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Rodewald, Hans-Reimer, Claudia Waskow und Corinne Haller. „Essential Requirement for C-KIT and Common γ Chain in Thymocyte Development Cannot Be Overruled by Enforced Expression of Bcl-2“. Journal of Experimental Medicine 193, Nr. 12 (18.06.2001): 1431–38. http://dx.doi.org/10.1084/jem.193.12.1431.
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The thymus in mice lacking both the receptor tyrosine kinase c-kit and the common cytokine receptor γ chain (γc) is alymphoid because these receptors provide essential signals at the earliest stages of thymocyte development. The signals transduced by these receptors potentially regulate proliferation, survival, or differentiation, but the contribution of each receptor to distinct intracellular signaling cascades is only poorly defined. Here, we have examined whether enforced expression of Bcl-2 can rescue thymocyte development in c-kit and γc single or double mutant mice. A bcl-2 transgene (Eμ-bcl-2-25; expressed in the T cell lineage) was introduced into (a) c-kit and γc wild-type (c-kit+γc+bcl+), (b) c-kit–deficient (c-kit−γc+bcl+), (c) γc-deficient (c-kit+γc−bcl+), or (d) c-kit and γc double-deficient mice (c-kit−γc−bcl+). The bcl-2 transgene was functionally active in wild-type and c-kit or γc single mutants, as it promoted survival of ex vivo isolated thymocytes, including pro-T cells. In vivo, however, transgenic Bcl-2 did not release T cell precursors from their phenotypic block and failed to increase progenitor or total thymocyte cellularity in c-kit or γc single or double mutants. These data argue strongly against a role for Bcl-2 as a key mediator in signaling pathways linked to cytokine and growth factor receptors driving early thymocyte development.
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Vervliet, T., E. Decrock, J. Molgo, V. Sorrentino, L. Missiaen, L. Leybaert, H. De Smedt, N. N. Kasri, J. B. Parys und G. Bultynck. „Bcl-2 binds to and inhibits ryanodine receptors“. Journal of Cell Science 127, Nr. 12 (24.04.2014): 2782–92. http://dx.doi.org/10.1242/jcs.150011.
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Ibeas, Patricia, Ana Lopez-Gonzalez, Bernard Gaston Doger de Speville, Miriam Huelves, Roberto Lopez, Elena Almagro, Magda Palka, Andrea Ruiz-Valdepeñas, David Perez Callejo und Mariano Provencio. „Prognostic value of Bcl-2 in breast cancer.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): e11527-e11527. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e11527.
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e11527 Background: Breast cancer is a heterogeneous disease with prognostic factors used by the oncologists to decide the treatment. Bcl2 is an antiapoptotic proto-oncogen involved in DNA break process that has been defined historically as a poor prognostic factor. This study was conducted to confirm whether or not bcl-2 is an independent prognostic factor. Methods: In this study, we have reviewed all patients who were diagnosed at our hospital between January 2007 and December 2008 (99 patients). Inclusion criteria were patients diagnosed of breast cancer whose anatomopathological report showed bcl-2 status as well as the rest of the parameters measured. The parameters measured were age, past medical history, menopausal status, TNM, hormone receptors, HER2, p53, Ki67, bcl-2, treatment applied, date of relapse (if any), date of death ( if occurred). All of them characterized by centralization measures. We conducted an analysis of prognostic factor that influenced survival. Results: The average age of diagnosis is 54.6 years (30-94 years). 42.4% were premenopausal. The average tumor size was 2.59 cm ( 0.5-7.5 cm). 81.8% had positive estrogen receptors. 92% were HER2 negative by inmunohistochemistry. 62.6% were p53 negative. Bcl-2 was 84.8% positive. The distribution by stage at diagnosis was: stage I 26.3%; stage II 49.5%; stage III 22.2%. Disease free survival for patients bcl2(+) was 45.6 months versus 22.6 months for patients bcl2 (-) (0.12-22.2; p: 0.00125). Overall survival for the group bcl2(+) was 48 months (41.6-54.3) and bcl2 (-) was 48.24 months (42.48 to 54). Conclusions: We can state that bcl2 is not an independent prognostic factor. Despite the value in other diseases, the determination of bcl-2 by inmunohistochemistry in breast cancer in stages I, II and III at the moment of the diagnosis does not provide any prognostic information.
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Ueno, Hiroo, Eisaku Kondo, Ritsuko Yamamoto-Honda, Kazuyuki Tobe, Tetsuya Nakamoto, Ko Sasaki, Kinuko Mitani et al. „Association of Insulin Receptor Substrate Proteins with Bcl-2 and Their Effects on Its Phosphorylation and Antiapoptotic Function“. Molecular Biology of the Cell 11, Nr. 2 (Februar 2000): 735–46. http://dx.doi.org/10.1091/mbc.11.2.735.
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Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2.
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Yin, Xiaobei, Ting He, Rui Chen, Hui Cui und Genlin Li. „Impact of neurotrophic factors combination therapy on retinitis pigmentosa“. Journal of International Medical Research 48, Nr. 11 (November 2020): 030006052096783. http://dx.doi.org/10.1177/0300060520967833.
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Objective We aimed to determine the location of neurotrophic receptors tropomyosin receptor kinase (Trk)B, TrkC, and ciliary neurotrophic factor receptor (CNTFR)α in the retina of retinal degeneration ( rd) mice and to explore the dynamic changes of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X-protein (Bax), and microtubule-associated protein light chain 3 (LC3) expression and ultrastructure in the retina of rd mice intravitreally injected with neurotrophic factors. Methods Rd mice aged 2 and 3 weeks post-natally (PN) received intravitreal injections of neurotrophic factors. Two weeks later, their retinas were harvested for the detection of Bax, Bcl-2, and LC3 mRNA and protein expression. Results TrkB and TrkC expression levels were lower at 3 weeks PN compared with 0, 1, and 2 weeks PN, but CNTFRα expression was still detected in certain layers. The three receptors were expressed in different retinal layers at the same timepoint. Bax expression was downregulated in, rhBDNF + rhCNTF, rhBDNF + rhNT-3, groups 2 weeks after intravitreal injection; Bcl-2 expression was upregulated in the rhBDNF + rhCNTF + rhNT-3 group at PN-4w; and LC3 expression was upregulated in rhBDNF + rhCNTF + rhNT-3 groups. Conclusions The combined use of neurotrophic factors had a more significant effect on Bax, Bcl-2, and LC3 expression than the same factors used alone.
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Silvestrini, R., E. Benini, S. Veneroni, M. G. Daidone, G. Tomasic, P. Squicciarini und B. Salvadori. „p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients.“ Journal of Clinical Oncology 14, Nr. 5 (Mai 1996): 1604–10. http://dx.doi.org/10.1200/jco.1996.14.5.1604.
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BACKGROUND AND PURPOSE The tumor-suppressor gene TP53 and the proto-oncogene bcl-2 encode, respectively, for a nuclear phosphoprotein and for a mitochondrial protein involved in multiple cellular functions. The proteins provide prognostic information in node-negative breast cancer and are supposed to influence treatment responsiveness. We analyzed the predictive role of p53 and bcl-2 expression, alone and in association with other variables, in postmenopausal women with node-positive, estrogen receptor-positive (ER+) breast cancers treated with radical or conservative surgery plus radiotherapy and adjuvant tamoxifen for at least 1 year. PATIENTS AND METHODS On 240 resectable cancers, we determined the expression of p53 and bcl-2, using immunohistochemistry, cell proliferation (3H-thymidine labeling index [3H-dT LI]), and ER and progesterone receptors (PgR). RESULTS p53 expression and 3H-dT LI were weakly related to one another and both were unrelated to bcl-2. Relapse-free and distant metastasis-free survival at 5 years were significantly lower for patients with tumors that highly expressed p53 (P = .0001) and for those that weakly expressed or did not express bcl-2 (P = .02). However, p53, but not bcl-2, provided prognostic information independent of tumor size, axillary node involvement, steroid receptors, and 3H-dT LI. Moreover, the simultaneous p53 overexpression and lack of PgR identified patients at maximum risk of relapse, whereas bcl-2 overexpression, associated with a low 3H-dT LI or the presence of PgR, improved the prognostic resolution for low-risk patients. CONCLUSION p53 expression appears to be indicative of clinical outcome in postmenopausal patients treated with tamoxifen. Whether p53 overexpression and weak bcl-2 expression are indicators of biologic aggressiveness, regardless of treatment, or of hormone resistance remains to be defined.
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Mutiah, Roihatul, Muhammad Fawaz Hariz, Yen Yen Ari Indrawijaya und Burhan Ma'arif. „In Silico Prediction of Isoliquiritigenin and Oxyresveratrol Compounds to BCL-2 dan VEGF-2 Receptors“. Indonesian Journal of Cancer Chemoprevention 10, Nr. 2 (09.07.2019): 51. http://dx.doi.org/10.14499/indonesianjcanchemoprev10iss2pp51-59.
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Isoliquiritigenin and oxyresveratrol are compounds that have been reported to have anticancer activities. This study aimed to predict cytotoxic activity, toxicity and physicochemical properties of the compounds isoliquiritigenin and oxyresveratrol. Prediction of physicochemical properties referred to Lipinski rules of five using the pkCSM online tool. Prediction of compounds toxicity using Protox II online tool while ligand interaction with receptors using Molegro Virtual Docker (MVD). Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) (PDB: 2RL5) and B Cell Lymphoma BCL-2 (PDB: 4AQ3) were used as target cancer receptor proteins. In silico predictive results showed that oxyresveratrol and isoliquiritigenin complied with Lipinski rules of five, predictive values of LD50 between 500-2000 mg/kg respectively 1560 mg/kg and 1048 mg/kg. The docking result was in the form of bound energy described by Rerank Score (RS). A compound having a small RS value was predicted to have greater activity. RS of oxyresveratrol on 2RL5: -73.0413 and 4AQ3: -87.9985, while isoliquiritigenin on 2RL5: -68.0282 and 4AQ3: -78.5041. The cytotoxic activity of oxyresveratrol was also shown by hydrogen bonds in active amino acids (2RL5: Cys 919 in 4AQ3: Tyr 67). From docking results of both compounds, oxyreveratrol had greater activity than isoliquiritigenin to both target cancer receptor proteins and complied Lipinski rules of five and have a low toxicity.Keywords: cytotoxicity, toxicity, isoliquiritigenin, oxyresveratrol, in silico.
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Das, Samarjit, Gerald A. Cordis, Nilanjana Maulik und Dipak K. Das. „Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation“. American Journal of Physiology-Heart and Circulatory Physiology 288, Nr. 1 (Januar 2005): H328—H335. http://dx.doi.org/10.1152/ajpheart.00453.2004.
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Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning (PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 μM resveratrol; 3) 10 μM resveratrol + 1 μM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A1 receptor blocker); 4) 10 μM resveratrol + 1 μM 8-(3-chlorostyryl)caffeine (CSC; adenosine A2a receptor blocker); 5) 10 μM resveratrol + 1 μM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A3 receptor blocker); or 6) 10 μM resveratrol + 3 μM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI)3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A1 and A3 receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A1 and A3 receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.
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McCullers, Deanna L., und James P. Herman. „Mineralocorticoid receptors regulate bcl-2 and p53 mRNA expression in hippocampus“. NeuroReport 9, Nr. 13 (September 1998): 3085–89. http://dx.doi.org/10.1097/00001756-199809140-00031.
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Banta, Karl L., Xinyue Wang, Phani Das und Astar Winoto. „B cell lymphoma 2 (Bcl-2) residues essential for Bcl-2's apoptosis-inducing interaction with Nur77/Nor-1 orphan steroid receptors“. Journal of Biological Chemistry 293, Nr. 13 (02.02.2018): 4724–34. http://dx.doi.org/10.1074/jbc.ra117.001101.
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Taylor, Lydia J., Tracy L. Jackson, Janet G. Reid und Sean R. G. Duffy. „The differential expression of oestrogen receptors, progesterone receptors, Bcl-2 and Ki67 in endometrial polyps“. BJOG: An International Journal of Obstetrics and Gynaecology 110, Nr. 9 (September 2003): 794–98. http://dx.doi.org/10.1111/j.1471-0528.2003.02098.x.
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Lin, Yi-Yuan, Yi Hong, Shao-Hong Yu, Xu-Bo Wu, Woei-Cherng Shyu, Jwo-Sheng Chen, Hua Ting, Ai-Lun Yang und Shin-Da Lee. „Antiapoptotic and mitochondrial biogenetic effects of exercise training on ovariectomized hypertensive rat hearts“. Journal of Applied Physiology 126, Nr. 6 (01.06.2019): 1661–72. http://dx.doi.org/10.1152/japplphysiol.00038.2019.
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This study was to investigate the effects of exercise training on antiapoptotic pathways and mitochondrial biogenesis in ovariectomized hypertensive rats. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from female spontaneously hypertensive rats (SHR), which were divided into a sham-operated sedentary hypertensive (SHR-S), a sedentary hypertensive ovariectomized (SHR-O), and hypertensive ovariectomized rats that underwent treadmill exercise training (SHR-OT; 60 min/day, 5 days/wk) for 8 wk, along with normotensive Wistar Kyoto rats (WKY). When compared with the WKY group, the SHR-S group exhibited decreased protein levels of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial OPA-1 (mitochondrial biogenesis) and decreased further in the SHR-O group. The protein levels of p-PI3K, p-Akt, Bcl-2, Bcl-xL (prosurvival pathways), and the protein levels of PGC-1α and mitochondrial OPA1 (mitochondrial biogenesis) were increased in the SHR-OT group, but estrogen receptor (ER)α and ERβ were not changed when compared with the SHR-O group. The protein levels of t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3 (mitochondria-dependent apoptotic pathways), as well as Fas ligand, TNF-α, Fas receptors, Fas-associated death domain, activated caspase 8 (Fas receptor-dependent apoptotic pathways) were decreased in the SHR-OT group, when compared with the SHR-O group. Exercise training protection on the coexistence of hypertension and ovariectomy-induced cardiac mitochondria-dependent and Fas receptor-dependent apoptotic pathways by enhancing the Bcl2-related and mitochondrial biogenetic prosurvival pathways might provide a new therapeutic effect on cardiac protection in oophorectomized early postmenopausal hypertensive women. NEW & NOTEWORTHY Widely dispersed cardiac apoptosis was found in the coexistence of hypertension and ovariectomy. Exercise training on a treadmill could prevent ovariectomized hypertension-induced widely dispersed cardiac apoptosis via mitochondria-dependent apoptotic pathway (t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3) and Fas receptor-dependent apoptotic pathway (Fas ligand, tumor necrosis factor-α, Fas receptors, Fas-associated death domain, activated caspase 8, and activated caspase 3) through enhancing the Bcl2-related (p-PI3K, p-Akt, Bcl-2, Bcl-xL) and mitochondrial biogenetic (PGC-1α and mitochondrial optic atrophy 1) prosurvival pathways.
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Basset, Olivier, François-Xavier Boittin, Christian Cognard, Bruno Constantin und Urs T. Ruegg. „Bcl-2 overexpression prevents calcium overload and subsequent apoptosis in dystrophic myotubes“. Biochemical Journal 395, Nr. 2 (28.03.2006): 267–76. http://dx.doi.org/10.1042/bj20051265.
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Duchenne muscular dystrophy (DMD) is a lethal disease caused by the lack of the cytoskeletal protein dystrophin. Altered calcium homoeostasis and increased calcium concentrations in dystrophic fibres may be responsible for the degeneration of muscle occurring in DMD. In the present study, we used subsarcolemmal- and mitochondrial-targeted aequorin to study the effect of the antiapoptotic Bcl-2 protein overexpression on carbachol-induced near-plasma membrane and mitochondrial calcium responses in myotubes derived from control C57 and dystrophic (mdx) mice. We show that Bcl-2 overexpression decreases subsarcolemmal and mitochondrial calcium overload that occurs during activation of nicotinic acetylcholine receptors in dystrophic myotubes. Moreover, our results suggest that overexpressed Bcl-2 protein may prevent near-plasma membrane and mitochondrial calcium overload by inhibiting IP3Rs (inositol 1,4,5-trisphosphate receptors), which we have shown previously to be involved in abnormal calcium homoeostasis in dystrophic myotubes. Most likely as a consequence, the inhibition of IP3R function by Bcl-2 also inhibits calcium-dependent apoptosis in these cells.
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Bilalović, Nurija, Semir Vranić, Senad Hasanagić, Hiba Basić, Aida Tatarević, Semir Bešlija und Ivan Selak. „The Bcl-2 protein: a prognostic indicator strongly related to ER and PR in breast cancer“. Bosnian Journal of Basic Medical Sciences 4, Nr. 4 (20.11.2004): 5–12. http://dx.doi.org/10.17305/bjbms.2004.3352.
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Bcl-2, the protein product of the Bcl-2 gene, is a member of the Bcl-2 family of proteins that play a crucial role in a complex mechanism of apoptosis. It was recently proposed that bcl-2 could inhibit cancer progression. In this study, we evaluated the expression patterns of Bcl-2, estrogen receptors (ER), progesterone receptors (PR) in 71 primary invasive breast carcinomas and their association with other clinicopathological parameters. Samples from 71 patients with invasive breast cancer with follow-up ranging from 4-103 months (median 57 months) were included in the study. Forty-six patients (66%) obtained a complete response, while 5 (9%) were considered non-responders during the follow up period of 103 months. Eighteen (25%) patients died, 15 (21%) from primary disease and 3 (4%) from other disease. In unvaried analysis, tumor size (<2 cm), lymph node (<4 lymph nodes), hormonal status and Bcl-2 expression are correlated with longer overall (OS) and relapse-free survival (RFS). Patients with 4 or more positive axillary lymph nodes had significantly shorter OS (p=0.01) and RFS (p=0.009). Higher expression of Bcl-2 was associated with longer OS (p=0.02) and RFS (p=0.03), and this result were independent of axillary lymph nodes and tumor size in Cox multivariate analysis.
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Bürger, Susanne, Jie Meng, Annette Zwanzig, Mike Beck, Maik Pankonin, Peter Wiedemann, Wolfram Eichler und Jan Darius Unterlauft. „Pigment Epithelium-Derived Factor (PEDF) Receptors Are Involved in Survival of Retinal Neurons“. International Journal of Molecular Sciences 22, Nr. 1 (31.12.2020): 369. http://dx.doi.org/10.3390/ijms22010369.
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The demise of retinal ganglion cells (RGCs) is characteristic of diseases of the retina such as glaucoma and diabetic or ischemic retinopathies. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted protein that mediates neuroprotection and inhibition of angiogenesis in the retina. We have studied expression and regulation of two of several receptors for PEDF, patatin-like phospholipase 2 gene product/PEDF-R and laminin receptor (LR), in serum-starved RGC under normoxia and hypoxia and investigated their involvement in the survival of retinal neuronal cells. We show that PEDF-R and LR are co-expressed in RGC and R28 retinal precursor cells. Expression of both receptors was enhanced in the presence of complex secretions from retinal glial (Müller) cells and upregulated by VEGF and under hypoxic conditions. PEDF-R- and LR-knocked-down cells demonstrated a markedly attenuated expression of anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL) and neuroprotective mediators (PEDF, VEGF, BDNF) suggesting that both PEDF-R and LR mediate pro-survival effects of PEDF on RGC. While this study does not provide evidence for a differential survival-promoting influence of either PEDF-R or LR, it nevertheless highlights the importance of both PEDF receptors for the viability of retinal neurons.
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Daniel, Peter T., Klaus Schulze-Osthoff, Claus Belka und Dilek Güner. „Guardians of cell death: the Bcl-2 family proteins“. Essays in Biochemistry 39 (01.10.2003): 73–88. http://dx.doi.org/10.1042/bse0390073.
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Apoptosis is mediated through at least three major pathways that are regulated by (i) the death receptors, (ii) the mitochondria and (iii) the ER (endoplasmic reticulum). In most cells, these pathways are controlled by the Bcl-2 family of proteins that can be divided into anti-apoptotic and pro-apoptotic members. Although the overall amino acid sequence homology between the family members is relatively low, they contain highly conserved domains, referred to as BH (Bcl-2 homology) domains (BH1-4), that are essential for homo- and hetero-complex formation, as well as for their cell-death-inducing capacity. Structural and functional analyses revealed that the pro-apoptotic homologues can be subdivided into the Bax subfamily and the growing BH3-only subfamily. Recent data indicate that BH3-only proteins act as mediators that link various upstream signals, including death receptors and DNA damage signalling, to the mitochondrial and the ER pathway. This review discusses recent structural and functional insights into how these subfamilies promote or inhibit cell-death signals, and how these properties may be utilized for development of apoptosis-promoting small molecules, e.g. in cancer therapy.
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Chen, Rui, Ignacio Valencia, Fei Zhong, Karen S. McColl, H. Llewelyn Roderick, Martin D. Bootman, Michael J. Berridge et al. „Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate“. Journal of Cell Biology 166, Nr. 2 (19.07.2004): 193–203. http://dx.doi.org/10.1083/jcb.200309146.
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Inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) are channels responsible for calcium release from the endoplasmic reticulum (ER). We show that the anti-apoptotic protein Bcl-2 (either wild type or selectively localized to the ER) significantly inhibited InsP3-mediated calcium release and elevation of cytosolic calcium in WEHI7.2 T cells. This inhibition was due to an effect of Bcl-2 at the level of InsP3Rs because responses to both anti-CD3 antibody and a cell-permeant InsP3 ester were decreased. Bcl-2 inhibited the extent of calcium release from the ER of permeabilized WEHI7.2 cells, even at saturating concentrations of InsP3, without decreasing luminal calcium concentration. Furthermore, Bcl-2 reduced the open probability of purified InsP3Rs reconstituted into lipid bilayers. Bcl-2 and InsP3Rs were detected together in macromolecular complexes by coimmunoprecipitation and blue native gel electrophoresis. We suggest that this functional interaction of Bcl-2 with InsP3Rs inhibits InsP3R activation and thereby regulates InsP3-induced calcium release from the ER.
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Villunger, Andreas, Lorraine A. O'Reilly, Nils Holler, Jerry Adams und Andreas Strasser. „FAS Ligand, Bcl-2, Granulocyte Colony-Stimulating Factor, and p38 Mitogen-Activated Protein Kinase“. Journal of Experimental Medicine 192, Nr. 5 (28.08.2000): 647–58. http://dx.doi.org/10.1084/jem.192.5.647.
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The short life span of granulocytes, which limits many inflammatory responses, is thought to be influenced by the Bcl-2 protein family, death receptors such as CD95 (Fas/APO-1), stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), and proinflammatory cytokines like granulocyte colony-stimulating factor (G-CSF). To clarify the roles of these various regulators in granulocyte survival, we have investigated the spontaneous apoptosis of granulocytes in culture and that induced by Fas ligand or chemotherapeutic drugs, using cells from normal, CD95-deficient lpr, or vav-bcl-2 transgenic mice. CD95-induced apoptosis, which required receptor aggregation by recombinant Fas ligand or the membrane-bound ligand, was unaffected by G-CSF treatment or Bcl-2 overexpression. Conversely, spontaneous and drug-induced apoptosis occurred normally in lpr granulocytes but were suppressed by G-CSF treatment or Bcl-2 overexpression. Although activation of p38 MAPK has been implicated in granulocyte death, their apoptosis actually was markedly accelerated by specific inhibitors of this kinase. These results suggest that G-CSF promotes granulocyte survival largely through the Bcl-2–controlled pathway, whereas CD95 regulates a distinct pathway to apoptosis that is not required for either their spontaneous or drug-induced death. Moreover, p38 MAPK signaling contributes to granulocyte survival rather than their apoptosis.
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Collins, Patricia E., Domenico Somma, David Kerrigan, Felicity Herrington, Karen Keeshan, Robert J. B. Nibbs und Ruaidhrí J. Carmody. „The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus“. Proceedings of the National Academy of Sciences 116, Nr. 51 (26.11.2019): 25828–38. http://dx.doi.org/10.1073/pnas.1900408116.
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Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity. We reveal that TPL-2 is a nucleocytoplasmic shuttling protein and identify the nucleus as the primary site for TPL-2 degradation. BCL-3 interacts with TPL-2 and promotes its degradation by promoting its nuclear localization. As a consequence,Bcl3−/−macrophages have increased TPL-2 stability following TLR stimulation, leading to increased MAPK activity and MAPK-dependent responses. Moreover, BCL-3–mediated regulation of TPL-2 stability sets the MAPK activation threshold and determines the amount of TLR ligand required to initiate the production of inflammatory cytokines. Thus, the nucleus is a key site in the regulation of TLR-induced MAPK activity. BCL-3 links control of the MAPK and NF-ĸB pathways in the nucleus, and BCL-3–mediated TPL-2 regulation impacts on the cellular decision to initiate proinflammatory cytokine production in response to TLR activation.
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Sirtl, Simon, Gertrud Knoll, Dieu Thuy Trinh, Isabell Lang, Daniela Siegmund, Stefanie Gross, Beatrice Schuler-Thurner et al. „Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors“. Oncogene 37, Nr. 30 (30.04.2018): 4122–36. http://dx.doi.org/10.1038/s41388-018-0265-5.
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Distelhorst, C. W., und H. L. Roderick. „Ins(1,4,5)P3-mediated calcium signals and apoptosis: is there a role for Bcl-2?“ Biochemical Society Transactions 31, Nr. 5 (01.10.2003): 958–59. http://dx.doi.org/10.1042/bst0310958.
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In this review we speculate that the anti-apoptotic protein Bcl-2 may regulate calcium signals involved in mediating cell death. Evidence that Ins(1,4,5)P3-mediated calcium release from the endoplasmic reticulum triggers apoptosis in response to diverse signals is summarized. Also, we review evidence that Bcl-2 regulates calcium release from the endoplasmic reticulum, and speculate that Bcl-2 may interact either functionally or physically with Ins(1,4,5)P3 receptors to modulate calcium signals that determine life or death decisions.
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Gillissen, Bernhard, Jana Wendt, Antje Richter, Anja Richter, Annika Müer, Tim Overkamp, Nina Gebhardt et al. „Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma“. Journal of Cell Biology 188, Nr. 6 (22.03.2010): 851–62. http://dx.doi.org/10.1083/jcb.200912070.
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Tumor necrosis factor (α)–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in the majority of tumor cells. Thus, TRAIL-induced cell death entirely depends on the proapoptotic Bcl-2 family member Bax, which is often lost as a result of epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against TRAIL-induced apoptosis. Despite expression of Bak, Bax-deficient cells are resistant to TRAIL-induced apoptosis. In this study, we show that the Bax dependency of TRAIL-induced apoptosis is determined by Mcl-1 but not Bcl-xL. Both are antiapoptotic Bcl-2 family proteins that keep Bak in check. Nevertheless, knockdown of Mcl-1 but not Bcl-xL overcame resistance to TRAIL, CD95/FasL and tumor necrosis factor (α) death receptor ligation in Bax-deficient cells, and enabled TRAIL to activate Bak, indicating that Mcl-1 rather than Bcl-xL is a major target for sensitization of Bax-deficient tumors for death receptor–induced apoptosis via the Bak pathway.
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Lu, Qing. „Transforming growth factor-β1 protects against pulmonary artery endothelial cell apoptosis via ALK5“. American Journal of Physiology-Lung Cellular and Molecular Physiology 295, Nr. 1 (Juli 2008): L123—L133. http://dx.doi.org/10.1152/ajplung.00402.2007.
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Transforming growth factor (TGF)-β1 has been reported to cause endothelial cell apoptosis. However, conflicting data have also demonstrated that TGF-β1 promotes endothelial cell survival. In this study, the effect of TGF-β1 on apoptosis of cultured bovine pulmonary artery endothelial cells (PAEC) induced by multiple stimuli was investigated. TGF-β1 protected against apoptosis of bovine PAEC induced by serum deprivation or the VEGF receptor inhibitor SU-5416, but not by UV light exposure or TNFα. Neither caspase-8 nor caspase-12 was activated by serum deprivation or the VEGF receptor blocker. However, blockade of VEGF receptors activated caspase-9, an effect that was abolished by TGF-β1. Furthermore, serum deprivation and inhibition of VEGF receptors significantly decreased the protein level of Bcl-2, an effect that was also abrogated by TGF-β1. In addition, the baseline level of Bcl-2 was enhanced by TGF-β1 and reduced by inhibition of activin receptor-like kinase 5 (ALK5), a TGF-β1 type I receptor. Furthermore, inhibition of ALK5 caused apoptosis of bovine PAEC. These results suggest that TGF-β1 signaling is critical for maintenance of bovine PAEC survival. Finally, the protective effects of TGF-β1 on bovine PAEC apoptosis and Bcl-2 reduction were abolished by ALK5 inhibition, but not by inhibition of non-SMAD signaling pathways. Also, TGF-β1 activated SMAD2 and SMAD1/5, an effect that was abolished by ALK5 inhibition. The results of this study suggest that TGF-β1 protects against bovine PAEC apoptosis, possibly through ALK5-mediated Bcl-2 induction and subsequent inhibition of the mitochondria-mediated intrinsic pathway of apoptosis. Understanding the mechanism by which TGF-β1 promotes endothelial cell survival may provide a better treatment for apoptosis-dependent vascular diseases, such as emphysema.
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Rudner, Justine, Albrecht Lepple-Wienhues, Wilfried Budach, Johannes Berschauer, Björn Friedrich, Sebastian Wesselborg, Klaus Schulze-Osthoff und Claus Belka. „Wild-type, mitochondrial and ER-restricted Bcl-2 inhibit DNA damage-induced apoptosis but do not affect death receptor-induced apoptosis“. Journal of Cell Science 114, Nr. 23 (01.12.2001): 4161–72. http://dx.doi.org/10.1242/jcs.114.23.4161.
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The proto-oncogene Bcl-2 is expressed in membranes of mitochondria and endoplasmic reticulum and mediates resistance against a broad range of apoptotic stimuli. Although several mechanisms of Bcl-2 action have been proposed, its role in different cellular organelles remains elusive. Here, we analyzed the function of Bcl-2 targeted specifically to certain subcellular compartments in Jurkat cells. Bcl-2 expression was restricted to the outer mitochondrial membrane by replacing its membrane anchor with the mitochondrial insertion sequence of ActA (Bcl-2/MT) or the ER-specific sequence of cytochrome b5 (Bcl-2/ER). Additionally, cells expressing wild-type Bcl-2 (Bcl-2/WT) or a transmembrane domain-lacking mutant (Bcl-2/ΔTM) were employed. Apoptosis induced by ionizing radiation or by the death receptors for CD95L or TRAIL was analyzed by determination of the mitochondrial membrane potential (ΔΨm) and activation of different caspases. Bcl-2/WT and Bcl-2/MT strongly inhibited radiation-induced apoptosis and caspase activation, whereas Bcl-2/ΔTM had completely lost its anti-apoptotic effect. Interestingly, Bcl-2/ER conferred protection against radiation-induced mitochondrial damage and apoptosis similarly to Bcl-2/MT. The finding that ER-targeted Bcl-2 interfered with mitochondrial ΔΨm breakdown and caspase-9 activation indicates the presence of a crosstalk between both organelles in radiation-induced apoptosis. By contrast, Bcl-2 in either subcellular position did not influence CD95- or TRAIL-mediated apoptosis.
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Rodriguez, I., K. Matsuura, K. Khatib, J. C. Reed, S. Nagata und P. Vassalli. „A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection.“ Journal of Experimental Medicine 183, Nr. 3 (01.03.1996): 1031–36. http://dx.doi.org/10.1084/jem.183.3.1031.
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Stimulation of the Fas (APO-1, CD95) receptor, which is present on a variety of cells, usually triggers a process of programmed cell death. Systemic injection of anti-Fas antibody into mice leads to fulminant liver destruction resulting from massive hepatocyte apoptosis, and to rapid death. Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis. We have generated mice whose liver expresses Bcl-2 as the result of bcl-2 transgene placed under the control of the hepatocyte-specific alpha1-anti-trypsin gene promoter, but is otherwise not distinguishable from that of normal mice. These mice display a marked to almost total resistance to liver damage induced by anti-Fas antibody injection. This protective effect of Bcl-2 occurs in the absence of significant variations, in the stimulated livers, in the level of expression of other proteins also involved in resistance or sensitivity to apoptosis, namely Bcl-x, Bax, Bad, Bak, and p53. Mice with protected livers, however, die almost as rapidly as normal mice, which indicates that acute lethality results from stimulation of Fas receptors present on other target organs or cells.
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Pokkula, Swapna, und Santh Rani Thakur. „Icariin ameliorates partial sciatic nerve ligation induced neuropathic pain in rats: an evidence of in silico and in vivo studies“. Journal of Pharmacy and Pharmacology 73, Nr. 7 (03.04.2021): 874–80. http://dx.doi.org/10.1093/jpp/rgab021.
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Abstract Objectives Neuropathic pain (NP) is a chronic inflammation of the sciatic nerve, associated with complex pathophysiological events like neuronal ectopic discharge with changes in neurotransmitters, growth factors, receptors/ion channels including N-methyl-d-aspartate receptors, Transient receptor cation channels, Voltage-gated calcium channels. All these events eventually lead to inflammation and apoptosis of the sciatic nerve in NP. Icariin (ICA), a natural flavonoid is well known for its anti-inflammatory potential. Hence, the present study is designed to evaluate its anti-inflammatory potential against neuropathic pain using in silico and in vivo studies. Methods In silico studies were conducted using targets of N-methyl-D-aspartate receptor subtype-2B (NR2B), The capsaicin receptor transient receptor cation channel subfamily-V member-1 (TRPV1), N-type voltage-gated calcium (CaV2.2) channels. In in vivo studies, after partial sciatic nerve ligation surgery to animals, received their respective treatment for 21 days, further TNF-α, IL-6, Bax (proapoptotic) and Bcl-2 (antiapoptotic) expressions were estimated. Key findings ICA decreased the expressions of TNF-α, IL-6, Bax and increased expression of Bcl-2. In silico studies revealed a good energy binding score towards NR2B, TRPV1 receptors and CaV2.2 ion Channel. Conclusions ICA could be a promising agent in alleviating neuropathic pain by inhibiting NR2B, TRPV1 receptors and Cav2.2 channels, which induces anti-apoptotic potential and inhibits inflammation.
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Eroles, Pilar, Isabel Benet, Isabel Marugan, Ana Belen Teruel, Carlos Solano und Maria Jose Terol. „Study of the Expression of Angiogenic Factors and Dopaminergic Receptors: Correlation with ZAP70, CD38 and the Mutational State in Chronic Lymphocytic Leukaemia (CLL).“ Blood 108, Nr. 11 (16.11.2006): 4928. http://dx.doi.org/10.1182/blood.v108.11.4928.4928.
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Abstract The angiogenesis is a well known process implicate in the progression of CLL. In this disease has been described an increase of angiogenic and pro-angiogenic factors in serum and angiogenic receptors in B cells, mainly in advances stages. Recently had been known that the agonist of the dopaminergic receptor D2 can inhibit the tumour growth and a possible mechanism mediator is the internalization of VEGFR-2. The aim of this work had been to analyze the expression of the dopaminergic receptors (D1, D2, D3, D4 and D5), the angiogenic receptors and its correlation with the main biological factor implicated in the illness (ZAP-70, CD38 and the mutational status of IgVH/BCL-6). We had determinate the levels of the receptors VEGFR-1, VEGFR-2, VEGFR-3 and c-kit, the angiogenic factor bFGF and the dopaminergic receptors D1, D2, D3, D4 and D5 in B lymphocytes from peripheral blood of 29 patients with CLL in A stage (using positive selection and quantitative PCR), and we had analyzed the possible correlation with the values of CD38 and ZAP70 and the mutational status of IgVH/BCL-6 (using flow cytometry and direct sequenciation). Results: The lymphocytes B-CLL show a significant increment of the expression of the receptors VEGFR-1, VEGFR-2 and c-kit versus normal lymphocytes B. The patients with positive ZAP70 (> 20%) show a higher expression of all the factors studied except D1. The difference is statistically significant for D5, VEGFR-2 and c-kit (3 ×), D2 and bFGF (2 ×). The patients with positive CD38 show an increment in the expression of D2 (1,4x) and bFGF (1,9x) versus patients with negative CD38. The patients with both ZAP70 and CD38 positive present a higher expression of D2 and bFGF (2,2x and 1,9x) versus negatives ZAP70 and CD38, which show higher expression of D1 (4,8x). We had not found significant correlations between the studied factor and the mutational status of IgVH and BCL-6, only D1 shows a higher expression (3,6x) in patients with mutations IgVH versus unmutated independently of the BCL-6 status. Conclusion: The lymphocytes B-CLL in stage A of Binet show high levels of expression of the angiogenic receptors VEGFR-1, VEGFR-2 and c-kit, the dopaminergic receptors D1 and D2, and the angiogenic factor bFGF that are significant higher that in normal lymphocytes B. The biological factor of bad prognostic (ZAP-70 and CD38) in patients in the initial A stage are associated with a higher expression of the receptors VEGF-R, c-kit, and D2 and the factor bFGF. Oppositely, negatives ZAP-70 and CD38 have correlation with the elevated expression of the receptor D1. This patron of differential expression can contribute to the tumoral progression of the patients in the initial stage of the illness.
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Vervliet, Tim, Jan B. Parys und Geert Bultynck. „Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites: the complexity of protein–protein interactions for channel regulation“. Biochemical Society Transactions 43, Nr. 3 (01.06.2015): 396–404. http://dx.doi.org/10.1042/bst20140298.
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The 12- and 12.6-kDa FK506-binding proteins, FKBP12 (12-kDa FK506-binding protein) and FKBP12.6 (12.6-kDa FK506-binding protein), have been implicated in the binding to and the regulation of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs), both tetrameric intracellular Ca2+-release channels. Whereas the amino acid sequences responsible for FKBP12 binding to RyRs are conserved in IP3Rs, FKBP12 binding to IP3Rs has been questioned and could not be observed in various experimental models. Nevertheless, conservation of these residues in the different IP3R isoforms and during evolution suggested that they could harbour an important regulatory site critical for IP3R-channel function. Recently, it has become clear that in IP3Rs, this site was targeted by B-cell lymphoma 2 (Bcl-2) via its Bcl-2 homology (BH)4 domain, thereby dampening IP3R-mediated Ca2+ flux and preventing pro-apoptotic Ca2+ signalling. Furthermore, vice versa, the presence of the corresponding site in RyRs implied that Bcl-2 proteins could associate with and regulate RyR channels. Recently, the existence of endogenous RyR–Bcl-2 complexes has been identified in primary hippocampal neurons. Like for IP3Rs, binding of Bcl-2 to RyRs also involved its BH4 domain and suppressed RyR-mediated Ca2+ release. We therefore propose that the originally identified FKBP12-binding site in IP3Rs is a region critical for controlling IP3R-mediated Ca2+ flux by recruiting Bcl-2 rather than FKBP12. Although we hypothesize that anti-apoptotic Bcl-2 proteins, but not FKBP12, are the main physiological inhibitors of IP3Rs, we cannot exclude that Bcl-2 could help engaging FKBP12 (or other FKBP isoforms) to the IP3R, potentially via calcineurin.
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Guinan, Patrick, Marvin Rubenstein und Courtney M. P. Hollowell. „Potential increase in androgen sensitivity following antisense oligonucleotide suppression of Bcl-2 in a prostate cancer model.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): e13532-e13532. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13532.
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e13532 Background: Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth stimulatory gene products. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis and mediators of androgen action. In LNCaP cells we evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein bcl-2. To evaluate the specificity of this type of gene therapy, targeted and non-targeted genes were evaluated for their expression. The purpose was to identify whether additional (non-targeted) genes altered their expression in a manner which could circumvent or compensate for the suppression of bcl-2, promoting growth through increased androgen sensitivity. Methods: LNCaP prostate cells were treated with mono- and bispecific oligos directed against bcl-2. Employing RT-PCR the expression of both targeted and non-targeted genes (androgen receptor [AR], coactivators p300 and creb binding protein [CREB]) was determined. Results: LNCaP cells adapted to the suppression of bcl-2 (an apoptosis inhibitor) with enhanced expression of both AR and p300. This suggests an increased sensitivity to androgens. Conclusions: In this model, oligo treatment directed against bcl-2, may be evaded through a compensatory increase in both AR and p300 expression. This promotion of tumor growth, and the altered expression of AR coactivators normally seen in advanced disease, suggests a tumor transition to a more aggressive phenotype following suppressive treatment directed against bcl-2.
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Čečka, Filip, Helena Hornychová, Bohuslav Melichar, Aleš Ryška, Pavel Jandík, Jindřiška Mergancová und Hana Klozová-Urminská. „Expression of Bcl-2 in Breast Cancer: Correlation with Clinicopathological Characteristics and Survival“. Acta Medica (Hradec Kralove, Czech Republic) 51, Nr. 2 (2008): 107–12. http://dx.doi.org/10.14712/18059694.2017.11.
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Breast cancer is the most common malignancy in women. It is an immensely heterogeneous disease, characterised by a broad variety of clinical development. The research in recent years has focused on finding new markers of prognosis. This study investigates the role of expression of the bcl-2 protein in breast cancer. We analysed bcl-2 expression in 57 women with primary breast carcinoma who were treated with neoadjuvant (primary) chemotherapy, followed by a surgical procedure. The bcl-2 expression was correlated with other clinicopathological characteristics of the tumour – histological grade, stage, expression of hormonal receptors, proliferation rate, and with the survival of the patients. No significant association of bcl-2 expression with either overall survival or disease free survival was found.
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Witters, L., A. Witkoski, M. Planas-Silva, J. Viallet, M. S. Berger und A. Lipton. „Synergistic inhibition of breast cancer cell lines with the combination of a dual inhibitor of EGFR/HER-2/neu and a Bcl-2 inhibitor“. Journal of Clinical Oncology 24, Nr. 18_suppl (20.06.2006): 13100. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13100.
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13100 Background: The epidermal growth factor receptor (EGFR; ErbB1) and HER-2/neu (ErbB2), members of the ErbB family of receptor tyrosine kinases, are overexpressed in a variety of human tumors and overexpression generally correlates with poor prognosis and decreased survival. Use of inhibitors of these receptors as monotherapies, e.g., trastuzumab, Iressa, and erlotinib, has led to advances in treatment, but many patients do not respond or develop resistance. The anti-apoptotic protein, Bcl-2, is also overexpressed in a number of human tumors. Inhibitors of Bcl-2 induce apoptosis and sensitize cancer cells to other therapies. This study assesses the effects of a combination of a reversible inhibitor of both EGFR and HER-2/neu that is similar to lapatinib (GW2974) and a pan inhibitor of the Bcl-2 family (GX15–070: Gemin X Biotechnologies, Inc.) on the growth of human breast cancer cells. Methods: The MCF-7 human breast cancer cell line transfected with a control vector, MCF/neo, and the HER-2/neu transfected MCF-7 cell line, MCF/18, were treated with various concentrations of GW2974 (0.25–10 μM) and/or the GX15–070 pan Bcl-2 inhibitor (50–500 nM). After a 3 day exposure, cell number was determined using the colorimetric MTT tetrazolium dye assay. Percent of control was normalized to corresponding concentrations of the solvent for both agents (DMSO). Results: Treatment with the GW2974 dual inhibitor or the GX15–070 pan Bcl-2 inhibitor resulted in dose-dependent growth inhibition in both the control and HER-2/neu transfected MCF-7 cell lines. The combination of both agents produced synergistic growth inhibition in both cell lines as confirmed by isobologram analysis. Conclusions: This study has demonstrated synergy with the combination of a dual inhibitor of EGFR and HER-2/neu and an inhibitor of Bcl-2 in control and HER-2/neu overexpressing MCF-7 human breast cancer cells. This finding warrants an evaluation of this combination in clinical trials for the treatment of patients with metastatic breast cancer. [Table: see text]
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Caruso, Carla, Daniela Durand, Helgi B. Schiöth, Rodolfo Rey, Adriana Seilicovich und Mercedes Lasaga. „Activation of Melanocortin 4 Receptors Reduces the Inflammatory Response and Prevents Apoptosis Induced by Lipopolysaccharide and Interferon-γ in Astrocytes“. Endocrinology 148, Nr. 10 (01.10.2007): 4918–26. http://dx.doi.org/10.1210/en.2007-0366.
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α-MSH exerts an immunomodulatory action in the brain and may play a neuroprotective role acting through melanocortin 4 receptors (MC4Rs). In the present study, we show that MC4Rs are constitutively expressed in astrocytes as determined by immunocytochemistry, RT-PCR, and Western blot analysis. α-MSH (5 μm) reduced the nitric oxide production and the expression of inducible nitric oxide synthase (iNOS) induced by bacterial lipopolysaccharide (LPS, 1 μg/ml) plus interferon-γ (IFN-γ, 50 ng/ml) in cultured astrocytes after 24 h. α-MSH also attenuated the stimulatory effect of LPS/IFN-γ on prostaglandin E2 release and cyclooxygenase-2 (COX-2) expression. Treatment with HS024, a selective MC4R antagonist, blocked the antiinflammatory effects of α-MSH, suggesting a MC4R-mediated mechanism in the action of this melanocortin. In astrocytes, LPS/IFN-γ treatment reduced cell viability, increased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and activated caspase-3. α-MSH prevented these apoptotic events, and this cytoprotective effect was abolished by HS024. LPS/IFN-γ decreased Bcl-2, whereas it increased Bax protein expression in astrocytes, thus increasing the Bax/Bcl-2 ratio. α-MSH produced a shift in Bax/Bcl-2 ratio toward astrocyte survival because it increased Bcl-2 expression and also prevented the effect of LPS/IFN-γ on Bax and Bcl-2 expression. In summary, these findings suggest that α-MSH, through MC4R activation, attenuates LPS/IFN-γ-induced inflammation by decreasing iNOS and COX-2 expression and prevents LPS/IFN-γ-induced apoptosis of astrocytes by modulating the expression of proteins of the Bcl-2 family.
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Sun, Ruili, Yu Zhang, Qingshan Lv, Bei Liu, Miao Jin, Weijia Zhang, Qing He et al. „Toll-like Receptor 3 (TLR3) Induces Apoptosis via Death Receptors and Mitochondria by Up-regulating the Transactivating p63 Isoform α (TAP63α)“. Journal of Biological Chemistry 286, Nr. 18 (02.03.2011): 15918–28. http://dx.doi.org/10.1074/jbc.m110.178798.
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Toll-like receptor 3 (TLR3), a member of the pathogen recognition receptors, is widely expressed in various cells and has been shown to activate immune signaling pathways by recognizing viral double-stranded RNA. Recently, it was reported that the activation of TLR3 induced apoptosis in some cells, but the detailed molecular mechanism is not fully understood. In this study, we found that in endothelial cells polyinosinic-polycytidylic acid (poly(I-C)) induced dose- and time-dependent cell apoptosis, which was elicited by TLR3 activation, as TLR3 neutralization and down-regulation repressed the apoptosis. Poly(I-C) induced the activation of both caspases 8 and 9, indicating that TLR3 triggered the signaling of both the extrinsic and intrinsic apoptotic pathways. Poly(I-C) up-regulated tumor necrosis factor-related apoptosis-inducing ligand and its receptors, death receptors 4/5, resulting in initiating the extrinsic pathway. Furthermore, poly(I-C) down-regulated anti-apoptotic protein, B cell lymphoma 2 (Bcl-2), and up-regulated Noxa, a key Bcl-2 homology 3-only antagonist of Bcl-2, leading to the priming of the intrinsic pathway. A p53-related protein, the transactivating p63 isoform α (TAp63α), was induced by TLR3 activation and contributed to the activation of both the intrinsic and extrinsic apoptotic pathways. Both the cells deficient in p63 gene expression by RNA interference and cells that overexpressed the N-terminally truncated p63 isoform α (ΔNp63α), a dominant-negative variant of TAp63α, by gene transfection, survived TLR3 activation. Taken together, TAp63α is a crucial regulator downstream of TLR3 to induce cell death via death receptors and mitochondria.
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Silva, M., D. Grillot, A. Benito, C. Richard, G. Nunez und JL Fernandez-Luna. „Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2“. Blood 88, Nr. 5 (01.09.1996): 1576–82. http://dx.doi.org/10.1182/blood.v88.5.1576.1576.
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Abstract Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.
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Silva, M., D. Grillot, A. Benito, C. Richard, G. Nunez und JL Fernandez-Luna. „Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2“. Blood 88, Nr. 5 (01.09.1996): 1576–82. http://dx.doi.org/10.1182/blood.v88.5.1576.bloodjournal8851576.
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Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.
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Smets, LA, J. Van den Berg, D. Acton, B. Top, H. Van Rooij und M. Verwijs-Janssen. „BCL-2 expression and mitochondrial activity in leukemic cells with different sensitivity to glucocorticoid-induced apoptosis“. Blood 84, Nr. 5 (01.09.1994): 1613–19. http://dx.doi.org/10.1182/blood.v84.5.1613.1613.
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Abstract The present study investigates the relationship between mitochondrial activity and the expression of the BCL-2 gene in a panel of six human and murine leukemia/lymphoma cell lines. The cell lines all contained normal glucocorticoid receptors but differed widely in sensitivity to dexamethasone, ranging from very sensitive S49 lymphoma to completely resistant HL-60 acute leukemia cells. In this panel, 10- to 15-fold differences in basal adenosine triphosphate (ATP) content and adenosine diphosphate (ADP)/ATP ratio were correlated with up to fivefold differences in bcl-2 protein (in human cells) and approximately 25-fold difference in bcl-2 mRNA content (all cell lines). Moreover, ATP content and BCL-2 gene expression were inversely correlated with glucocorticoid sensitivity and cell cycle length. In resistant cell lines, sensitivity to dexamethasone was restored by the mitochondrial inhibitors rotenone and meta-iodobenzylguanidine. This sensitization was not accompanied by detectable reductions in bcl-2 mRNA or protein content, suggesting that the inhibitors were capable of overriding BCL- 2-mediated inhibition of apoptosis. Increased mitochondrial activity and (overexpressed) BCL-2 appeared closely related properties of glucocorticoid-resistant cells, sharing common cellular targets in hormone-induced apoptosis.
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Smets, LA, J. Van den Berg, D. Acton, B. Top, H. Van Rooij und M. Verwijs-Janssen. „BCL-2 expression and mitochondrial activity in leukemic cells with different sensitivity to glucocorticoid-induced apoptosis“. Blood 84, Nr. 5 (01.09.1994): 1613–19. http://dx.doi.org/10.1182/blood.v84.5.1613.bloodjournal8451613.
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The present study investigates the relationship between mitochondrial activity and the expression of the BCL-2 gene in a panel of six human and murine leukemia/lymphoma cell lines. The cell lines all contained normal glucocorticoid receptors but differed widely in sensitivity to dexamethasone, ranging from very sensitive S49 lymphoma to completely resistant HL-60 acute leukemia cells. In this panel, 10- to 15-fold differences in basal adenosine triphosphate (ATP) content and adenosine diphosphate (ADP)/ATP ratio were correlated with up to fivefold differences in bcl-2 protein (in human cells) and approximately 25-fold difference in bcl-2 mRNA content (all cell lines). Moreover, ATP content and BCL-2 gene expression were inversely correlated with glucocorticoid sensitivity and cell cycle length. In resistant cell lines, sensitivity to dexamethasone was restored by the mitochondrial inhibitors rotenone and meta-iodobenzylguanidine. This sensitization was not accompanied by detectable reductions in bcl-2 mRNA or protein content, suggesting that the inhibitors were capable of overriding BCL- 2-mediated inhibition of apoptosis. Increased mitochondrial activity and (overexpressed) BCL-2 appeared closely related properties of glucocorticoid-resistant cells, sharing common cellular targets in hormone-induced apoptosis.
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Lao, Y., und D. C. Chang. „Study of the functional role of Bcl-2 family proteins in regulating Ca2+ signals in apoptotic cells“. Biochemical Society Transactions 35, Nr. 5 (25.10.2007): 1038–39. http://dx.doi.org/10.1042/bst0351038.
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Recently, it was found that Bcl-2 family proteins can affect the apoptotic process by modifying Ca2+ released from the ER (endoplasmic reticulum). In this review, we summarize the evidence that Bcl-2 and Bax can modulate Ca2+ mobilization from the ER to the cytosol and mitochondria. We also found evidence that both Bcl-2 and Bax can interact with IP3Rs (InsP3 receptors) to modify the Ca2+ efflux from the ER. On the basis of our findings, we suggest that Bax may interact with IP3Rs to facilitate the release of Ca2+ from the ER during apoptosis.
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Del Poeta, Giovanni, Maria Ilaria Del Principe, Adriano Venditti, Luca Maurillo, Francesco Buccisano, Maria Irno Consalvo, Carla Mazzone et al. „Clinical Significance of Apoptosis Is Independent from Proliferation in Acute Myeloid Leukemia (AML).“ Blood 104, Nr. 11 (16.11.2004): 198. http://dx.doi.org/10.1182/blood.v104.11.198.198.
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Abstract Multidrug resistance and recurrent disease are key problems in the variable response of AML pts to treatment. Tumor cells in a high proliferative state have a high density of transferrin receptors, as demonstrated in breast cancer (Yang DC, 2001) and in adult T-cell leukemia/lymphoma (Moura IC, 2004). On the other hand, defects in apoptotic pathways such as higher levels of bcl-2 and Mcl-1 were reported in “poor risk” AML pts. Current availability of antisense oligonucleotides targeted both to the transferrin receptor genes and bcl-2 incited us to evaluate the impact of proliferative and/or apoptotic pathways on AML prognosis. Therefore, a large series of 325 pts, affected by de novo AML, except FAB M3, median age 55 years, treated with intensive chemotherapy regimens, were studied. The aims of our research were: 1) to correlate bax/bcl-2 ratio with the proliferation levels, determined by the transferrin receptor (CD71) and 2) to demonstrate that the clinical significance of spontaneous apoptosis is independent from proliferation. CD71, bcl-2 and bax proteins were determined by multicolor flow cytometry. CD71 was evaluated as mean fluorescence intensity (MFI) and bax/bcl-2 ratio was obtained by dividing MFI bax/MFI bcl-2. One hundred-seventy five pts (53.8%) were bax/bcl-2 ratio positive and 204/324 (63%) were CD71 positive, respectively. There was a close correlation between higher CD71 expression and Ki-67 positive staining by flow cytometry (r=0.86), confirming that transferrin receptor overexpression is really linked to increased cellular proliferation in AML. No significant correlation was found between a higher bax/bcl-2 ratio and a lower CD71 MFI (p=0.16), confirming that an apoptosis resistant protein profile may have variable proliferation levels. A significant lower complete remission (CR) rate was found in pts with lower bax/bcl-2 ratio (43% vs 72%, p<0.00001) or higher CD71 (47% vs 74%, p=0.00001). Overall survival (OS) was significantly shorter either in pts with lower bax/bcl-2 ratio (1% vs 15% at 4 years; p=0.00001) or higher CD71 MFI (5% vs 104% at 5 years; p=0.002). Noteworthy, higher bax/bcl-2 ratio plus lower CD71 MFI identified an AML subset at better prognosis with regard to CR (91% vs 32%; p<0.00001) and OS (31% vs 0% at 2 years; p<0.00001). In order to confirm the independent prognostic value of bax/bcl-2 ratio from proliferation levels, we investigated the CD71 + (203 pts) and the CD71- (121 pts) AML subgroups. As a matter of fact, a lower CR rate was found in patients with lower bax/bcl-2 ratio either within CD71+ (34% vs 61%, p=0.0009) or CD71- (60% vs 90%, p=0.0006) pts. Also a lower bax/bcl-2 ratio was associated with a shorter OS both within CD71+ (2% vs 10% at 4 years, p=0.008) and within CD71- (0% vs 24% at 3.5 years, p=0.00008) pts. The independent prognostic value of bax/bcl-2 ratio was confirmed in multivariate analysis with regard to CR (p=0.00007) and OS (p=0.00003). The lack of significant correlation between bax/bcl-2 ratio and CD71 MFI confirms the independence of apoptosis from proliferation pathways. Furthermore, the capacity of bax/bcl-2 ratio of clearly identifying patients at different prognosis within the CD71+ and CD71- subgroups implies that apoptosis has an intrinsic more relevant clinical significance as compared to proliferation. That has to be taken in account when strategies are to be planned in order to resolve both chemoresistance and relapse in AML.
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Song, Shanshan, Krista N. Jacobson, Kimberly M. McDermott, Sekhar P. Reddy, Anne E. Cress, Haiyang Tang, Steven M. Dudek et al. „ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells“. American Journal of Physiology-Cell Physiology 310, Nr. 2 (15.01.2016): C99—C114. http://dx.doi.org/10.1152/ajpcell.00092.2015.
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Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvironment. ATP regulates cell functions by acting on purinergic receptors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca2+ signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca2+] ([Ca2+]cyt) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca2+ eliminated the plateau phase increase of [Ca2+]cyt in lung cancer cells, indicating that the plateau phase of [Ca2+]cyt increase is due to Ca2+ influx. The distribution of P2X (P2X1-7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 demonstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca2+ or chelating intracellular Ca2+ with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/Bax ratio, indicating that a rise in [Ca2+]cyt through Ca2+ influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression.
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Lee, Choung Han. „Expression of P53, Bcl-2 Proteins and Hormone Receptors in Human Breast Cancer“. Journal of Korean Breast Cancer Society 1, Nr. 1 (1998): 92. http://dx.doi.org/10.4048/jkbcs.1998.1.1.92.
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Osorio, Lyda M., Mikael Jondal und Miguel Aguilar-Santeliseb. „Regulation of B-CLL Apoptosis Through Membrane Receptors and Bcl-2 Family Proteins“. Leukemia & Lymphoma 30, Nr. 3-4 (Januar 1998): 247–56. http://dx.doi.org/10.3109/10428199809057538.
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Dubal, Dena B., Paul J. Shughrue, Melinda E. Wilson, Istvan Merchenthaler und Phyllis M. Wise. „Estradiol Modulates bcl-2 in Cerebral Ischemia: A Potential Role for Estrogen Receptors“. Journal of Neuroscience 19, Nr. 15 (01.08.1999): 6385–93. http://dx.doi.org/10.1523/jneurosci.19-15-06385.1999.
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BUDD, David C., Elizabeth J. SPRAGG, Katie RIDD und Andrew B. TOBIN. „Signalling of the M3-muscarinic receptor to the anti-apoptotic pathway“. Biochemical Journal 381, Nr. 1 (22.06.2004): 43–49. http://dx.doi.org/10.1042/bj20031705.
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The process of programmed cell death (or apoptosis) occurs widely in tissue maintenance and embryonic development, and is under tight regulatory control. It is now clear that one of the important regulators of apoptosis are G-protein-coupled receptors. In the present study, we investigate the regulatory mechanism employed by the Gq/11-coupled M3-muscarinic receptor in mediating an anti-apoptotic response. Using a CHO (Chinese-hamster ovary) cell model, we demonstrate that the M3-muscarinic receptor anti-apoptotic response is independent of calcium/phospholipase C signalling. This response can, however, be inhibited by the transcriptional inhibitor actinomycin D at a concentration that inhibits the rapid increase in gene transcription mediated by M3-muscarinic receptor stimulation. Furthermore, apoptosis in CHO cells induced by the DNA-damaging agent, etoposide, is associated with a fall in the levels of the anti-apoptotic Bcl-2 protein. This fall in Bcl-2 protein concentration can be attenuated by M3-muscarinic receptor stimulation. We conclude, therefore, that the M3-muscarinic receptor signals to the anti-apoptotic pathway via a mechanism that is independent of calcium/phospholipase C signalling, but in a manner that involves both gene transcription and the up-regulation of Bcl-2 protein.
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Colucci, Silvia, Giacomina Brunetti, Rita Rizzi, Antonia Zonno, Giorgio Mori, Graziana Colaianni, Davide Del Prete et al. „T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction“. Blood 104, Nr. 12 (01.12.2004): 3722–30. http://dx.doi.org/10.1182/blood-2004-02-0474.
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The development of multiple myeloma (MM) bone disease is mediated by increased number and activity of osteoclasts (OCs). Using an in vitro osteoclastogenesis model consisting of unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) from patients with MM, we showed that T cells support the formation of OCs with longer survival. Different from T-cell–depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) were necessary for the formation of OCs; however, they did not exhibit longer survival. We found up-regulated production of RANKL, osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) by fresh MM T cells. Despite high OPG levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex demonstrated by immunoprecipitation experiments and the addition of anti-TRAIL antibody which decreases OC formation. OCs overexpressed TRAIL decoy receptor DcR2 in the presence of MM T cells and death receptor DR4 in T-cell–depleted cultures. In addition, increased Bcl-2/Bax (B-cell lymphoma-2/Bcl2-associated protein X) ratio, following Bcl-2 up-regulation, was detected in OCs generated in the presence of T cells. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction and unbalanced OC expression of TRAIL death and decoy receptors.
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Saleh, Mohamed A., Ahmed M. Awad, Tarek M. Ibrahim und Nashwa M. Abu-Elsaad. „Small-Dose Sunitinib Modulates p53, Bcl-2, STAT3, and ERK1/2 Pathways and Protects against Adenine-Induced Nephrotoxicity“. Pharmaceuticals 13, Nr. 11 (17.11.2020): 397. http://dx.doi.org/10.3390/ph13110397.
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The therapeutic use of numerous pharmacological agents may be limited due to their nephrotoxicity and associated kidney injury. The aim of our study is to test the hypothesis that the blockade of tyrosine kinase-linked receptors signaling protects against chemically induced nephrotoxicity. To test our hypothesis, we investigated sunitinib as an inhibitor for tyrosine kinase signaling for both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR) against adenine-induced nephrotoxicity. Four groups of adult male Swiss albino mice were investigated: normal group, adenine group, sunitinib group, and the adenine+sunitinib group that received concurrent administration for both adenine and sunitinib. Kidney function and oxidative stress biomarkers were analyzed. Tubular injury and histopathological changes were examined. Renal expression of B-cell lymphoma-2 (Bcl-2), the tumor suppressor p53, transforming growth factor beta-1 (TGF-β1), phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phospho-signal transducer and activator of transcription (phospho-STAT3) were measured. The results obtained showed significant improvement (p < 0.05) in kidney function and antioxidant biomarkers in the adenine+sunitinib group. Kidney fibrosis and tubular injury scores were significantly (p < 0.05) less in the adenine+sunitinib group and that of p53 expression as well. Furthermore, sunitinib decreased (p < 0.5) renal levels of TGF-β1, p-ERK1/2, and phospho-STAT3 while elevating Bcl-2 expression score. In conclusion, sunitinib diminished adenine-induced nephrotoxicity through interfering with profibrogenic pathways, activating anti-apoptotic mechanisms, and possessing potential antioxidant capabilities.
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de la Coste, Alix, Monique Fabre, Nathalie McDonell, Arlette Porteu, Helène Gilgenkrantz, Christine Perret, Axel Kahn und Alexandre Mignon. „Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice“. American Journal of Physiology-Gastrointestinal and Liver Physiology 277, Nr. 3 (01.09.1999): G702—G708. http://dx.doi.org/10.1152/ajpgi.1999.277.3.g702.
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Fas ligand (CD95L) and tumor necrosis factor-α (TNF-α) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-α-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing[Formula: see text]in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous[Formula: see text]or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-α caused massive apoptosis and death only when transcription was inhibited. Under these conditions,[Formula: see text]mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-α receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.
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Luong, Khanh Vinh Quốc, und Lan Thi Hoàng Nguyen. „The role of Vitamin D in malaria“. Journal of Infection in Developing Countries 9, Nr. 01 (15.01.2015): 008–19. http://dx.doi.org/10.3855/jidc.3687.
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An abnormal calcium-parathyroid hormone (PTH)-vitamin D axis has been reported in patients with malaria infection. A role for vitamin D in malaria has been suggested by many studies. Genetic studies have identified numerous factors that link vitamin D to malaria, including human leukocyte antigen genes, toll-like receptors, heme oxygenase-1, angiopoietin-2, cytotoxic T lymphocyte antigen-4, nucleotide-binding oligomerization domain-like receptors, and Bcl-2. Vitamin D has also been implicated in malaria via its effects on the Bacillus Calmette-Guerin (BCG) vaccine, matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, reactive oxidative species, and nitric oxide synthase. Vitamin D may be important in malaria; therefore, additional research on its role in malaria is needed.
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Skelton, Henry, und Kathleen J. Smith. „Spindle Cell Epithelioma of the Vagina Shows Immunohistochemical Staining Supporting Its Origin From a Primitive/Progenitor Cell Population“. Archives of Pathology & Laboratory Medicine 125, Nr. 4 (01.04.2001): 547–50. http://dx.doi.org/10.5858/2001-125-0547-sceotv.
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Abstract Spindle cell epitheliomas of the vagina (SCEVs) coexpresses epithelial and mesenchymal markers and were first described as a “mixed tumors of the vagina.” However, unlike mixed tumors of other organs, which are believed to originate from myoepithelial cells, SCEVs neither immunohistochemically nor ultrastructurally show features of myoepithelial cells. The present expanded battery of immunohistochemical stains is presented on this rare tumor, including cytokeratin AE1/AE3, CK7, CK20, S100 protein, epithelial membrane antigen, α-smooth muscle actin, desmin, CD34, CD99, Bcl-2, vimentin, estrogen and progesterone receptors, and Ki-67. There was minimal expression of α-smooth muscle actin and negative staining with S100 protein, with coexpression of cytokeratins and vimentin and expression of estrogen and progesterone receptors, as previously reported in SCEVs. In addition, diffuse expression of CD34, CD99, and Bcl-2 immunohistochemical stains was found, which has not previously been reported. The coexpression of CD34, CD99, and Bcl-2 in SCEVs is consistent with its origin from a primitive/progenitor cell population.
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Zhai, Dayong, Eduard Sergienko, Shinichi Kitada, Frederic Luciano, Arnold C. Satterswait, Xiaokun Zhang und John C. Reed. „Exploiting the Tr3 Interaction with Bcl-2 as a Novel Therapeutic Strategy of Cancer and Leukemia Therapy.“ Blood 108, Nr. 11 (16.11.2006): 256. http://dx.doi.org/10.1182/blood.v108.11.256.256.
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Abstract TR3 (Nur77) is an orphan member of the retinoid/steroid family of nuclear receptors, which translocates from nucleus to mitochondria where it binds Bcl-2 and converts Bcl-2 from an anti-apoptotic to a pro-apoptotic protein (Li, et al. Science289: 1159, 2000; Lin, et al CELL116: 527, 2004). Because Bcl-2 is pathologically over-expressed in many ca cancers and leukemias, contributing to chemoresistance, we sought to exploit the TR3 interaction with Bcl-2 as a novel therapeutic approach. Mutagenesis studies identified a 9 amino-acid peptide from TR3 that mimics the effects of the full-length protein in terms of binding Bcl-2 and inducing conformational changes that covert Bcl-2 into a killer. A cell-permeable version of this TR3 peptide induced apoptosis of cultured leukemia cell lines (CEM; Jurkat), such that gene transfer-mediated over-expression of Bcl-2 enhanced sensitivity to the TR3 peptide. In contrast, Bcl-2 over-expression rendered these leukemia cells resistant to other inducers of apoptosis, such as the broad-spectrum kinase inhibitor Staurosporine. Mutant TR3 peptides that fail to bind Bcl-2 did not induce apoptosis. To identify chemical compounds that mimic the pro-apoptotic TR3 peptide, a Fluorescence Polarization Assay (FPA) was developed in which FITC-conjugated TR3 peptide binding to Bcl-2 or other appropriate anti-apoptotic Bcl-2-family proteins was measured in high-throughput mode. This high-throughput screening (HTS) assay performs well in 384 well format, with Z′ > 0.75. A chemical library of ~70,000 compounds was screened to identify compounds that displace the TR3 peptide, thus yielding hits that may serve as a potential starting point for drug discovery. Characterization of the properties of these compounds and their analogs will be described. (Supported by NIH grants R01-GM60554 and U54-HG003916).