription-PCR. RNA expression of CASP8 stayed unchanged whereas DUSP1 RNA was up-regulated in normal and tumor cells starting 30 minutes after irradiation. In contrast, FOS RNA was found continuously up-regulated over time in all three cell lines. Induction of DUSP1 protein expression was clearly shown after 1 hour using Western blot analysis. Interestingly, no changes of caspase-8 protein expression but activation of catalytic activity was detected only in UROtsa cells starting 1 hour after photodynamic therapy, whereas no changes were seen in both tumor cell lines. According to caspase-8, the active caspase 3 fragment was found only in the normal urothelial cell line (UROtsa) 1 hour after photodynamic therapy. Combined data analysis suggests that photodynamic therapy in vitro (LD50) leads to apoptosis in UROtsa and to necrosis in the tumor cell lines, respectively. RNA expression profiling of normal and tumor cell lines following photodynamic therapy with 5-aminolevulinic acid gave insight into the major molecular mechanisms induced by photodynamic therapy.
Mol Cancer Ther 2005 Apr
PMID:RNA expression profiling of normal and tumor cells following photodynamic therapy with 5-aminolevulinic acid-induced protoporphyrin IX in vitro. 1582 24

Bovine lactoferricin (LfcinB) is a cationic, amphipathic peptide that is cytotoxic for human and rodent cancer cells. However, the mechanism by which LfcinB causes the death of cancer cells is not well understood. Here, we show that in vitro treatment with LfcinB rapidly induced apoptosis in several different human leukemia and carcinoma cell lines as determined by DNA fragmentation assays and phosphatidylserine headgroup inversion detected by Annexin V binding to the surface of cancer cells. Importantly, LfcinB treatment did not adversely affect the viability of untransformed human lymphocytes, fibroblasts, or endothelial cells. Studies with different LfcinB-derived peptide fragments revealed that the cytotoxic activity of LfcinB resided within the amino acid sequence FKCRRWQWRM. Treatment of Jurkat T leukemia cells with LfcinB resulted in the production of reactive oxygen species followed by caspase-2-induced dissipation of mitochondrial transmembrane potential and subsequent activation of caspase-9 and caspase-3. Selective inhibitors of caspase-2 (Z-VDVAD-FMK), caspase-9 (Z-LEHD-FMK), and caspase-3 (Z-DEVD-FMK) protected both leukemia and carcinoma cells from LfcinB-induced apoptosis. Conversely, a caspase-8 inhibitor (Z-IETD-FMK) had no effect, which argued against a role for caspase-8 and was consistent with the finding that death receptors were not involved in LfcinB-induced apoptosis. Furthermore, Jurkat T leukemia cells that overexpressed Bcl-2 were less sensitive to LfcinB-induced apoptosis, which was characterized by mitochondrial swelling and the release of cytochrome c from mitochondria into the cytosolic compartment. We conclude that LfcinB kills cancer cells by triggering the mitochondrial pathway of apoptosis at least in part through the generation of reactive oxygen species.
Mol Cancer Ther 2005 Apr
PMID:Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. 1582 35


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