Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Downregulation of the catalytic subunit of the mitochondrial H(+)-ATP synthase (beta-F1-ATPase) is a hallmark of many types of cancer. The expression of beta-F1-ATPase is stringently controlled by posttranscriptional mechanisms. Herein, we pursue the identification of beta-F1-ATPase messenger RNA-binding proteins (beta-mRNABPs) that interact and could define the bioenergetic phenotype of the cancer cell in order to establish its relevance as markers of breast cancer progression. RNA immunoprecipitation and RNA affinity chromatography identify HuR as a beta-mRNABP that interacts with the 3'-untranslated region of the transcript. Subcellular fractionation and high-resolution immunoelectron microscopy revealed the cofractionation and presence of HuR in subcellular structures associated to liver mitochondria. Analysis of the expression level of HuR in a cohort of breast carcinomas shows its association with the degree of alteration of the bioenergetic phenotype of the tumor. Moreover, HuR expression is shown to be an independent marker of breast cancer prognosis. A low tumor expression of HuR predicts a higher risk of disease recurrence in early stage breast cancer patients as assessed by clinical and bioenergetic markers of prognosis, strongly supporting the incorporation of HuR as an additional marker for the follow-up of these patients. Mechanistically, overexpression experiments and short hairpin RNA-mediated silencing of HuR in human embryonic kidney and HeLa cells indicate that HuR is not regulating beta-F1-ATPase expression. Overall, the participation of additional RNA-binding proteins in controlling beta-F1-ATPase expression and therefore in defining the bioenergetic signature of the cancer cell is expected.
 ...
PMID:HuR and the bioenergetic signature of breast cancer: a low tumor expression of the RNA-binding protein predicts a higher risk of disease recurrence. 1868 67

Thirty years after Peter Mitchell was awarded the Nobel Prize for the chemiosmotic hypothesis, which links the mitochondrial membrane potential generated by the proton pumps of the electron transport chain to ATP production by ATP synthase, the molecular players involved once again attract attention. This is so because medical research increasingly recognizes mitochondrial dysfunction as a major factor in the pathology of numerous human diseases, including diabetes, cancer, neurodegenerative diseases, and ischemia reperfusion injury. We propose a model linking mitochondrial oxidative phosphorylation (OxPhos) to human disease, through a lack of energy, excessive free radical production, or a combination of both. We discuss the regulation of OxPhos by cell signaling pathways as a main regulatory mechanism in higher organisms, which in turn determines the magnitude of the mitochondrial membrane potential: if too low, ATP production cannot meet demand, and if too high, free radicals are produced. This model is presented in light of the recently emerging understanding of mechanisms that regulate mammalian cytochrome c oxidase and its substrate cytochrome c as representative enzymes for the entire OxPhos system.
 ...
PMID:Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. 1884 28

To evaluate the effect of galectin-3 in cell cycle regulation of colon cancer cells, we looked for binding molecules interacting with galectin-3 and examined the changes in cell cycle by suppressing galectin-3 and the binding molecule. To identify target molecules interacting with galectin-3, we analyzed immunoprecipitate of the anti-galectin-3 antibody obtained from human colon cancer cell line, using matrix-assisted laser desorption ionization-mass spectrometry. We validated subcellular localization of galectin-3 and ATP synthase identified, and ATP synthase activity was determined in the presence of galectin-3. Cell cycle regulation was monitored after galectin-3 siRNA transfection. ATP synthase b-subunit was identified in immunoprecipitate of the anti-galectin-3 antibody. Galectin-3 and ATP synthase were co-isolated in the inner membrane vesicles of mitochondria. Galectin-3 has an inhibitory activity against ATP synthase, and intracellular ATP content showed increasing tendency after galectin-3 suppression. Suppression of galectin-3 resulted in G0/G1 progression of human colon cancer cells arrested at S, S/G2 and G2/M phase in the presence of doxorubicin, and etoposide or nocodazole, respectively. Compared to cells in which ATP synthase d-subunit was suppressed alone, sub-G1 fraction caused by etoposide or nocodazole was decreased in cells with galectin-3 suppression alone. In conclusion, galectin-3 co-localized with ATP synthase in the inner membrane of mitochondria and has an inhibitory effect on ATP synthase in human colon cancer cells. In the presence of cell cycle synchronizing drugs, doxorubicin, etoposide, or nocodazole, suppression of galectin-3 induced cell cycle progression to G0/G1 phase.
Cancer Sci 2008 Oct
PMID:Identification of mitochondrial F(1)F(0)-ATP synthase interacting with galectin-3 in colon cancer cells. 1901 46

The mutated K-ras gene is involved in approximately 30% of human cancers. In order to search for K-ras oncogene-induced modulators in lung tissues of K-ras transgenic mice, we performed microarray and proteomics (LC/ESI-MS/MS) analysis. Genes (RAB27b RAS family, IL-1RA, IL-33, chemokine ligand 6, epiregulin, EGF-like domain and cathepsin) related to cancer development (Wnt signaling pathway) and inflammation (chemokine/cytokine signaling pathway, Toll receptor signaling) were up-regulated while genes (troponin, tropomodulin 2, endothelial lipase, FGFR4, integrin alpha8 and adenylate cyclase 8) related to the tumor suppression such as p53 pathway, TGF-beta signaling pathway and cadherin signaling pathway were down-regulated by K-ras oncogene. Proteomics approach revealed that up-regulated proteins in lung adenomas of K-ras mice were classified as follows: proteins related to the metabolism/catabolism (increased from 7 to 22% by K-ras gene), proteins related to translation/transcription and nucleotide (from 4 to 6%), proteins related to signal transduction (from 3 to 5%), proteins related to phosphorylation (from 1 to 2%). ATP synthase, Ras oncogene family, cytochrome c oxidase, flavoprotein, TEF 1, adipoprotein A-1 BP, glutathione oxidase, fatty acid BP 4, diaphorase 1, MAPK4 and transgelin were up-regulated by K-ras oncogene. However, integrin alpha1, Ras-interacting protein (Rain), endothelin-converting enzyme-1d and splicing factor 3b were down-regulated. These studies suggest that genes related to cancer development and inflammation were up-regulated while genes related to the tumor suppression were down-regulated by K-ras, resulting in the tumor growth. Putative biomarkers such as cell cycle related genes (Cdc37), cancer cell adhesion (Glycam 1, integrin alpha8, integrin alphaX and Clec4n), signal transduction (Tlr2, IL-33, and Ccbp2), migration (Ccr1, Ccl6, and diaphorase 1 (Cyb5r3) and cancer development (epiregulin) can be useful for diagnosis and as prognosis markers and some of the target molecules can be applied for prevention of cancer.
 ...
PMID:Profiling of transcripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omics approaches. 1908 87

The analysis of a small number of patients with atypical chronic myeloid leukemia showing balanced chromosomal translocations has revealed diverse tyrosine kinase fusion genes, most commonly involving FGFR1, PDGFRA, PDGFRB, JAK2, and ABL. We present a case of aCML with a 3q22;21q22-translocation that led to truncation of the receptor-like tyrosine kinase (RYK) gene and its juxtaposition with sequences from chromosome 21 including the ATP5O gene coding for a mitochondrial ATP synthase. The resulting fusion was not in frame, however, which is why we speculate that an abrogated RYK gene product rather than a chimeric protein might be the leukemogenic result.
Cancer Lett 2009 May 18
PMID:t(3;21)(q22;q22) leading to truncation of the RYK gene in atypical chronic myeloid leukemia. 1916 82

The introduction of the tumorigenic v-Ha-ras oncogene-transformed rat liver epithelial cells (WBras), which is deficient in gap junctional intercellular communication (GJIC), into F344 rats, induces significant formation of hepatocellular tumors. GJIC plays a major role in maintaining tissue homeostasis. Using this in vivo tumor model system, we used 2-dimensional electrophoresis with isoelectric focusing in the first dimension and SDS-PAGE in the second dimension to globally identify proteins that are uniquely expressed in the livers of WBras-treated rats as compared to the sham control. Immunoblotting was used to identify Ras and Connexin43, which were the positive and negative marker proteins, respectively, of the introduced WBras cells. As predicted, immunoblotting indicated that the whole liver of tumor-bearing animals exhibited a decreased level of Connexin43 and an increased level of Ras. Connexin43 and GJIC were expressed and functional in normal liver, but not in the tumor. In addition to these 2 markers, an additional 4 proteins exhibited decreased levels and 2 proteins exhibited increased levels in the livers of tumor-bearing animals. N-Terminal sequencing analysis was used to identify these proteins, which were glucose-regulated protein 78, 2 isoforms of heat shock protein 60, and the beta-chain of ATP synthase for the down regulated proteins, and beta-Actin with a 46 amino acid deletion from its N-terminus and Vimentin with a 71 amino acid deletion from its N-terminus for the up regulated proteins. These data offer potentially new markers of liver tumorigenicity, particularly, Vimentin. (
Int J Cancer 2009 Jun 01
PMID:Actin and Vimentin proteins with N-terminal deletion detected in tumor-bearing rat livers induced by intraportal-vein injection of Ha-ras-transfected rat liver cells. 1919 59

To identify new biomarkers that facilitate the accurate early diagnosis of osteosarcoma and that may possibly include novel therapeutic candidates, we performed a proteomic approach to compare osteosarcoma cells and human primary cultured osteoblastic cells. Image analysis of silver-stained 2-DE gels revealed that the level of 12 protein spots was significantly different between the two groups of samples (p < .004). After mass spectroscopic identification and database searches, we found that in osteosarcoma cells, the level of HSP70, actin capping protein, ATP synthase, Mthsp75, UQCRC1, Ras-related nuclear protein, UCH-L1, and PRDX4 was elevated. However, the level of pyruvate dehydrogenase E1, Prohibitin, and Annexin V was decreased. Subsequent Western blot analyses of UQCRC1, UCH-L1, and PRDX4 in osteosarcoma tissues confirmed the results obtained by the proteomic analyses. These identified proteins may be potential molecular targets for osteosarcomatous diagnostics and therapeutics.
Cancer Invest 2009 Mar
PMID:Comparative proteomic analysis of osteosarcoma cell and human primary cultured osteoblastic cell. 1921 29

Daphnetoxin is a daphnane type orthoester diterpene found exclusively in plants of the family Thymelaeaceae while daphnoretin, a bis-coumarin derivative that is the major constituent of the bark of some plants of this family, can also be found in Leguminosae and Rutaceae. These two compounds are recognized to have different biological effects, including a possible anti-cancer activity. The subject of the present research was to compare their mitochondrial toxicity and also investigate a possible selectivity towards tumor cell lines. Wistar rat liver mitochondria and three distinct cell lines were used to investigate compound-induced toxicity. The results indicate that both test compounds are toxic to isolated mitochondrial fractions, especially when used at concentrations higher than 100 microM. However, daphnetoxin presented the highest toxicity including increased proton leak in the inner mitochondrial membrane, increased induction of the mitochondrial permeability transition pore, inhibition of ATP synthase and inhibition of the mitochondrial respiratory chain. Both compounds also inhibited cell proliferation, regardless of the cell line used. Up to the maximal concentration tested in cells, no mitochondrial effects were detected by vital epifluorescence imaging, indicating that inhibition of cell proliferation may also originate from mitochondrial-independent mechanisms. The results warrant careful assessment of toxicity vs. pharmacology benefits of both molecules.
 ...
PMID:Mitochondrial toxicity of the phyotochemicals daphnetoxin and daphnoretin--relevance for possible anti-cancer application. 1936 37

Autoantibody response to tumor antigens has been widely used to identify novel tumor markers for different cancers, including that of the head and neck. The oral cavity, which is in the head and neck region, comprises of many sub sites with distinct biologies and incidence of cancer of each sub site of the oral cavity is different. It is anticipated therefore that each sub site of the oral cavity may elicit a differential autoantibody response. This report evaluates the autoantibody response in 15 patients with cancer of gingivo-buccal complex and in 15 patients with cancer of tongue using Immunoproteomics, and shows that the autoantibody response to alpha-enolase, HSP 70, peroxiredoxin-VI, annexin II, pyruvate kinase, alpha-tubulin, beta-tubulin, ATP synthase, triose phosphate isomerase and aldose reductase seen in patients with cancer of gingivo-buccal complex is absent in patients with cancer of tongue. This suggests that cancer of these sub sites should be studied separately because of their different biology and emerging site specific molecular signatures including autoantibody responses to ensure unambiguous clinical interpretations.
Cancer Biomark 2009
PMID:Immunoproteomics reveals that cancer of the tongue and the gingivobuccal complex exhibit differential autoantibody response. 1940 67

Recently, the inevitable metabolic reprogramming experienced by cancer cells as a result of the onset of cellular proliferation has been added to the list of hallmarks of the cancer cell phenotype. Proliferation is bound to the synchronous fluctuation of cycles of an increased glycolysis concurrent with a restrained oxidative phosphorylation. Mitochondria are key players in the metabolic cycling experienced during proliferation because of their essential roles in the transduction of biological energy and in defining the life-death fate of the cell. These two activities are molecularly and functionally integrated and are both targets of commonly altered cancer genes. Moreover, energetic metabolism of the cancer cell also affords a target to develop new therapies because the activity of mitochondria has an unquestionable tumor suppressor function. In this review, we summarize most of these findings paying special attention to the opportunity that translation of energetic metabolism into the clinics could afford for the management of cancer patients. More specifically, we emphasize the role that mitochondrial beta-F1-ATPase has as a marker for the prognosis of different cancer patients as well as in predicting the tumor response to therapy.
 ...
PMID:The tumor suppressor function of mitochondria: translation into the clinics. 1941 7


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