UNIPROT:P10415 - FACTA Search

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

Hypoxia is an important regulator of bone biology and stimulates osteoclast differentiation from monocytic precursors. Hypoxia-inducible factor (HIF) is a key pro-tumourigenic transcription factor mediating pathways of hypoxia-inducible gene expression. We have described expression of HIF-1alpha and HIF-2alpha in the multi-nucleated, osteoclast-like giant cells and the mononuclear stromal component of giant cell tumour of bone (GCTB), a locally osteolytic primary bone tumour. HIF induction was observed in culture in the osteoblastic MG-63 cell line, primary GCTB stromal cells, and monocyte-derived osteoclasts following stimulation with hypoxia (0.1% O2) or the osteoclastogenic cytokines hepatocyte growth factor (HGF) and macrophage colony-stimulating factor (M-CSF). This was accompanied by increased expression of the downstream target genes Bcl-2/adenovirus E1B 19 kD-interacting protein 3 (BNIP3), Glut-1, and vascular endothelial growth factor (VEGF). As VEGF can substitute for M-CSF to support osteoclastogenesis in the presence of receptor activator for nuclear factor kappaB ligand (RANKL), we assessed the effect of MG-63 hypoxic conditioned media on osteoclast differentiation. In the presence of RANKL, hypoxic conditioned media induced the formation of active osteoclasts, as assessed from the numbers of TRAP-positive multi-nucleated cells and the area of lacunar bone resorption, which was inhibited by co-incubation with a neutralizing anti-VEGF antibody. Targeted siRNA ablated HIF-1alpha and/or HIF-2alpha expression in MG-63 cells and reduced hypoxic secretion of VEGF. Hypoxic conditioned media from cells treated with siRNA for (HIF-1alpha + HIF-2alpha) produced a significant decrease in osteoclast number (p < 0.005) and activity (p < 0.05) in comparison with the scrambled siRNA control. These results suggest that local hypoxia could indirectly influence osteoclastogenesis via autocrine and paracrine secretion of VEGF under the control of HIF. This is potentially an important mechanism of pathogenesis for GCTB and other osteolytic lesions.
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PMID:Hypoxia-inducible factor is expressed in giant cell tumour of bone and mediates paracrine effects of hypoxia on monocyte-osteoclast differentiation via induction of VEGF. 1828 16

Selenium (Se) is an essential micronutrient as well as a toxic trace element in animal and human nutrition. The effects of Se in the immune system and some diseases are well documented. The objective of the present study was to examine the role of Se in reducing the hypoxia induced apoptosis in neuroblastoma cell line. Hypoxia showed an enhanced cytotoxicity, increased free radical production and apoptosis (p<0.001) which was measured in terms of DNA break down by comet assay. Hypoxia has decreased reduced Glutathione (GSH) content, Glutathione Reductase (GR), Glutathione peroxidase (GPx) and Superoxide Dismutase (SOD) activities as compared to control cells. During hypoxic condition the expression of cytochrome C, pro and active caspase-3 levels were enhanced significantly followed by nonsignificant upregulation of Bcl-2. But, the Se supplementation inhibited the cytotoxicity, free radical generation and stabilized the HIF-1alpha accumulation in cells under hypoxia. The GSH content, GR, GPx and SOD activities increased significantly in Se-treated hypoxic cells, as compared to control. Further there was an appreciable inhibition of apoptosis by upregulation of Bcl-2 proteins, in the presence of Se under hypoxia. Selenium supplementation to cells significantly inhibited the hypoxia induced DNA fragmentation and restored the antioxidant status back to control levels. This study suggests that Se supplementation prevented the cells from hypoxia induced apoptosis by triggering upregulation of Bcl-2 protein and reducing the oxidative stress.
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PMID:Selenium protects the hypoxia induced apoptosis in neuroblastoma cells through upregulation of Bcl-2. 1840 86

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

Therapy targeting hypoxia-inducible factor-1 (HIF-1) to reverse the hypoxia-related drug resistance has received much interest. Despite a close interaction between HIF-1 and p53 and that p53 mutation is seen in >50% of tumors, whether HIF-1 silencing by targeted therapy depends on tumor p53 status remains unknown. Two isogenic fibrosarcoma cells HT1080 (wild-type p53) and HT1080-6TG (mutant p53) were transduced with HIF-1alpha-specific RNAi lentiviral vectors and selected with blasticidin. Real-time PCR and western blot analysis of HIF-1alpha mRNA and protein respectively validated the silencing effects. Cells were first preconditioned under hypoxia (0.5% O(2)) for 4 h and then co-treated with cisplatin for another 24 h. MTT was used for assessment of chemosensitivity to cisplatin. Moreover, annexin V and propidium iodide staining was detected on flow cytometry for analysis of cisplatin-induced apoptosis. Furthermore, changes of some Bcl-2 family members were detected on western blotting. Exposure to hypoxia significantly increased resistance to cisplatin than exposure to normoxia. HIF-1alpha knockdown could reverse hypoxia-related resistance to cisplatin and apoptotic resistance only in HT1080 cells, but had little effect on HT1080-6TG cells. With HIF-1alpha knockdown, Bid expression was higher in HT1080 than in HT1080-6TG under hypoxia. In summary, HIF-1 targeted therapy to reverse hypoxia-related cisplatin resistance depends on normal p53 status. Changes of Bid expression levels under hypoxia might contribute in part to the differential response to HIF-1alpha silencing in cells with different p53 status.
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PMID:Effects of lentivirus-mediated HIF-1alpha knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells. 1842 7

Cytokines are released in response to brain injury and inflammation. By binding to receptors, they can cause, exacerbate or inhibit cellular injury and repair. We studied RNA expression of cytokine receptors and members of inflammatory pathways in human NT2-N neurons during 3 h of hypoxia and glucose deprivation followed by 21 h of reoxygenation, and the impact of acidosis. Right after acidotic hypoxia, RNA of IL-10RA and CXCR4 were significantly increased relative to acidotic control, while Bcl-2 and Bcl-xL were significantly decreased. After 21 h of neutral reoxygenation after neutral hypoxia, there was a significant increase in RNA of CXCR1 (relative quantification (RQ)=4.1, p<0.05), CXCR2 (3.6, p<0.05), CCR2 (3.8, p<0.05), Hsp70 (2.4, p<0.05), HIF-1alpha (1.5, p<0.001), TRAF6 (1.3, p<0.05) and TNFR1 (1.6, p<0.05). After 21 h of acidotic reoxygenation after acidotic hypoxia, we found a significant increase in RNA of IL-1R1, IL-10RA, CXCR4 and Hsp70 compared to control, and a significant decrease in FAS and TRAF6. There was a significant increase in Bax expression and a significant decrease in Bcl-2 and Bcl-xL expression in three out of four pH groups after 21 h of reoxygenation. Acidotic, relative to neutral, hypoxia and reoxygenation also influenced the expression of various genes. We conclude that inflammatory receptors and pathways are activated during hypoxia and reoxygenation in NT2-N neurons, and that this activation is pH dependent. This supports the concept that inflammatory pathways play a role in cerebral hypoxic-ischemic damage, and that they may represent important pharmacological targets.
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PMID:Inflammatory receptors and pathways in human NT2-N neurons during hypoxia and reoxygenation. Impact of acidosis. 1850 2

Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1alpha, a primary constituent associated with hypoxic angiogenesis and a regulator of neuroprotective responses. The rationale that the utilization of ketones by the brain results in elevation of intracellular succinate, a known inhibitor of prolyl hydroxylase (the enzyme responsible for the degradation of HIF-1alpha) was deemed as a potential mechanism of ketosis on the upregulation of HIF-1alpha. The neuroprotective effect of diet-induced ketosis (3 weeks of feeding a ketogenic diet), as pretreatment, on infarct volume, after reversible middle cerebral artery occlusion (MCAO), and the upregulation of HIF-1alpha were investigated. The effect of beta-hydroxybutyrate (BHB), as a pretreatment, via intraventricular infusion (4 days of infusion before stroke) was also investigated following MCAO. Levels of HIF-1alpha and Bcl-2 (anti-apoptotic protein) proteins and succinate content were measured. A 55% or 70% reduction in infarct volume was observed with BHB infusion or diet-induced ketosis, respectively. The levels of HIF-1alpha and Bcl-2 proteins increased threefold with diet-induced ketosis; BHB infusions also resulted in increases in these proteins. As hypothesized, succinate content increased by 55% with diet-induced ketosis and fourfold with BHB infusion. In conclusion, the biochemical link between ketosis and the stabilization of HIF-1alpha is through the elevation of succinate, and both HIF-1alpha stabilization and Bcl-2 upregulation play a role in ketone-induced neuroprotection in the brain.
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PMID:Neuroprotection in diet-induced ketotic rat brain after focal ischemia. 1864 82

Hypoxic preconditioning may afford protection against subsequent lethal hypoxia. As hypoxic tolerance induces changes in the expression of genes involved in DNA damage and repair response pathways, we investigated whether DNA-dependent protein kinase (DNA-PK), one of the DNA double-strand break repair proteins, could be involved in hypoxic preconditioning-induced protective signaling cascades. We showed that induction of hypoxia-inducible factor-1alpha expression during hypoxic preconditioning by repeated hypoxic exposure was associated with increased mRNA and protein levels of DNA-PK catalytic subunit (DNA-PKcs) and Ku70/Ku80, the DNA-PK components, in human hepatoma HepG2 cells, followed by upregulation of Hsp70/Hsp90 and Bcl-2 and concurrent downregulation of Bax. Additionally, loss of DNA-PKcs led to attenuated expression of Hsp70/Hsp90, accelerated hypoxia-inducible factor-1alpha degradation, and increased susceptibility to hypoxia-induced cell death. We also found that the mRNA and protein levels of heat shock factor-1 (HSF1) were progressively increased with DNA-PK activation during hypoxic preconditioning, and inhibition of HSF1 function by KNK437 resulted in a significant decrease in the level of protein kinase Akt as well as of DNA-PKcs, with downregulation of Hsp70/Hsp90 and HIF-1alpha. Our results suggest the possibility that DNA-PK-mediated signaling pathway is required for the increase in HIF-1alpha expression through activation of HSF1 and subsequent upregulation of heat shock proteins after hypoxic reconditioning.
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PMID:DNA-dependent protein kinase is involved in heat shock protein-mediated accumulation of hypoxia-inducible factor-1alpha in hypoxic preconditioned HepG2 cells. 1902 71

The effects and potential molecular mechanisms underlying carbon dioxide (CO(2)) pneumoperitoneum on gastric cancer cell apoptosis are not fully understood. In this study, we assessed the effects of CO(2) pneumoperitoneum on the apoptosis of MKN-45 gastric cancer cells. Additionally, we investigated the role of HIF-1alpha in CO(2) pneumoperitoneum-induced apoptosis of gastric cancer cells. MKN-45 cells were cultured in CO(2) or air pneumoperitoneum at 0, 12 and 15 mmHg pressures for 4 h. We observed a change in cells morphology and increasing apoptotic ratios in MKN-45 cells when they were put into a 15 mmHg CO(2) pneumoperitoneum environment. However, there was no significant difference between the 0, 12 mmHg CO(2) pneumoperitoneum and the control groups. Exposure to 15 mmHg CO(2) pneumoperitoneum significantly enhanced the expression levels of HIF-1alpha and Bax, while it attenuated Bcl-2 expression levels. When we inhibited HIF-1alpha by small interfering RNA (siRNA), we found that the apoptotic ratio of MKN-45 cells decreased in 15 mmHg CO(2) pneumoperitoneum. This treatment markedly elevated Bcl-2 levels and decreased Bax expression. These data suggest that CO(2) pneumoperitoneum may accelerate the apoptosis of MKN-45 cells at higher pressures. HIF-1alpha is a crucial factor that affects gastric cancer cell apoptosis by downregulating the Bcl-2/Bax ratio.
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PMID:Effects of HIF-1alpha on human gastric cancer cell apoptosis at different CO(2) pressures. 1904 82

A novel cancer stem-like cell line (3AB-OS), expressing a number of pluripotent stem cell markers, was irreversibly selected from human osteosarcoma MG-63 cells by long-term treatment (100 days) with 3-aminobenzamide (3AB). 3AB-OS cells are a heterogeneous and stable cell population composed by three types of fibroblastoid cells, spindle-shaped, polygonal-shaped, and rounded-shaped. With respect to MG-63 cells, 3AB-OS cells are extremely smaller, possess a much greater capacity to form spheres, a stronger self-renewal ability and much higher levels of cell cycle markers which account for G1-S/G2-M phases progression. Differently from MG-63 cells, 3AB-OS cells can be reseeded unlimitedly without losing their proliferative potential. They show an ATP-binding cassette transporter ABCG2-dependent phenotype with high drug efflux capacity, and a strong positivity for CD133, marker for pluripotent stem cells, which are almost unmeasurable in MG-63 cells. 3AB-OS cells are much less committed to osteogenic and adipogenic differentiation than MG-63 cells and highly express genes required for maintaining stem cell state (Oct3/4, hTERT, nucleostemin, Nanog) and for inhibiting apoptosis (HIF-1alpha, FLIP-L, Bcl-2, XIAP, IAPs, and survivin). 3AB-OS may be a novel tumor cell line useful for investigating the mechanisms by which stem cells enrichment may be induced in a tumor cell line. The identification of a subpopulation of cancer stem cells that drives tumorigenesis and chemoresistance in osteosarcoma may lead to prognosis and optimal therapy determination. Expression patterns of stem cell markers, especially CD133 and ABCG2, may indicate the undifferentiated state of osteosarcoma tumors, and may correlate with unfavorable prognosis in the clinical setting.
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PMID:Identification and expansion of human osteosarcoma-cancer-stem cells by long-term 3-aminobenzamide treatment. 1916 Apr 14

We tested whether transplant arteriosclerosis can be reduced by pre-treatment of the donor with immunosuppressive agents, using a rat allogeneic aorta transplantation model. Donor rats received no pre-treatment, or tacrolimus, methylprednisolone, rapamycin, or mycofenolate mofetil (MMF) 16 and 2h before explantation of the grafts. Eight weeks after transplantation, aorta allografts were harvested. Percent intima area/intima+media area (I/I+M), inflammatory cells and in situ MMP-2 and -9 activity were determined. In pre-transplantation biopsies, MMP-2 and -9 ratio, and mRNA levels for genes of interest were determined. In pre-transplantation biopsies we found no differences in MMP-2/9 ratio, and Bcl-2, Bax, TGF-beta, HO-1, p21, and HIF-1alpha mRNA expression between the groups. Aorta allografts, pre-treated with tacrolimus, showed significantly lower I/I+M ratio compared to untreated controls (p<0.01). Pre-treatment with methylprednisolone, rapamycin or MMF did not significantly reduce I/I+M ratio. In situ MMP-2/MMP-9 activity was significantly reduced in grafts treated with tacrolimus and rapamycin compared to controls (p<0.05). Immunohistochemistry revealed a high number of CD4+ cells and high CD4/CD8 ratio in grafts pre-treated with tacrolimus. Donor pre-treatment with tacrolimus significantly reduces transplant arteriosclerosis and is associated with reduced in situ MMP-2/MMP-9 activity and increased number of CD4+ cells.
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PMID:Donor pre-treatment with tacrolimus reduces transplant vasculopathy. 1916 89

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