UNIPROT:P10415 - FACTA Search

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)

Fetal brown adipocytes are insulin-like growth factor-I (IGF-I) target cells. To assess the importance of the IGF-I receptor (IGF-IR) in brown adipocytes during fetal life, we have generated immortalized brown adipocyte cell lines from the IGF-IR(-/-) mice. Using this experimental model, we demonstrate that the lack of IGF-IR in fetal brown adipocytes increased the susceptibility to apoptosis induced by serum withdrawal. Culture of cells in the absence of serum and growth factors produced rapid DNA fragmentation (4 h) in IGF-IR(-/-) brown adipocytes, compared with the wild type (16 h). Consequently, cell viability was decreased more rapidly in fetal brown adipocytes in the absence of IGF-IR. Furthermore, caspase-3 activity was induced much earlier in cells lacking IGF-IR. At the molecular level, IGF-IR deficiency in fetal brown adipocytes altered the balance of the expression of several proapoptotic (Bcl-xS and Bim) and antiapoptotic (Bcl-2 and Bcl-xL) members of the Bcl-2 family. This imbalance was irreversible even though in IGF-IR-reconstituted cells. Likewise, cytosolic cytochrome c levels increased rapidly in IGF-IR-deficient cells compared with the wild type. A rapid entry of Foxo1 into the nucleus accompanied by a rapid exit from the cytosol and an earlier activation of caspase-8 were observed in brown adipocytes lacking IGF-IR upon serum deprivation. Activation of caspase-8 was inhibited by 50% in both cell types by neutralizing anti-Fas-ligand antibody. Adenoviral infection of wild-type brown adipocytes with constitutively active Foxol (ADA) increased the expression of antiapoptotic genes, decreased Bcl-xL and induced caspase-8 and -3 activities, with the final outcome of DNA fragmentation. Up-regulation of uncoupling protein-1 (UCP-1) expression in IGF-IR-deficient cells by transduction with PGC-1alpha or UCP-1 ameliorated caspase-3 activation, thereby retarding apoptosis. Finally, insulin treatment prevented apoptosis in both cell types. However, the survival effect of insulin on IGF-IR(-/-) brown adipocytes was elicited even in the absence of phosphatidylinositol 3-kinase/Akt signaling. Thus, our results demonstrate for the first time the unique role of IGF-IR in maintaining the balance of death and survival in fetal brown adipocytes.
...
PMID:Susceptibility to apoptosis in insulin-like growth factor-I receptor-deficient brown adipocytes. 1535 71

The protective effect of synthetic serum thymic factor (FTS) nonapeptide on lipopolysaccharide (LPS)-induced pancreatic cell damage in 10-week-old BALB/c male mice was investigated. Mice were divided into three groups. Group I was treated with LPS (10 micro g/head; i.p.) (LPS-treated mice). Group II was administered with FTS (50 micro g/head; i.p.) 24 hr before treatment with LPS and complemented immediately before LPS injection with FTS (50 micro g/head; i.p.) (FTS-administered mice). Group III was only treated with the same volume of saline (control mice). Treatment of LPS in vivo resulted in the destruction of pancreatic acinar cells. In those cells, many apoptotic cells were detected by immunohistochemistry using an anti-single stranded DNA antibody. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) revealed that LPS treatment also caused low or a lack of insulin expression in pancreatic islets. In contrast, morphological change was not seen and apoptotic cell death was suppressed in pancreatic cells of FTS-administered mice. Moreover, insulin expression was normal in those mice. FTS administration enhanced expression of Bcl-2 mRNA levels in pancreatic tissues and IL-6 mRNA levels in splenocytes significantly compared with those of LPS treatment at 3 hr after LPS injection. These findings suggest that FTS prevents LPS-induced cell damage via enhancing Bcl-2 expression in the pancreas and systemic IL-6 production.
...
PMID:Serum thymic factor prevents LPS-induced pancreatic cell damage in mice via up-regulation of Bcl-2 expression in pancreas. 1538 98

The mammalian target of rapamycin (mTOR) is a central regulator of ribosome biogenesis, protein synthesis, cell growth and neurite plasticity. The mTOR kinase controls the translation machinery, in response to amino acids and growth factors, via activation of p70 ribosomal S6 kinase (p70S6K) and inhibition of eIF-4E binding protein (4E-BP1). The mTOR protein belongs to the PI3K pathway activated by insulin, nutrients and growth factors. The PI3K pathway involves the Akt kinase, an upstream regulator of mTOR. Rapamycin is a potent immunosuppressant and investigational anticancer drug, which inhibits mTOR, blocking protein synthesis and arresting the cell cycle in G1 phase. A wide body of evidence supports the role of mTOR in cell signaling related to cell growth and proliferation. Nevertheless, our recent findings have revealed that mTOR may be also involved in a signaling pathway activated by microtubule-damaging drugs, including taxol and nocodazole. It is known that agents affecting the integrity of microtubules activate apoptotic program by inducing phosphorylation and inactivation of the antiapoptotic Bcl-2 protein in G2-M phase. We have some evidence that mTOR is involved in the enzymatic cascade that, starting from damaged microtubules, induces downstream phosphorylation of the Bcl-2 protein. We also found that the level of activity of Akt can regulate Bcl-2 phosphorylation, through the mTOR kinase. Since mTOR activation by survival signals occurs in G1 phase and damaged microtubules activate proapoptotic signals in G2-M phase, we suggest that mTOR might mediate these two different pathways in two different phases of the cell cycle.
...
PMID:mTOR: a protein kinase switching between life and death. 1550 91

Radiotherapy plays an important role in the management of breast cancer. Whilst its role in achieving local control following surgery in patients with early stage cancer is well established, there is still unclear evidence to explain the factors governing radioresistance in patients who develop recurrences both in the breast and axilla. Radiotherapy induces damage to the DNA. Various cell cycle damage check points and DNA damage repair pathways have been demonstrated. Ataxia telangiectasia mutant (ATM) kinase, which is a member of phosphatidylinositol-3 kinase (PI-3K) family appears to play a central role in DNA damage check point pathways. Over-expression of Insulin like growth factor-I receptor (IGF-IR), Human Epidermal Growth factor receptors (HERS), Vascular Endothelial growth factor (VEGF) on the cell surface and increased concentration of Epidermal Growth factor in the extracellular fluid have been associated with radioresistance. Specific genes such as p53, BRCA, Bcl-2 and chromosomal characteristics like telomere lengths have also been identified as playing significant roles in radiation responsiveness of a cell. This article reviews the current data on general principles of radiotherapy, the cellular mechanisms that operate in response to radiation damage and various molecular markers, intranuclear and extranuclear which have been demonstrated to influence radiation sensitivity in breast cancer cells.
...
PMID:Radioresistance in carcinoma of the breast. 1556 51

This study examined the potential roles of astragalus and angiotensin II type 2 receptor (AT2) in rats with streptozotocin (STZ)-induced diabetic cardiomyopathy. Of 52 female 4-week-old Wistar rats treated with high glucose and lipid diet to induce insulin resistance, 7 treated with sodium citrate buffer (pH=4.5) served as controls (con1) and the other 45 were treated by intraperitoneal injection (ip) of STZ to induce type 2 diabetes. After 20 weeks, the maximal velocity decrease of pressure per second in left ventricle within the period of isovolumic relaxation (-dp/dtmax) was detected by inserting cannula through right carotid artery. Of the 45 rats, 24 with -dp/dtmax < or = 700 mmHg/s (1 mmHg=0.133 kPa) developing diabetic cardiomyopathy were grouped as follows: 7 treated with double distilled H2O (ip) were included in control group 2 (con2); other 8 treated with AT2 agonist (CGP42112A, ip) were included in experimental group1 (exp); 9 treated with astragalus (po) constituted experimental group 2 (exp2). All injections lasted 4 weeks (qd) and the heart weight (HW) was recorded. Cardiomyocyte apoptosis index (CAI), mRNA of AT2 and Bcl-2 as well as AT2 and Bcl-2 protein values in cardiomyocytes were also measured. Our results showed that -dp/dtmax in exp1, exp2 and con2 were much lower than those in con1 (P<0.01). CAI and AT2 in both mRNA and protein in con1 were lower than those in the other three groups (P<0.01). The three parameters above were higher in exp1 but less in exp2 than those in con2, respectively (P<0.01). The three parameters and HW in exp1 were much higher than those in exp2 (P<0.01). Changes of Bcl-2 were opposite to those of AT2. Our results suggested that high expression of AT2 might accelerate the apoptosis of cardiomyocytes in diabetic rats and play an important role in precipitating diabetic cardiomyopathy and astragalus protects diabetic rats from developing cardiomyopathy by downregulating AT2.
...
PMID:Astragalus prevents diabetic rats from developing cardiomyopathy by downregulating angiotensin II type2 receptors' expression. 1558 4

Immunosuppressive drugs are routinely used to provide tolerance after whole pancreas and islet cell transplantations. While they are essential in inhibiting graft rejection, little is known about their effect on islet function and beta-cell viability. In this study, we report that tacrolimus, sirolimus, and mycophenolic acid, when added to cultures of freshly isolated human islets, induce a downregulation of the synthesis and secretion of insulin. These functional changes are associated with decreased islet cell viability. All three agents induce a decrease of intracellular levels of Bcl-2 and Bcl-xL, with an increased level of Smac, indicating that they are capable of promoting a downregulation of anti-apoptotic factors and an accumulation of pro-apoptotic mediators. Transduction of islet cells with the anti-apoptotic gene XIAP prevents the negative effects of these drugs on the function and viability of islets. XIAP-infected cells show a higher expression of phospho-CREB (cAMP-responsive element binding protein) and a reduced level of Smac, resulting in a significant reduction of apoptotic cells and a preservation of the glucose-dependent secretion of insulin. In conclusion, the present study demonstrates that genetically modified human islets expressing XIAP are resistant to the negative effects of immunosuppressive drugs on insulin secretion and cell viability.
...
PMID:Adenovirus-mediated XIAP gene transfer reverses the negative effects of immunosuppressive drugs on insulin secretion and cell viability of isolated human islets. 1567

The hormone glucose-dependent insulinotropic polypeptide (GIP) potently stimulates insulin secretion and promotes beta-cell proliferation and cell survival. In the present study we identified Forkhead (Foxo1)-mediated suppression of the bax gene as a critical component of the effects of GIP on cell survival. Treatment of INS-1(832/13) beta-cells with GIP resulted in concentration-dependent activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)/Foxo1 signaling module. In parallel studies, GIP decreased bax promoter activity. Serial deletion analysis of the bax promoter demonstrated that the region -682 to -320, containing FHRE-II (5AAAACAAACA), was responsible for GIP-mediated effects. Foxo1 bound to FHRE-II in gel mobility shift assays, and Foxo1-FHRE-II interactions conferred GIP responsiveness to the bax promoter. INS-1 cells incubated under proapoptotic and glucolipotoxic conditions demonstrated increased nuclear localization of Foxo1 and bax promoter activity and decreased cytoplasmic phospho-PKB/Foxo1. GIP partially restored expression PKB/Foxo1 and bax promoter activity. Similar protective effects were found with dispersed islet cells from C57BL/6 mice, but not with those from GIP receptor knock-out (GIPR(-/-)) mice. GIP treatment reduced glucolipotoxicity-induced cell death in C57 BL/6 and Bax(-/-) islets, but not GIPR(-/-) mouse islets. Chronic treatment of Vancouver diabetic fatty Zucker rats with GIP resulted in down-regulation of Bax and up-regulation of Bcl-2 in pancreatic beta-cells. The results show that PI3K/PKB/Foxo1 signaling mediates GIP suppression of bax gene expression and that this module is a key pathway by which GIP regulates beta-cell apoptosis in vivo.
...
PMID:Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. 1581 64

Glucose intolerance is often observed after pancreatic islet cell transplantation. The administration of immunosuppressive agents (ISD), necessary to avoid tissue rejection, is in part responsible for hyperglycemia. To investigate whether mouse insulinoma (MIN6) cells transfected with the glucagon like peptide-1 (GLP-1) fragment of the proglucagon gene (RIP/GLP-1 MIN6 cells) are resistant to the toxicity derived from the administration of ISD. RIP/GLP-1 MIN6 cells, as well as parental MIN6 cells, were exposed to a cocktail of ISD. The secretion of insulin and the expression of apoptosis-related proteins were investigated by RIA and western blot analysis. Cell apoptosis was quantified by FACS analysis. Finally, to study whether the antiapoptotic action of GLP-1 was a function of its effect on insulin secretion, or rather it was a direct effect of GLP-1, cells were cultured with or without diazoxide or exendin-9. GLP-1 improved the functional activity and the viability of cells exposed to ISD. The insulin secretion of RIP/GLP-1 MIN6 cells after exposure to ISD was preserved. The expression of GLP-1 by beta-cells reduced the number of apoptotic cells and increased the expression of the antiapoptotic protein Bcl-2. GLP-1 also decreased the abundance of the proapoptotic markers PARP-p85 and Smac/Diablo. Treatment of cells with the diazoxide did not abolish the protective advantage that cells transfected with GLP-1 had; conversely the exposure of cells to exendin-9 was associated with a restored susceptibility to apoptosis. This report demonstrates that GLP-1 is capable of preserving beta-cell function and protecting cells from apoptotic cell death.
...
PMID:Pancreatic beta-cells expressing GLP-1 are resistant to the toxic effects of immunosuppressive drugs. 1582 Nov 4

The unfolded protein response pathway (UPR) compensates for excessive protein accumulation in the endoplasmic reticulum (ER). As insulin induces global protein synthesis, it may cause accumulation of unfolded proteins in the ER, thus triggering UPR. We assessed UPR activation in insulin-treated murine peritoneal macrophages using a number of markers including 78 kDa glucose response protein (GRP78), X-box-binding protein (XBP)-1, pancreatic ER kinase (PERK), eukaryotic initiation factor 2 (eIF2)alpha, and growth arrest and DNA damage (GADD)34. Exposure of cells to insulin activated UPR, as evidenced by an increased expression of GRP78, XBP-1, phosphorylated PERK (p-PERK), and p-eIF2alpha. The insulin-induced, elevated expression of GRP78 was comparable with that observed with tunicamycin, a classical inducer of ER stress. Concomitantly, insulin also up-regulated prosurvival mechanisms by elevating GADD34 and elements of the antiapoptotic pathway including Bcl-2, X-linked inhibitor of apoptosis, and phosphorylated forkhead transcription factor. In conclusion, we show here that insulin treatment does cause ER stress in macrophages, but insulin-dependent mechanisms overcome this ER stress by up-regulating UPR and the antiapoptotic pathway to promote cell survival.
...
PMID:Up-regulation of GRP78 and antiapoptotic signaling in murine peritoneal macrophages exposed to insulin. 1584 44

PANcreatic DERived factor (PANDER, FAM3B) is a recently discovered islet-specific cytokine. We have previously shown that, in vitro, truncated recombinant PANDER isoforms (20 and 21 kDa) are cytotoxic to beta-cell lines but the effects of full-length PANDER on islet biology remain unclear. In this study, we used adenovirus (Ad-PANDER) to overexpress full-length cDNA of PANDER in islets and betaTC3 cells. BetaTC3 cells were infected with Ad-PANDER or control vector. After 48 h, cell viability was significantly decreased as evaluated by MTT assay. The number of dead cells was significantly increased as indicated by the fluorescent intensity of the propidium iodide-stained cells (160 +/- 13 vs. control 100 +/- 7%, P = 0.001). Flow cytometric Tunel assay showed that overexpressing PANDER induced a significant fourfold increase in beta-cell apoptosis (19.4 +/- 6.3 vs. control 4.1 +/- 0.8%, P < 0.05). There was a significant increase in the number of annexin V-positive (apoptotic) cells and propidium iodide-positive (dead) cells in mouse islets infected with Ad-PANDER compared with control cells infected with Ad-LacZ. Addition of 4 nM recombinant PANDER protein to betaTC3 cells or infection of Ad-PANDER did not affect Akt and STAT1 phosphorylation, Bcl-2, Fas, and NF-kappaB protein levels. However, activation of caspase-3 was observed in betaTC3 and islets infected with Ad-PANDER. Overexpression of PANDER in mouse islets or addition of recombinant PANDER decreased insulin secretion induced by carbachol plus glucose or high potassium but not that by glucose alone. Culture with recombinant PANDER did not affect glucose-induced NAD(P)H elevation in mouse islets. In conclusion, Ad-PANDER infection is as effective as truncated recombinant PANDER to induce betaTC3 cell and mouse islet apoptosis.
...
PMID:Effects of overexpression of pancreatic derived factor (FAM3B) in isolated mouse islets and insulin-secreting betaTC3 cells. 1592 25

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