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1
Flórez, Paola, Emanuela Di Martino, and Laís V. Ramalho. "Early Miocene coral reef-associated bryozoans from Colombia. Part I: Cyclostomata, “Anasca” and Cribrilinoidea Cheilostomata." Journal of Paleontology 95, no. 4 (March 16, 2021): 694–719. http://dx.doi.org/10.1017/jpa.2021.5.
Повний текст джерелаАнотація:
AbstractThis is the first of two comprehensive taxonomic works on the early Miocene (ca. 23–20 Ma) bryozoan fauna associated with coral reefs from the Siamaná Formation, in the remote region of Cocinetas Basin in the La Guajira Peninsula, northern Colombia, southern Caribbean. Fifteen bryozoan species in 11 families are described, comprising two cyclostomes and 13 cheilostomes. Two cheilostome genera and seven species are new: Antropora guajirensis n. sp., Calpensia caribensis n. sp., Atoichos magnus n. gen. n. sp., Gymnophorella hadra n. gen. n. sp., Cribrilaria multicostata n. sp., Cribrilaria nixor n. sp., and Figularia bragai n. sp. Eight species are identified only at genus level and remain in open nomenclature. Of the species found, 27% have erect colonies and 73% encrusting colonies. Both types contributed to the reef framework and produced sediment. The observed bryozoan diversity was higher in the barrier reefs than in the lagoonal patch reefs.UUID: http://zoobank.org/5c8468ef-31b0-4e7e-ba93-60a2e2f30b76.
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Gronostajski, Z. J. "Model describing the characteristic values of flow stress and strain of brass M63 and aluminium bronze BA93." Journal of Materials Processing Technology 78, no. 1-3 (June 1998): 84–89. http://dx.doi.org/10.1016/s0924-0136(97)00467-6.
Повний текст джерела
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Dalimunthe, Cici Indriani, Radite Tistama, and Elia Wike Wijayanti Wijaya. "UJI BAKTERI ANTAGONIS UNTUK MENGENDALIKAN PENYAKIT MOULDY ROT (Ceratocystis fimbriata) DI LABORATORIUM." Jurnal Agro Estate 5, no. 1 (June 14, 2021): 39–48. http://dx.doi.org/10.47199/jae.v5i1.78.
Повний текст джерелаАнотація:
Ceratocystis fimbriata menyebabkan penyakit pada bidang sadap tanaman karet (Hevea brasiliensis), yang menyebabkan jamur abu-abu atau busuk pada panel sadap yang mempengaruhi hasil lateks. Tujuan penelitian adalah untuk memperoleh bakteri antagonis yang dapat menghambat pertumbuhan penyakit mouldy rot (Ceratocystis fimbriata) pada skala laboratorium. Penelitian ini menggunakan rancangan acak lengkap non-faktorial yang terdiri dari sepuluh perlakuan dan tiga ulangan. Bakteri Antagonis yang digunakan adalah BA1, BA3, BA4, BA5, BA6, BA7, BA8, BA9, dan BA10. Isolat bakteri diambil dari hasil isolasi kulit yang dipulihkan dan kulit tanaman karet perawan. Hasil penelitian menunjukkan bahwa isolat bakteri yang dapat menghambat pertumbuhan patogen sekitar > 80% adalah BA1, BA4, BA5, BA9, dan BA1. Isolat BA2, BA3, BA6, BA7, dan BA8 dapat menghambat pertumbuhan patogen jamur sekitar 40% hingga <80%. Isolat BA10 memiliki persentase penghambatan tinggi sekitar 92,84%. Pengujian lebih lanjut perlu dilakukan pada skala lapangan untuk menentukan efektivitasnya sebagai kontrol biologis penyakit mouldy rot.
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ROCH, Anne-Marie, Gerard QUASH, Yvonne MICHAL, Jacqueline CHANTEPIE, Bernard CHANTEGREL, Christian DESHAYES, Alain DOUTHEAU, and Jacqueline MARVEL. "Altered methional homoeostasis is associated with decreased apoptosis in BAF3 bcl2 murine lymphoid cells." Biochemical Journal 313, no. 3 (February 1, 1996): 973–81. http://dx.doi.org/10.1042/bj3130973.
Повний текст джерелаАнотація:
Methional is a potent inducer of apoptosis in an interleukin 3-dependent murine lymphoid cell line BAF3 b0 when it is added to the culture medium. In these cells transfected with the bcl2 gene, BAF3 bcl2, the apoptotic-inducing activity of methional is dramatically reduced. The addition of disulfiram (an inhibitor of aldehyde dehydrogenase) in order to reduce methional oxidation brought about an increase in apoptosis in BAF3 b0 but not in BAF3 bcl2 cells. In contrast, the addition of quercetin (an inhibitor of aldehyde reductase) in an attempt to diminish methional reduction increased apoptosis in both BAF3 b0 and BAF3 bcl2 cells. The extent of DNA fragmentation in BAF3 bcl2 cells approached that in BAF3 b0 cells in the presence of quercetin and exogenous methional, suggesting a defect in methional biosynthesis in BAF3 bcl2 cells. Direct evidence for this was obtained by measuring labelled methional in cells incubated with the sodium salt of [U-14C]4-methylthio-2-oxobutanoic acid (MTOB), the precursor of methional. The 80% decrease in labelled methional in BAF3 bcl2 compared with BAF3 b0 cells was accompanied by a concomitant rise in the transamination of [14C]MTOB to [14C]methionine in BAF3 bcl2 cells. Inhibition of the transaminase, however, by a synthetic transition-state-type compound, pyridoxal-L-methionine ethyl ester, induced apoptosis in BAF3 b0 but not in BAF3 bcl2 cells, confirming that the defect in BAF3 bcl2 cells was not in the transaminase itself but rather in the oxidative decarboxylation step MTOB →methional. In addition, no evidence was obtained for the synthesis of [14C]malondialdehyde from [14C]methional in BAF3 bcl2 cells. As these cells show no deficiency in their content of reactive oxygen species compared with that of BAF3 b0 cells, they may possess some other defect in the β-hydroxylase enzyme system itself.
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Hiebel, Christof, Elisabeth Stürner, Meike Hoffmeister, Georg Tascher, Mario Schwarz, Heike Nagel, Christian Behrends, Christian Münch, and Christian Behl. "BAG3 Proteomic Signature under Proteostasis Stress." Cells 9, no. 11 (November 4, 2020): 2416. http://dx.doi.org/10.3390/cells9112416.
Повний текст джерелаАнотація:
The multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3) represents a key player in the quality control of the cellular proteostasis network. In response to stress, BAG3 specifically targets aggregation-prone proteins to the perinuclear aggresome and promotes their degradation via BAG3-mediated selective macroautophagy. To adapt cellular homeostasis to stress, BAG3 modulates and functions in various cellular processes and signaling pathways. Noteworthy, dysfunction and deregulation of BAG3 and its pathway are pathophysiologically linked to myopathies, cancer, and neurodegenerative disorders. Here, we report a BAG3 proteomic signature under proteostasis stress. To elucidate the dynamic and multifunctional action of BAG3 in response to stress, we established BAG3 interactomes under basal and proteostasis stress conditions by employing affinity purification combined with quantitative mass spectrometry. In addition to the identification of novel potential BAG3 interactors, we defined proteins whose interaction with BAG3 was altered upon stress. By functional annotation and protein-protein interaction enrichment analysis of the identified potential BAG3 interactors, we confirmed the multifunctionality of BAG3 and highlighted its crucial role in diverse cellular signaling pathways and processes, ensuring cellular proteostasis and cell viability. These include protein folding and degradation, gene expression, cytoskeleton dynamics (including cell cycle and transport), as well as granulostasis, in particular.
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Liu, Yubo, Renjie Xu, Jinfu Xu, Tiantian Wu, and Xiangxin Zhang. "BAG3 regulates bone marrow mesenchymal stem cell proliferation by targeting INTS7." PeerJ 11 (August 9, 2023): e15828. http://dx.doi.org/10.7717/peerj.15828.
Повний текст джерелаАнотація:
Background BAG3 is an essential regulator of cell survival and has been investigated in the context of heart disease and cancer. Our previous study used immunoprecipitation-liquid chromatography-tandem mass spectrometry to show that BAG3 might directly interact with INTS7 and regulate bone marrow mesenchymal stem cell (BMMSCs) proliferation. However, whether BAG3 bound INTS7 directly and how it regulated BMMSCs expansion was unclear. Methods BAG3 expression was detected by quantitative real-time PCR in BMMSCs after siRNA-mediated BAG3 knockdown. BMMSC proliferation was determined using the CCK-8 and colony formation assays. The transwell migration, flow cytometry and TUNEL assays were performed to measure BMMSC migration, cell cycle and apoptosis, respectively. Moreover, co-immunoprecipitation, protein half-life assay and western blotting analyses were used to determine the regulatory mechanism underlying the BAG3-mediated increase in BMMSC proliferation. Results The results showed that knocking down BAG3 in BMMSCs markedly decreased their proliferative activity, colony formation and migratory capacity, and induced cell apoptosis as well as cell cycle arrest. Meanwhile, overexpression of BAG3 had the opposite effect. Bioinformatics and BAG3-INTS7 co-immunoprecipitation analyses revealed that BAG3 directly interacted with INTS7. Moreover, the downregulation of BAG3 inhibited the expression of INTS7 and promoted its ubiquitination. We also observed that BAG3 knockdown increased the levels of reactive oxygen species and the extent of DNA damage in BMMSCs. Notably, the upregulation of INTS7 or the addition of an antioxidant scavenger could rescue the BMMSC phenotype induced by BAG3 downregulation. Conclusions BAG3 directly interacts with INTS7 and promotes BMMSC expansion by reducing oxidative stress.
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Lee, Jae Chang, Sung Ae Koh, Kyung Hee Lee, and Jae-Ryong Kim. "BAG3 contributes to HGF-mediated cell proliferation, migration, and invasion via the Egr1 pathway in gastric cancer." Tumori Journal 105, no. 1 (December 4, 2018): 63–75. http://dx.doi.org/10.1177/0300891618811274.
Повний текст джерелаАнотація:
Introduction: Bcl2-associated athanogene 3 (BAG3) is elevated in several types of cancers. However, the role of BAG3 in progression of gastric cancer is unknown. Therefore, the present study aims to find out the role of BAG3 in hepatocyte growth factor (HGF)–mediated tumor progression and the molecular mechanisms by which HGF regulates BAG3 expression. Methods: BAG3 mRNA and protein were measured using reverse transcription polymerase chain reaction and Western blot in the 2 human gastric cancer cell lines, NUGC3 and MKN28, treated with or without HGF. The effects of BAG3 knockdown on cell proliferation, cell invasion, and apoptosis were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the in vitro 2-chamber invasion assay, and flow cytometry in BAG3 short hairpin RNA (shRNA)–transfected cells and control cells. The signaling pathways involved in BAG3 that are regulated by HGF were analyzed. The chromatin immunoprecipitation assay was used to determine binding of Egr1 to the BAG3 promoter. Results: BAG3 mRNA and protein levels were increased following treatment with HGF. HGF-mediated BAG3 upregulation increased cell proliferation and cell invasion; however, it decreased apoptosis. HGF-mediated BAG3 upregulation is regulated by an ERK and Egr1-dependent pathway. BAG3 may have an important role in HGF-mediated cell proliferation and metastasis in gastric cancer through an ERK and Egr1-dependent pathway. Conclusion: This pathway may provide novel therapeutic targets and provide information for further identification of other targets of therapeutic significance in gastric cancer.
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An, Ming-Xin, Si Li, Han-Bing Yao, Chao Li, Jia-Mei Wang, Jia Sun, Xin-Yu Li, Xiao-Na Meng, and Hua-Qin Wang. "BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells." Journal of Cell Biology 216, no. 12 (November 7, 2017): 4091–105. http://dx.doi.org/10.1083/jcb.201701064.
Повний текст джерелаАнотація:
Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.
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McCollum, Andrea K., Giovanna Casagrande, and Elise C. Kohn. "Caught in the middle: the role of Bag3 in disease." Biochemical Journal 425, no. 1 (December 14, 2009): e1-e3. http://dx.doi.org/10.1042/bj20091739.
Повний текст джерелаАнотація:
Bag3 is a Bag family co-chaperone that regulates the ATPase activity of Hsp70 (heat-shock protein 70) chaperones. Recent studies have demonstrated that Bag3 can initiate macroautophagy in co-operation with small heat-shock protein HspB8. In this issue of the Biochemical Journal, Fuchs and co-workers have discovered the IPV motif in Bag3 that is necessary for binding to HspB8. The authors have also identified HspB6 as a new binding partner for Bag3 and characterized further the binding of both HspB8 and HspB6 in Bag3-mediated clearance of aggregated polyglutamine-containing protein Htt43Q (huntingtin exon 1 fragment with 43 CAG repeats). It is clear from recent identification of a Bag3 mutation that causes a form of muscular dystrophy that the full function of Bag3 in disease is not clear. We will apply the findings of Fuchs et al. in this issue to reconcile the phenotypes of Bag3 homologue knockouts with the emerging role of Bag3 in autophagy.
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Lyu, Chuang, Wei-Dong Li, Shu-Wen Wang, Jin-Mei Peng, Yong-Bo Yang, Zhi-Jun Tian, and Xue-Hui Cai. "Host BAG3 Is Degraded by Pseudorabies Virus pUL56 C-Terminal 181L-185L and Plays a Negative Regulation Role during Viral Lytic Infection." International Journal of Molecular Sciences 21, no. 9 (April 29, 2020): 3148. http://dx.doi.org/10.3390/ijms21093148.
Повний текст джерелаАнотація:
Bcl2-associated athanogene (BAG) 3, which is a chaperone-mediated selective autophagy protein, plays a pivotal role in modulating the life cycle of a wide variety of viruses. Both positive and negative modulations of viruses by BAG3 were reported. However, the effects of BAG3 on pseudorabies virus (PRV) remain unknown. To investigate whether BAG3 could modulate the PRV life cycle during a lytic infection, we first identified PRV protein UL56 (pUL56) as a novel BAG3 interactor by co-immunoprecipitation and co-localization analyses. The overexpression of pUL56 induced a significant degradation of BAG3 at protein level via the lysosome pathway. The C-terminal mutations of 181L/A, 185L/A, or 181L/A-185L/A in pUL56 resulted in a deficiency in pUL56-induced BAG3 degradation. In addition, the pUL56 C-terminal mutants that lost Golgi retention abrogated pUL56-induced BAG3 degradation, which indicates a Golgi retention-dependent manner. Strikingly, BAG3 was not observed to be degraded in either wild-type or UL56-deleted PRV infected cells as compared to mock infected ones, whereas the additional two adjacent BAG3 cleaved products were found in the infected cells in a species-specific manner. Overexpression of BAG3 significantly suppressed PRV proliferation, while knockdown of BAG3 resulted in increased viral yields in HEK293T cells. Thus, these data indicated a negative regulation role of BAG3 during PRV lytic infection. Collectively, our findings revealed a novel molecular mechanism on host protein degradation induced by PRV pUL56. Moreover, we identified BAG3 as a host restricted protein during PRV lytic infection in cells.
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Zhu, Huayuan, Peng Liu, and Jianyong Li. "The Expression of BAG3 Gene in Chronic Lymphocytic Leukemia and Its Clinical Significance." Blood 118, no. 21 (November 18, 2011): 4605. http://dx.doi.org/10.1182/blood.v118.21.4605.4605.
Повний текст джерелаАнотація:
Abstract Abstract 4605 Objective: BAG3 (BCL2-associated athanogene 3) is a member of BAG family. Previously, many reports indicated that BAG3 was over-expressed in different human cancer tissues, such as thyroid carcinoma, pancreatic cancer, prostate cancer, and leukemic cells. However, there is no or low expression of BAG3 in normal tissues. These imply that BAG3 maybe have some important roles in the human cancers. This study was aimed to investigate the expression level of BAG3 mRNA in chronic lymphocytic leukemia (CLL) and its significance in evaluation of CLL prognosis. Methods: 100 CLL human patients and 20 healthy controls were enrolled in this study. The BAG3 mRNA expressions were measured by real-time PCR with fluorescent dye SYBR Green I, the β-actin was used as internal control. The relative quantitative value of BAG3 expression was calculated by means of 2 (–ΔCt). We analyzed the results with established CLL prognostic factors, overall survival (OS) and treatment-free survival (TFS). Results: The expression of BAG3 mRNA in 100 CLL patients was significantly higher than 20 normal control (p = 0.038). Furthermore, The BAG3 expression was obviously increased in CD38 positive patients CD38 (n = 31) than CD38 negetive patients it (n = 61, p = 0.0238). We also found that the expression of BAG3 in the patients with unmutated immunoglobulin heavy-chain (n = 29) was markedly higher than those with mutated immunoglobulin heavy-chain (IgHV) (n = 62, p = 0.0326). It is also found that the patients with enlarged lymph nodes (n = 24) have higher BAG3 expression, compared with those without enlarged lymph nodes (n = 76, p = 0.0004). The increased BAG3 level can also be found in the patients with splenomegaly (n = 32),compared with those without splenomegaly (n=68, p = 0.0393). No association was found between BAG3 expression and patient clinical baseline information (gender and age), as well as other established prognostic factors (lymphocyte count, cytogenetics analysis and p53 mutation status). 25 of these patients were treated with fludarabine-based therapy, interestingly, BAG3 expression level was significantly increased in patients who were relapse and/or refractory to fludarabine-based treatment (n = 10, p = 0.019). However, there are no differences in OS and TFS between patients with low BAG3 expressions and high expression, which indicated BAG3 didn’t affect the patients’ OS and TFS. Conclusion: These results showed that the BAG3 expression in CLL patients is markedly higher than normal controls. CD38, mutation of IgHV, lymph nodes and splenomegaly are related to the expression of BAG3 in CLL. Furthermore, the patients, who were relapse and/or refractory to fludarabine, have a higher expression of BAG3. These imply that BAG3 may be involved in the pathogenesis of CLL and the roles of BAG3 in CLL need further investigation. Disclosures: No relevant conflicts of interest to declare.
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Diao, Hongtao, Kaili Wu, Dingming Lan, Dongwei Wang, Jingjing Zhao, Bingying Huang, Xiaoqi Shao, et al. "BAG3 Alleviates Atherosclerosis by Inhibiting Endothelial-to-Mesenchymal Transition via Autophagy Activation." Genes 13, no. 8 (July 26, 2022): 1338. http://dx.doi.org/10.3390/genes13081338.
Повний текст джерелаАнотація:
Atherosclerosis is a chronic systemic inflammatory disease that causes severe cardiovascular events. B cell lymphoma 2-associated athanogene (BAG3) was proven to participate in the regulation of tumor angiogenesis, neurodegenerative diseases, and cardiac diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the role of BAG3 in atherosclerosis and elucidate the potential molecular mechanism. In this study, ApoE−/− mice were given a tail-vein injection of BAG3-overexpressing lentivirus and fed a 12-week high-fat diet (HFD) to investigate the role of BAG3 in atherosclerosis. The overexpression of BAG3 reduced plaque areas and improved atherosclerosis in ApoE−/− mice. Our research proves that BAG3 promotes autophagy in vitro, contributing to the suppression of EndMT in human umbilical vein endothelial cells (HUVECs). Mechanically, autophagy activation is mediated by BAG3 via the interaction between BAG3 and its chaperones HSP70 and HSPB8. In conclusion, BAG3 facilitates autophagy activation via the formation of the chaperone-assisted selective autophagy (CASA) complex interacting with HSP70 and HSPB8, leading to the inhibition of EndMT during the progression of atherosclerosis and indicating that BAG3 is a potential therapeutic target for atherosclerosis.
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Grover, Ajay, and Angelo Izzo. "Role of BAT3 in modulating the immune response (111.12)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 111.12. http://dx.doi.org/10.4049/jimmunol.186.supp.111.12.
Повний текст джерелаАнотація:
Abstract HLA-B-associated transcript 3 (BAT3) also known as Scythe or BAG6, is a nuclear protein that has recently been implicated in the control of apoptosis and in NK-DC cell cross-talk. Here, we demonstrate that BAT3 modulates the immune response by regulating the function of macrophages and dendritic cells. BAT3 is secreted by macrophages and dendritic cells in vitro and extracellular BAT3 down-regulates the production of nitric oxide and proinflammatory cytokines in IFN-γ and LPS stimulated macrophages. Extracellular BAT3 also down-regulates the LPS-stimulated maturation of dendritic cells. The immunodominant Mycobacterium tuberculosis antigen ESAT-6 (early secreted antigenic target-6) up-regulates BAT3 expression in macrophages and dendritic cells in vitro. Intracellular BAT3 regulates ESAT-6 induced apoptosis of macrophages by interacting with the anti-apoptotic protein BCL-2 (B-cell lymphoma 2) indicating that BAT3 may play a role in pathogenesis of tuberculosis. Taken together, the data suggest that BAT3 may exert different immunomodulatory regulations depending on whether it is intra-or extracellular.
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Fang, Xi, Julius Bogomolovas, Paul Shichao Zhou, Yongxin Mu, Xiaolong Ma, Zee Chen, Lunfeng Zhang, et al. "P209L mutation in Bag3 does not cause cardiomyopathy in mice." American Journal of Physiology-Heart and Circulatory Physiology 316, no. 2 (February 1, 2019): H392—H399. http://dx.doi.org/10.1152/ajpheart.00714.2018.
Повний текст джерелаАнотація:
Bcl-2-associated athanogene 3 (BAG3) is a cochaperone protein and a central player of the cellular protein quality control system. BAG3 is prominently expressed in the heart and plays an essential role in cardiac protein homeostasis by interacting with chaperone heat shock proteins (HSPs) in large, functionally distinct multichaperone complexes. The BAG3 mutation of proline 209 to leucine (P209L), which resides in a critical region that mediates the direct interaction between BAG3 and small HSPs (sHSPs), is associated with cardiomyopathy in humans. However, the mechanism by which the BAG3 P209L missense mutation leads to cardiomyopathy remains unknown. To determine the molecular basis underlying the cardiomyopathy caused by the BAG3 P209L mutation, we generated a knockin (KI) mouse model in which the endogenous Bag3 gene was replaced with mutant Bag3 containing the P215L mutation, which is equivalent to the human P209L mutation. We performed physiological, histological, and biochemical analyses of Bag3 P209L KI mice to determine the functional, morphological, and molecular consequences of the P209L mutation. We found that Bag3 P209L KI mice exhibited normal cardiac function and morphology up to 16 mo of age. Western blot analysis further revealed that levels of sHSPs, stress-inducible HSPs, ubiquitinated proteins, and autophagy were unaffected in P209L mutant mouse hearts. In conclusion, the P209L mutation in Bag3 does not cause cardiomyopathy in mice up to 16 mo of age under baseline conditions. NEW & NOTEWORTHY Bcl-2-associated athanogene 3 (BAG3) P209L mutation is associated with human cardiomyopathy. A recent study reported that transgenic mice overexpressing human BAG3 P209L in cardiomyocytes have cardiac dysfunction. In contrast, our P209L mice that express mutant BAG3 at the same level as that of wild-type mice displayed no overt phenotype. Our results suggest that human cardiomyopathy may result from species-specific requirements for the conserved motif that is disrupted by P209L mutation or from genetic background-dependent effects.
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Alsharif, Haifa, Mary N. Latimer, Katherine C. Perez, Justin Alexander, Md Mostafizur Rahman, Anil K. Challa, Jeong-A. Kim, Sasanka Ramanadham, Martin Young, and Sushant Bhatnagar. "Loss of Brain Angiogenesis Inhibitor-3 (BAI3) G-Protein Coupled Receptor in Mice Regulates Adaptive Thermogenesis by Enhancing Energy Expenditure." Metabolites 13, no. 6 (May 31, 2023): 711. http://dx.doi.org/10.3390/metabo13060711.
Повний текст джерелаАнотація:
Effective energy expenditure is critical for maintaining body weight (BW). However, underlying mechanisms contributing to increased BW remain unknown. We characterized the role of brain angiogenesis inhibitor-3 (BAI3/ADGRB3), an adhesion G-protein coupled receptor (aGPCR), in regulating BW. A CRISPR/Cas9 gene editing approach was utilized to generate a whole-body deletion of the BAI3 gene (BAI3−/−). In both BAI3−/− male and female mice, a significant reduction in BW was observed compared to BAI3+/+ control mice. Quantitative magnetic imaging analysis showed that lean and fat masses were reduced in male and female mice with BAI3 deficiency. Total activity, food intake, energy expenditure (EE), and respiratory exchange ratio (RER) were assessed in mice housed at room temperature using a Comprehensive Lab Animal Monitoring System (CLAMS). While no differences were observed in the activity between the two genotypes in male or female mice, energy expenditure was increased in both sexes with BAI3 deficiency. However, at thermoneutrality (30 °C), no differences in energy expenditure were observed between the two genotypes for either sex, suggesting a role for BAI3 in adaptive thermogenesis. Notably, in male BAI3−/− mice, food intake was reduced, and RER was increased, but these attributes remained unchanged in the female mice upon BAI3 loss. Gene expression analysis showed increased mRNA abundance of thermogenic genes Ucp1, Pgc1α, Prdm16, and Elov3 in brown adipose tissue (BAT). These outcomes suggest that adaptive thermogenesis due to enhanced BAT activity contributes to increased energy expenditure and reduced BW with BAI3 deficiency. Additionally, sex-dependent differences were observed in food intake and RER. These studies identify BAI3 as a novel regulator of BW that can be potentially targeted to improve whole-body energy expenditure.
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Chiappetta, Gennaro, Massimo Ammirante, Anna Basile, Alessandra Rosati, Michela Festa, Mario Monaco, Emilia Vuttariello, et al. "The Antiapoptotic Protein BAG3 Is Expressed in Thyroid Carcinomas and Modulates Apoptosis Mediated by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand." Journal of Clinical Endocrinology & Metabolism 92, no. 3 (March 1, 2007): 1159–63. http://dx.doi.org/10.1210/jc.2006-1712.
Повний текст джерелаАнотація:
Abstract Context: We previously showed that BAG3 protein, a member of the BAG (Bcl-2-associated athanogene) co-chaperone family, modulates apoptosis in human leukemias. The expression of BAG3 in other tumor types has not been extensively investigated so far. Objective: The objective of this study was to analyze BAG3 expression in thyroid neoplastic cells and investigate its influence in cell apoptotic response to TNF-related apoptosis-inducing ligand (TRAIL). Design, Setting, and Patients: We investigated BAG3 expression in human thyroid carcinoma cell lines, including NPA, and the effect of BAG3-specific small interfering RNA on TRAIL-induced apoptosis in NPA cells. Subsequently, we analyzed BAG3 expression in 30 benign lesions and 56 carcinomas from patients of the Naples Tumor Institute Fondazione Senatore Pascale. Main Outcome Measures: The main outcome measures were: analysis of BAG3 protein in NPA cells by Western blot and immunocytochemistry; analysis of apoptosis in TRAIL-stimulated NPA cells by flow cytometry; and evaluation of BAG3 expression in specimens from thyroid lesions by immunohistochemistry. Results: BAG3 was expressed in human thyroid carcinoma cell lines; small interfering RNA-mediated downmodulation of its levels significantly (P < 0.0195) enhanced NPA cell apoptotic response to TRAIL. The protein was not detectable in 19 of 20 specimens of normal thyroid or goiters, whereas 54 of 56 analyzed carcinomas (15 follicular, 28 papillary, and 13 anaplastic) were clearly positive for BAG3 expression. Conclusions: BAG3 downmodulates the apoptotic response to TRAIL in human neoplastic thyroid cells. The protein is specifically expressed in thyroid carcinomas and not in normal thyroid tissue or goiter.
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Fuchs, Margit, Dominic J. Poirier, Samuel J. Seguin, Herman Lambert, Serena Carra, Steve J. Charette, and Jacques Landry. "Identification of the key structural motifs involved in HspB8/HspB6–Bag3 interaction." Biochemical Journal 425, no. 1 (December 14, 2009): 245–57. http://dx.doi.org/10.1042/bj20090907.
Повний текст джерелаАнотація:
The molecular chaperone HspB8 [Hsp (heat-shock protein) B8] is member of the B-group of Hsps. These proteins bind to unfolded or misfolded proteins and protect them from aggregation. HspB8 has been reported to form a stable molecular complex with the chaperone cohort protein Bag3 (Bcl-2-associated athanogene 3). In the present study we identify the binding regions in HspB8 and Bag3 crucial for their interaction. We present evidence that HspB8 binds to Bag3 through the hydrophobic groove formed by its strands β4 and β8, a region previously known to be responsible for the formation and stability of higher-order oligomers of many sHsps (small Hsps). Moreover, we demonstrate that two conserved IPV (Ile-Pro-Val) motifs in Bag3 mediate its binding to HspB8 and that deletion of these motifs suppresses HspB8 chaperone activity towards mutant Htt43Q (huntingtin exon 1 fragment with 43 CAG repeats). In addition, we show that Bag3 can bind to the molecular chaperone HspB6. The interaction between HspB6 and Bag3 requires the same regions that are involved in the HspB8–Bag3 association and HspB6–Bag3 promotes clearance of aggregated Htt43Q. Our findings suggest that the co-chaperone Bag3 might prevent the accumulation of denatured proteins by regulating sHsp activity and by targeting their substrate proteins for degradation. Interestingly, a mutation in one of Bag3 IPV motifs has recently been associated with the development of severe dominant childhood muscular dystrophy, suggesting a possible important physiological role for HspB–Bag3 complexes in this disease.
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Xiao, Heng, Rongliang Tong, Shaobing Cheng, Zhen Lv, Chaofeng Ding, Chengli Du, Haiyang Xie, Lin Zhou, Jian Wu та Shusen Zheng. "BAG3 and HIF-1αCoexpression Detected by Immunohistochemistry Correlated with Prognosis in Hepatocellular Carcinoma after Liver Transplantation". BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/516518.
Повний текст джерелаАнотація:
Objective. The objective is to determine the effects of BAG3 and HIF-1αexpression on the prognosis of HCC patients after liver transplantation.Methods. Samples from 31 patients with HCC receiving liver transplantation were collected for this study. The immunohistochemistry was used to detect the expression of BAG3 and HIF-1αof HCC samples.Results. According to the immunohistochemistry results, BAG3 and HIF-1αstaining were significantly associated with tumor TNM stage (P=0.004,P=0.012). A significant association between high BAG3/HIF-1αlevels and a shorter overall survival was detected, so as the combined BAG3 and HIF-1αanalysis.Conclusion. The results suggested that the expression level of BAG3 and HIF-1αis efficient prognostic parameters in patients with HCC after liver transplantation.
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Wang, Yingying, and Yongjie Tian. "miR-206 Inhibits Cell Proliferation, Migration, and Invasion by Targeting BAG3 in Human Cervical Cancer." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 26, no. 6 (July 5, 2018): 923–31. http://dx.doi.org/10.3727/096504017x15143731031009.
Повний текст джерелаАнотація:
miR-206 and Bcl-2-associated athanogene 3 (BAG3) have been suggested as important regulators in various cancer types. However, the biological role of miR-206 and BAG3 in cervical cancer (CC) remains unclear. We investigated the expressions and mechanisms of miR-206 and BAG3 in CC using in vitro and in vivo assays. In the present study, miR-206 expression was expressed at a lower level in CC tissues and cells than adjacent normal tissues and NEECs. By contrast, BAG3 mRNA and protein were expressed at higher levels in CC tissues and cells. Furthermore, miR-206 overexpression repressed cell proliferation, migration, and invasion in vitro, and the 3′-untranslated region (3′-UTR) of BAG3 was a direct target of miR-206. miR-206 overexpression also inhibited EGFR, Bcl-2, and MMP2/9 protein expression, but promoted Bax protein expression. Besides, BAG3 overexpression partially abrogated miR-206-inhibited cell proliferation and invasion, while BAG3 silencing enhanced miR-206-mediated inhibition. In vivo assay revealed that miR-206 repressed tumor growth in nude mice xenograft model. In conclusion, miR-206 inhibits cell proliferation, migration, and invasion by targeting BAG3 in human CC. Thus, miR-206-BAG3 can be used as a useful target for CC.
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Kögel, Donat, Benedikt Linder, Andreas Brunschweiger, Silvia Chines, and Christian Behl. "At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer." Cells 9, no. 3 (February 28, 2020): 574. http://dx.doi.org/10.3390/cells9030574.
Повний текст джерелаАнотація:
BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins by regulating their turnover via the two major protein degradation pathways, i.e. proteasomal degradation and macroautophagy. On the one hand, BAG3 competes with BAG1 for binding to HSP70, thereby preventing the proteasomal degradation of its client proteins. By functionally interacting with HSP70 and LC3, BAG3 also delivers polyubiquitinated proteins to the autophagy pathway. BAG3 exerts a number of key physiological functions, including an involvement in cellular stress responses, proteostasis, cell death regulation, development, and cytoskeletal dynamics. Conversely, aberrant BAG3 function/expression has pathophysiological relevance correlated to cardiomyopathies, neurodegeneration, and cancer. Evidence obtained in recent years underscores the fact that BAG3 drives several key hallmarks of cancer, including cell adhesion, metastasis, angiogenesis, enhanced autophagic activity, and apoptosis inhibition. This review provides a state-of-the-art overview on the role of BAG3 in stress and therapy resistance of cancer, with a particular focus on BAG3-dependent modulation of apoptotic signaling and autophagic/lysosomal activity.
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Zhang, Jiankai, Zhangyou He, Wenjian Xiao, Qingqing Na, Tianxiu Wu, Kaixin Su, and Xiaojun Cui. "Overexpression of BAG3 Attenuates Hypoxia-Induced Cardiomyocyte Apoptosis by Inducing Autophagy." Cellular Physiology and Biochemistry 39, no. 2 (2016): 491–500. http://dx.doi.org/10.1159/000445641.
Повний текст джерелаАнотація:
Background: Hypoxia is a well-known factor in the promotion of apoptosis, which contributes to the development of numerous cardiac diseases, such as heart failure and myocardial infarction. Inhibiting apoptosis is an important therapeutic strategy for the treatment of related heart diseases caused by ischemia/hypoxic injury. Previous studies have demonstrated that BAG3 plays an important role in cardiomyocyte apoptosis and survival. However, the role of BAG3 in hypoxia-induced cardiomyocyte apoptosis remains to be clarified. Here, we demonstrate that BAG3 is induced by hypoxia stimuli in cultured cardiomyocytes. Methods: BAG3 expression level was measured in H9c2 cells treated with hypoxia for 48 h. Cell proliferation and apoptosis were tested using MTT assay and Annexin V FITC-PI staining assay, respectively. The mRNA or protein expression level of BAG3, LC3-I, LC3-II, Atg5, NF-κB p65 and phosphorylated NF-κB p65 were assessed by qRT-PCR and western blot assay, respectively. Resluts: Overexpression of BAG3 inhibited cell apoptosis and promoted proliferation in hypoxia-injured H9c2 cells. Furthermore, autophagy and NF-κB were activated by BAG3 overexpression, and the NF-κB inhibitor PDTC could inhibit the activation of autophagy induced by BAG3 overexpression. In addition, the autophagy inhibitor 3-MA partly impeded the inhibitory effect of BAG3 on hypoxia-induced cardiomyocyte apoptosis. Conclusion: these results suggested that overexpression of BAG3 promoted cell proliferation and inhibited apoptosis by activating autophagy though the NF-κB signaling pathway in hypoxia-injured cardiomyocytes.
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Carra, Serena, Samuel J. Seguin, Herman Lambert, and Jacques Landry. "HspB8 Chaperone Activity toward Poly(Q)-containing Proteins Depends on Its Association with Bag3, a Stimulator of Macroautophagy." Journal of Biological Chemistry 283, no. 3 (November 15, 2007): 1437–44. http://dx.doi.org/10.1074/jbc.m706304200.
Повний текст джерелаАнотація:
Mutations in HspB8, a member of the B group of heat shock proteins (Hsp), have been associated with human neuromuscular disorders. However, the exact function of HspB8 is not yet clear. We previously demonstrated that overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q. Here we report that HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8. Bag3 overexpression resulted in the accelerated degradation of Htt43Q, whereas Bag3 knockdown prevented HspB8-induced Htt43Q degradation. Additionally, depleting Bag3 caused a reduction in the endogenous levels of LC3-II, a key molecule involved in macroautophagy, whereas overexpressing Bag3 or HspB8 stimulated the formation LC3-II. These results suggested that the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy. This was confirmed by the observation that treatments with macroautophagy inhibitors significantly decreased HspB8- and Bag3-induced degradation of Htt43Q. We conclude that the HspB8 activity is intrinsically dependent on Bag3, a protein that may facilitate the disposal of doomed proteins by stimulating macroautophagy.
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Zhu, Huayuan, Peng Liu, and Jianyong Li. "The Biological Role of BAG3 in Human Chronic Lymphatic Leukemia." Blood 118, no. 21 (November 18, 2011): 4589. http://dx.doi.org/10.1182/blood.v118.21.4589.4589.
Повний текст джерелаАнотація:
Abstract Abstract 4589 Objective: BAG3, a member of BAG family, is shown to sustain cell survival and underlies resistance to chemotherapy in human cancer cells, through down-modulation of apoptosis. It can also enhance cell adhesion and migration to promote tumoral invasion. However, the role of BAG3 in human chronic lymphatic leukemia (CLL) remains unclear. Our study aims to discover the roles of BAG3 in the apoptosis and migration of primary CLL cells. Method: In our study, Peripheral blood mononuclear cells were freshly isolated from 18 previously untreated patients. The primary CLL cells were cultured for 6 hours, following, three siRNA (siRNA-1, siRNA-2 and siRNA-3) targeting with different regions of BAG3 mRNA and one non-targeting siRNA were transfected into CLL cells by using Lipofectamine 2000. 6 samples were collected for checking the transfection efficiency by real-time PCR and western blot after 24 or 48 hours. The other 6 samples were exposured with or without fludarabine 12 hours later after tansfection; with another 24 or 48 hours, both cells were harvested, stained with annexin V/PI,and then apoptosis were analyzed using a FACSCalibur flow cytometer.on the other hand, transwell assay were performed in another 6 samples 12 hours after tansfection. to analysis cell migration, the cells were collected and counted 24 hours later. Result: By using the siRNA technique, we successfully down-regulated the expression of BAG3 by 3 different siRNAs. BAG3 mRNA was decreased □‘6 folds (p < 0.05). In order to analyze the effect of BAG3 on CLL cell apoptosis, we used flow cytometry to measure cell apoptosis. Here, the apoptosis rates of CLL cells were increased □‘2 folds after 24 hours transfection by siRNA-2 and siRNA-3 (p < 0.05), and □‘2.5 folds after 48 hours transfection by BAG3 siRNA-1, siRNA-2 and siRNA-3 (p < 0.05). These indicate that BAG3 makes an anti-apoptotic, and knocking-down of it increases the cell apoptosis. To assess the role of BAG3 in the migration of CLL, we used transwell assay to measure cell migration. We found that the migration of CLL cells was decreased 28% by BAG3 siRNA-1 treatment (p < 0.05), 47% by siRNA-2 (p < 0.01) and 50% by siRNA-3 (p < 0.01), respectively. These data showed that BAG3 enhances the CLL migration, and down-regulation of it can inhibit cell migration. Furthermore, fludarabine and BAG3 siRNA were co-treated with CLL cells, to check whether knocking-down of BAG3 can reverse the CLL cells’ resistance against fludarabine. However, the apoptosis rates are not different between co-treated cells and fludarabine-treated cells, which indicated knocking-down of BAG3 may not reverse the fludarabine resistance, though it can promote cell apoptosis and inhibit cell migration. Conclusion: Based on these observations, we conclude that BAG3 may be a potential therapeutic target of human CLL, and inhibition of BAG3 expression can induce cell apoptosis and inhibit cell migration. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Rui, Di Cui, Teng Xue, Yue Lang, Yunfan Zhang, Lianjie Li, Haili Sun, Yu Kuang, Gebin Li, and Jun Tang. "HLA-B-associated transcript 3 (Bat3) stabilizes and activates p53 in a HAUSP-dependent manner." Journal of Molecular Cell Biology 12, no. 2 (October 24, 2019): 99–112. http://dx.doi.org/10.1093/jmcb/mjz102.
Повний текст джерелаАнотація:
Abstract The p53 pathway is a highly complex signaling network including several key regulators. HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2. Here, we identified a novel HAUSP-interacting protein, HLA-B-associated transcript 3 (Bat3) and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism, resulting in cell growth inhibition. Surprisingly, the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon. Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo, and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3. Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus. Notably, Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP. Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination, indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway. Together, our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.
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Li, Si, Hai-Yan Zhang, Tian Wang, Xin Meng, Zhi-Hong Zong, De-Hui Kong, Hua-Qin Wang, and Zhen-Xian Du. "BAG3 Promoted Starvation-Induced Apoptosis of Thyroid Cancer Cells via Attenuation of Autophagy." Journal of Clinical Endocrinology & Metabolism 99, no. 11 (November 1, 2014): E2298—E2307. http://dx.doi.org/10.1210/jc.2014-1779.
Повний текст джерелаАнотація:
Context: BAG3 plays a regulatory role in a number of cellular processes. Recent studies have attracted much attention on its role in activation of selective autophagy. In addition, we have very recently reported that BAG3 is implicated in a BECN1-independent autophagy, namely noncanonical autophagy. Objective: The current study aimed to investigate the potential involvement of BAG3 in canonical autophagy triggered by Earle's Balanced Salt Solution (EBSS) starvation. Setting and Design: Replacement of complete medium with EBSS was used to trigger canonical autophagy. BAG3 expression was measured using real-time RT-PCR and Western blot. Autophagy was monitored using LC3-II transition and p62/SQSTM1 accumulation by Western blot, as well as punctate distribution of LC3 by immunofluorescence staining. Cell growth and apoptotic cell death was investigated using real-time cell analyzer and flowcytometry, respectively. Results: BAG3 expression was potently reduced by EBSS starvation. Forced expression of BAG3 suppressed autophagy and promoted apoptotic cell death of thyroid cancer cells elicited by starvation. In addition, in the presence of autophagy inhibitor, the enhancing effect of BAG3 on apoptotic cell death was attenuated. Conclusions: These results suggest that BAG3 promotes apoptotic cell death in starved thyroid cancer cells, at least in part by autophagy attenuation.
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YANG, Li-jun, Wei-dong YU, Jun-bao DU, Shuang CHAO, Min-xia CHEN, He-hua ZHAO, and Jing-zhu GUO. "Overexpression or knock-down of runt-related transcription factor 1 affects BCR-ABL-induced proliferation and migration in vitro and leukemogenesis in vivo in mice." Chinese Medical Journal 122, no. 3 (February 2009): 331–37. http://dx.doi.org/10.3760/cma.j.issn.0366-6999.2009.03.018.
Повний текст джерелаАнотація:
Background Runt-related transcription factor 1 (Runx1) plays a crucial role in hematogenesis and its dysfunction may contribute to leukemogenesis. However, it is not clear whether or not abnormal expression of Runx1 will induce leukemia and how the change of Runx1 expression level could affect BCR-ABL-induced leukemogenesis. In the present study, we aimed to analyze if abnormal expression of Runx1 in BaF3 cells alone would induce leukemogenesis. And we also wanted to know if abnormal expression of Runx1 in leukemic cells would affect leukemogenesis. Furthermore, we investigated whether overexpression or knock-down of Runx1 in BaF3 cells would induce leukemogenesis. Methods Plasmids containing full-length Runx1 cDNA were transduced into BaF3 cells and BaF3-P185wt cells (BCR-ABL transformed BaF3 cells) by electroporation. Plasmids containing a short hairpin RNA of Runx1 were transduced into BaF3 cells and BaF3-P185wt cells by electroporation. Runx1 expression level was quantified by Western blotting and quantitative real-time PCR. The effects of overexpression or knock-down of Runx1 on proliferation, apoptosis and migration of cells were detected in vitro. Then, using MSCV-P185wt-EGFP as a control, we transplanted MSCV-P185wt-Runx1 cells or MSCV-P185wt-shRNA cells into Balb/c mice through tail vein and observed tumorgenesis of the different phenotypes. Results In vitro analysis revealed that overexpression of Runx1 in P185wt cells could inhibit cell proliferation and slow down cell migration; while knock-down of Runx1 could promote cell proliferation and speed up cell migration. In vivo analysis indicated that mice transplanted with MSCV-P185wt-Runx1 survived longer than controls. In contrast, mice transplanted with MSCV-P185wt-shRNA survived shorter than the control group. Gross pathological analysis revealed that the MSCV-P185wt-Runx1 group had less severe splenomegaly and hepatomegaly compared to the control group, and the MSCV-P185wt-shRNA group had more severe splenomegaly and hepatomegaly. No splenomegaly or hepatomegaly was detected in mice transplanted with MSCV-BaF3-Runx1 cells or MSCV-BaF3-shRNA cells. Both the mice of MSCV-BaF3-Runx1 group and MSCV-BaF3-shRNA group were healthy with no sign of leukemia for up to three months. Conclusions Overexpression or knock-down of Runx1 gene in BaF3 cells alone could not induce leukemogenesis. However, in BaF3-P185wt cells, alteration of Runx1 expression could affect BCR-ABL-induced proliferation and migration in vitro and leukemogenesis in vivo.
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Auzou, G., F. Brunat, S. Clot, T. Rocher, J. Turck, L. Maggio, B. Bollen Pinto, D. Viglino, D. Savary, and L. Belle. "Bloc auriculoventriculaire du troisième degré et infarctus du myocarde à la prise en charge initiale." Annales françaises de médecine d’urgence 8, no. 2 (April 2018): 89–93. http://dx.doi.org/10.3166/afmu-2018-0013.
Повний текст джерелаАнотація:
Les descriptions de l’incidence, de la gravité et des modalités de prise en charge des blocs auriculoventriculaires du troisième degré (BAV3) compliquant la phase aiguë des infarctus du myocarde, avec sus-décalage du segment ST (STEMI), sont rares et anciennes. Par ailleurs, les modalités de prise en charge des STEMI aigus ont beaucoup évolué. Le but de notre étude est d’évaluer l’incidence, de décrire la gravité et les modalités de prise en charge des BAV3 survenant à la phase aiguë des STEMI dans un contexte contemporain. Matériel et méthodes : Nous avons réalisé une étude observationnelle rétrospective de la prise en charge des STEMI aigus à partir du registre prospectif des STEMI du Réseau nord alpin des urgences (RENAU) sur les 19 hôpitaux des Alpes du Nord entre 2009 et 2012. Les patients présentant un BAV3 à la phase initiale de leur prise en charge ont été identifiés. Résultats : Deux mille sept cent neuf patients avec STEMI aigu ont été inclus sur la période d’étude. Cinquante-sept ont présenté un BAV3 (2 %). Cent cinquante-deux des 2 648 patients sans BAV3 (6 %) sont décédés à la phase hospitalière contre 7 des 57 patients (12 %) avec BAV3 (p = 0,047). Parmi les patients en BAV3, un traitement par atropine a été utilisé pour 26 patients et s’est révélé efficace pour (15 %) d’entre eux. L’isoprénaline a été utilisée pour huit patients et a induit une hypotension artérielle pour quatre d’entre eux. Une stimulation ventriculaire droite percutanée a été utilisée pour six patients et a toujours été efficace. Quatorze patients ont été thrombolysés (25 %). Une angioplastie de sauvetage a été nécessaire chez 10 des 14 patients en BAV3 traités par thrombolyse (71 %), comparés aux 325 des 840 patients sans BAV3 traités par thrombolyse (39 % ; p = 0,013). Conclusion : L’incidence des BAV3 à la phase aiguë des STEMI est faible. Le BAV3 représente un facteur de sévérité. Les stratégies thérapeutiques sont d’efficacité inégale, avec des effets indésirables induits par l’isoprenaline. La thrombolyse chez ces patients est moins efficace.
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Shibayama, Hirohiko, Naoyuki Anzai, Stephen E. Braun, Seiji Fukuda, Charlie Mantel, and Hal E. Broxmeyer. "H-Ras Is Involved in the Inside-out Signaling Pathway of Interleukin-3–Induced Integrin Activation." Blood 93, no. 5 (March 1, 1999): 1540–48. http://dx.doi.org/10.1182/blood.v93.5.1540.
Повний текст джерелаАнотація:
Abstract The proto-oncogene product, p21ras, has been implicated in the cellular mechanism of adhesion, although its precise role has been controversial. Numerous cytokines and growth-factors activate Ras, which is an important component of their growth-promoting signaling pathways. On the other hand, the role of Ras in cytokine-induced adhesion has not been elucidated. We therefore investigated the function of H-Ras in the inside-out signaling pathway of interleukin-3 (IL-3)–induced integrin activation in the murine Baf3 cell line after transfection of cells with either constitutively active, dominant-negative, or wild-type H-Ras cDNAs. Adhesion of Baf3 cells to fibronectin was induced by IL-3 in a dose-dependent manner via very late antigen-4 (VLA-4; 4β1 integrins) and VLA-5 (5β1 integrins) activation. On the other hand, IL-4 did not induce the adhesion of Baf3 cells to fibronectin, although IL-4 did stimulate the cell proliferation of Baf3 cells. Constitutively active H-Ras–transfected Baf3 cells adhered to fibronectin without IL-3 stimulation through VLA-4 and VLA-5, whereas dominant-negative H-Ras–transfected Baf3 cells showed significantly less adhesion induced by IL-3 compared with wild-type and constitutively active H-Ras–transfected Baf3 cells. Anti-β1 integrin antibody (clone; 9EG7), which is known to change integrin conformation and activate integrins, induced the adhesion of dominant-negative H-Ras–transfected Baf3 cells as much as the other types of H-Ras–transfected Baf3 cells. 8-Br-cAMP, Dibutyryl-cAMP, Ras-Raf-1 pathway inhibitors, and PD98059, a MAPK kinase inhibitor, suppressed proliferation and phosphorylation of MAPK detected by Western blotting with anti–phospho-MAPK antibody, but not adhesion of any type of H-Ras–transfected Baf3 cells, whereas U-73122, a phospholipase C (PLC) inhibitor, suppressed adhesion of these cells completely. These data indicate that H-Ras and PLC, but not Raf-1, MAPK kinase, or the MAPK pathway, are involved in the inside-out signaling pathway of IL-3–induced VLA-4 and VLA-5 activation in Baf3 cells.
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Shibayama, Hirohiko, Naoyuki Anzai, Stephen E. Braun, Seiji Fukuda, Charlie Mantel, and Hal E. Broxmeyer. "H-Ras Is Involved in the Inside-out Signaling Pathway of Interleukin-3–Induced Integrin Activation." Blood 93, no. 5 (March 1, 1999): 1540–48. http://dx.doi.org/10.1182/blood.v93.5.1540.405k10_1540_1548.
Повний текст джерелаАнотація:
The proto-oncogene product, p21ras, has been implicated in the cellular mechanism of adhesion, although its precise role has been controversial. Numerous cytokines and growth-factors activate Ras, which is an important component of their growth-promoting signaling pathways. On the other hand, the role of Ras in cytokine-induced adhesion has not been elucidated. We therefore investigated the function of H-Ras in the inside-out signaling pathway of interleukin-3 (IL-3)–induced integrin activation in the murine Baf3 cell line after transfection of cells with either constitutively active, dominant-negative, or wild-type H-Ras cDNAs. Adhesion of Baf3 cells to fibronectin was induced by IL-3 in a dose-dependent manner via very late antigen-4 (VLA-4; 4β1 integrins) and VLA-5 (5β1 integrins) activation. On the other hand, IL-4 did not induce the adhesion of Baf3 cells to fibronectin, although IL-4 did stimulate the cell proliferation of Baf3 cells. Constitutively active H-Ras–transfected Baf3 cells adhered to fibronectin without IL-3 stimulation through VLA-4 and VLA-5, whereas dominant-negative H-Ras–transfected Baf3 cells showed significantly less adhesion induced by IL-3 compared with wild-type and constitutively active H-Ras–transfected Baf3 cells. Anti-β1 integrin antibody (clone; 9EG7), which is known to change integrin conformation and activate integrins, induced the adhesion of dominant-negative H-Ras–transfected Baf3 cells as much as the other types of H-Ras–transfected Baf3 cells. 8-Br-cAMP, Dibutyryl-cAMP, Ras-Raf-1 pathway inhibitors, and PD98059, a MAPK kinase inhibitor, suppressed proliferation and phosphorylation of MAPK detected by Western blotting with anti–phospho-MAPK antibody, but not adhesion of any type of H-Ras–transfected Baf3 cells, whereas U-73122, a phospholipase C (PLC) inhibitor, suppressed adhesion of these cells completely. These data indicate that H-Ras and PLC, but not Raf-1, MAPK kinase, or the MAPK pathway, are involved in the inside-out signaling pathway of IL-3–induced VLA-4 and VLA-5 activation in Baf3 cells.
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Simhadri, Venkateswara Rao, Katrin S. Reiners, Peter J. McKinnon, Michael Hallek, Andreas Engert, and Elke Pogge von Strandmann. "HLA-B-Associated Transcript 3 (BAT3) is an activating ligand for NKp30 and released from dendritic cells (48.2)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S74. http://dx.doi.org/10.4049/jimmunol.178.supp.48.2.
Повний текст джерелаАнотація:
Abstract Natural-killer (NK)-cells, originally defined as innate lymphocytes are regulators of adaptive immune responses via cytokine secretion and cross-talk with dendritic cells (DCs). Both killing and maturation of DCs by NK cells is dependent on NKp30, a Natural Cytotoxicity Receptor (NCR) expressed on NK cells. However, the NKp30-specific ligands expressed on dendritic cells have remained elusive. We recently identified BAT3 as the tumor associated ligand for NKp30. BAT3 is a nuclear protein characterized by the conserved BAG domain (Bcl-2 associated anthogene), that interacts with HSP70. Here we show that immature and mature DCs express BAT3 mRNA and protein. The protein is released from DCs into the extracellular environment upon exposure to stress signals such as serum starvation and heat shock. Moreover, the purified, recombinant BAT3 is functional as it binds to NKp30 and induces NK cell-mediated cytokine secretion. The inhibition of BAT3 using polyclonal antibodies prevents tumor rejection in vivo, demonstrating that BAT3 is necessary for the tumor rejection in a xenograft tumor model. Thus, BAT3 is a novel ligand for the NK cell-receptor NKp30 and its role in the reciprocal activation of NK-DC cross-talk will be discussed. We present evidence that BAT3 is, together with HSP70 and HMGB1, a member of the emerging group of immune regulators that we call “Nucleokines”. Support- Koeln Fortune Programme (89/2004).
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Zhu, Chen, Karen O. Dixon, Kathleen Newcomer, Guangxiang Gu, Sheng Xiao, Sarah Zaghouani, Markus A. Schramm, et al. "Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion." Science Advances 7, no. 18 (April 2021): eabd2710. http://dx.doi.org/10.1126/sciadv.abd2710.
Повний текст джерелаАнотація:
T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell–mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3−/− T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions.
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Luthold, Carole, Herman Lambert, Solenn M. Guilbert, Marc-Antoine Rodrigue, Margit Fuchs, Alice-Anaïs Varlet, Amélie Fradet-Turcotte, and Josée N. Lavoie. "CDK1-Mediated Phosphorylation of BAG3 Promotes Mitotic Cell Shape Remodeling and the Molecular Assembly of Mitotic p62 Bodies." Cells 10, no. 10 (October 2, 2021): 2638. http://dx.doi.org/10.3390/cells10102638.
Повний текст джерелаАнотація:
The cochaperone BCL2-associated athanogene 3 (BAG3), in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation, and proper abscission of daughter cells. BAG3 and HSPB8 mitotic functions implicate the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the interplay between this chaperone-assisted pathway and the mitotic machinery is not known. Here, we show that BAG3 phosphorylation at the conserved T285 is regulated by CDK1 and activates its function in mitotic cell shape remodeling. BAG3 phosphorylation exhibited a high dynamic at mitotic entry and both a non-phosphorylatable BAG3T285A and a phosphomimetic BAG3T285D protein were unable to correct the mitotic defects in BAG3-depleted HeLa cells. We also demonstrate that BAG3 phosphorylation, HSPB8, and CDK1 activity modulate the molecular assembly of p62/SQSTM1 into mitotic bodies containing K63 polyubiquitinated chains. These findings suggest the existence of a mitotically regulated spatial quality control mechanism for the fidelity of cell shape remodeling in highly dividing cells.
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De Marco, M., A. Falco, F. Reppucci, L. Marzullo, A. Rosati, G. Armentaro, A. Minniti, et al. "POS0624 BAG3 PROTEIN: A PROMISING NOVEL BIOMARKER OF FIBROSIS IN SYSTEMIC SCLEROSIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 585.3–586. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4071.
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BackgroundSystemic Sclerosis (SSc) is a rare autoimmune disease characterized by an abnormal remodelling of tissue matrix, leading to fibrosis of skin and internal organs. Despite progresses made in terms of knowledge of pathogenic mechanisms, no study has yet identified specific biomarkers useful for assessing disease evolution and response to therapies. Bcl2-associated athanogene 3 (BAG3) protein is a member of a family of co-chaperones that interact with the ATPase domain of the heat shock protein (Hsp) 70 through their BAG domain. BAG3 is constitutively present in a few normal cell types and some tumours, while its expression is induced by stressful stimuli in a wide variety of cells. BAG3 interacts with several partner proteins regulating different pathways, including apoptosis, autophagy and motility. Recent studies have demonstrated a pivotal role of extracellular BAG3 in pro-tumor cell signaling in the tumor microenvironment, as well as its involvement in the development of fibrosis in tumor tissues [1]. In addition, a strong correlation betweenbag3gene expression and patients’ survival was found in several types of fibrotic tumors [1].ObjectivesOur aim was to evaluate the presence of BAG3 in the serum of patients with SSc and to investigate whether circulating levels of BAG3 could have any relationship with different SSc subsets and disease features.MethodsWe enrolled SSc patients, all classified according to the ACR-EULAR criteria. Videocapillaroscopy (NCV) was performed at the time of serum collection. Lung involvement was assessed by spirometry and high-resolution chest CT. Patients were classified into 3 subgroups (no ILD, limited ILD, and extensive ILD) according to the diagram described by Goh et al.[2]. SSc disease activity was assessed according to the activity indices defined by the EUSTAR score [3]. Evaluation of BAG3 protein in serum samples was performed by a sandwich ELISA assay.ResultsThe study cohort included 106 SSc patients (47 were classified with lcSSc and 59 with dcSSc) and 100 sex and age matched healthy controls (HC). Serum levels of BAG3 were significantly higher in SSc patients (mean value 85,3 pg/mL, 95% confidence interval CI 47,2-123,4) when compared with HC (0,68 pg/mL, 95%CI 0,13-1,23) (p=0.001). When analyzed according to disease subset, dcSSc patients showed values (143,3 pg/mL, 95%CI 78-208,5) significantly higher and lcSSc patients (8,7 pg/mL, 95%CI 1,64-15,9,5) (p=0.001). No correlation was found between BAG3 levels and digital ulcers, mRSS and disease activity. Conversely, BAG3 values positively correlated with the extent of lung damage (237,8 pg/mL, 95%CI 131,2-344 in the extensive lung disease vs 16,3 %CI 7,5-25,3 in the limited). Finally, BAG3 values were significantly higher in patients with late NVC pattern in comparison with NVC pattern early/active (p=0.0008).ConclusionRecent studies have highlighted a central role of extracellular BAG3 in maintaining the tumour microenvironment, as well as in the development of fibrosis in neoplastic tissues. To our knowledge, the presence of BAG3 in the serum of patients with SSc has never been described in the literature.Serum levels of BAG3 were found to be significantly higher in the dcSSc, mostly in those with lung involvement. This is not surprising since the diffuse form of disease has more extensive fibrosis, both in the skin and lung, than lcSSc. Accordingly, BAG3 values correlated with the late pattern at NVC, the one most frequently associated with the more advanced and fibrotic stages of the disease. Conversely, serum BAG3 values did not correlate with disease activity, since these scores reflect the evolution and progression of disease rather than the extent of fibrosis. Indeed, the close correlation between BAG3 levels and the more fibrotic features of the disease, suggests that BAG3 might be a new promising marker of fibrosis.References[1]M. De Marco, N. Del Papa et al., J Cell Biochem 2022[2]Goh et al. Am J Resp Crit Care Dis 2008[3]Valentini G et al. Ann Rheum Dis. 2017Acknowledgements:NIL.Disclosure of InterestsMargot De Marco Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies., Antonia Falco: None declared, Francesca Reppucci: None declared, Liberato Marzullo Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies., Alessandra Rosati Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies., Giuseppe Armentaro: None declared, Antonina Minniti: None declared, Claudia Iannone: None declared, Nicoletta Del Papa Speakers bureau: Boheringer-Ingelaim; Janssen, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB, Consultant of: Consultant of: AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, and UCB, Maria Caterina Turco Shareholder of: Shareholder of Fibrosys srl, an academic spin-off that provided anti-BAG3 antibodies.
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Mani, Arul M., Karthik Dhanabalan, Victor Lamin, Thomas Wong, Madhu V. Singh, and Ayotunde O. Dokun. "BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease." International Journal of Molecular Sciences 23, no. 18 (September 14, 2022): 10715. http://dx.doi.org/10.3390/ijms231810715.
Повний текст джерелаАнотація:
Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, resulting in ischemic limb injuries. Individuals with diabetes and PAD typically have more severe ischemic limb injuries and limb amputations, but the mechanisms involved are poorly understood. Previously, we identified BAG3 as a gene within a mouse genetic locus termed limb salvage QTL1 on mouse chromosome 7 that determined the extent of limb necrosis following ischemic injury in C57Bl/6 mice. Whether BAG3 deficiency plays a role in the severe ischemic injury observed in diabetic PAD is not known. In vitro, we found simulated ischemia enhanced BAG3 expression in primary human skeletal muscle cells, whereas BAG3 knockdown increased necroptosis markers and decreased cell viability. In vivo, ischemic skeletal muscles from hind limbs of high-fat diet (HFD)-fed mice showed poor BAG3 expression compared to normal chow diet (NCD)-fed mice, and this was associated with increased limb amputations. BAG3 overexpression in ischemic skeletal muscles from hind limbs of HFD mice rescued limb amputation and improved autophagy, necroptosis, skeletal muscle function and regeneration. Therefore, BAG3 deficiency in ischemic skeletal muscles contributes to the severity of ischemic limb injury in diabetic PAD, likely through autophagy and necroptosis pathways.
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Luthold, Carole, Alice-Anaïs Varlet, Herman Lambert, François Bordeleau, and Josée N. Lavoie. "Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin." International Journal of Molecular Sciences 22, no. 1 (December 25, 2020): 142. http://dx.doi.org/10.3390/ijms22010142.
Повний текст джерелаАнотація:
The fidelity of actin dynamics relies on protein quality control, but the underlying molecular mechanisms are poorly defined. During mitosis, the cochaperone BCL2-associated athanogene 3 (BAG3) modulates cell rounding, cortex stability, spindle orientation, and chromosome segregation. Mitotic BAG3 shows enhanced interactions with its preferred chaperone partner HSPB8, the autophagic adaptor p62/SQSTM1, and HDAC6, a deacetylase with cytoskeletal substrates. Here, we show that depletion of BAG3, HSPB8, or p62/SQSTM1 can recapitulate the same inhibition of mitotic cell rounding. Moreover, depletion of either of these proteins also interfered with the dynamic of the subcortical actin cloud that contributes to spindle positioning. These phenotypes were corrected by drugs that limit the Arp2/3 complex or HDAC6 activity, arguing for a role for BAG3 in tuning branched actin network assembly. Mechanistically, we found that cortactin acetylation/deacetylation is mitotically regulated and is correlated with a reduced association of cortactin with HDAC6 in situ. Remarkably, BAG3 depletion hindered the mitotic decrease in cortactin–HDAC6 association. Furthermore, expression of an acetyl-mimic cortactin mutant in BAG3-depleted cells normalized mitotic cell rounding and the subcortical actin cloud organization. Together, these results reinforce a BAG3′s function for accurate mitotic actin remodeling, via tuning cortactin and HDAC6 spatial dynamics.
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Hamoud, Noumeira, Viviane Tran, Louis-Philippe Croteau, Artur Kania, and Jean-François Côté. "G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates." Proceedings of the National Academy of Sciences 111, no. 10 (February 24, 2014): 3745–50. http://dx.doi.org/10.1073/pnas.1313886111.
Повний текст джерелаАнотація:
Muscle fibers form as a result of myoblast fusion, yet the cell surface receptors regulating this process are unknown in vertebrates. In Drosophila, myoblast fusion involves the activation of the Rac pathway by the guanine nucleotide exchange factor Myoblast City and its scaffolding protein ELMO, downstream of cell-surface cell-adhesion receptors. We previously showed that the mammalian ortholog of Myoblast City, DOCK1, functions in an evolutionarily conserved manner to promote myoblast fusion in mice. In search for regulators of myoblast fusion, we identified the G-protein coupled receptor brain-specific angiogenesis inhibitor (BAI3) as a cell surface protein that interacts with ELMO. In cultured cells, BAI3 or ELMO1/2 loss of function severely impaired myoblast fusion without affecting differentiation and cannot be rescued by reexpression of BAI3 mutants deficient in ELMO binding. The related BAI protein family member, BAI1, is functionally distinct from BAI3, because it cannot rescue the myoblast fusion defects caused by the loss of BAI3 function. Finally, embryonic muscle precursor expression of a BAI3 mutant unable to bind ELMO was sufficient to block myoblast fusion in vivo. Collectively, our findings provide a role for BAI3 in the relay of extracellular fusion signals to their intracellular effectors, identifying it as an essential transmembrane protein for embryonic vertebrate myoblast fusion.
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Kyratsous, Christos A., and Saul J. Silverstein. "BAG3, a Host Cochaperone, Facilitates Varicella-Zoster Virus Replication." Journal of Virology 81, no. 14 (May 2, 2007): 7491–503. http://dx.doi.org/10.1128/jvi.00442-07.
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ABSTRACT Varicella-zoster virus (VZV) establishes a lifelong latent infection in the dorsal root ganglia of the host. During latency, a subset of virus-encoded regulatory proteins is detected; however, they are excluded from the nucleus. ORF29p, a single-stranded DNA binding protein, is one of these latency-associated proteins. We searched for cell proteins that interact with ORF29p and identified BAG3. BAG3, Hsp70/Hsc70, and Hsp90 colocalize with ORF29p in nuclear transcription/replication factories during lytic replication of VZV. Pharmacological intercession of Hsp90 activity with ansamycin antibiotics or depletion of BAG3 by small interfering RNA results in inhibition of virus replication. Replication in BAG3-depleted cell lines is restored by complementation with exogenous BAG3. Alteration of host chaperone activity provides a novel means of regulating virus replication.
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Singh, Mahendra. "Isolation and characterization of insoluble inorganic phosphate solubilizer rice rhizosphere strain Enterobacter cloacae BAU3." Journal of Applied and Natural Science 10, no. 4 (December 1, 2018): 1204–9. http://dx.doi.org/10.31018/jans.v10i4.1929.
Повний текст джерелаАнотація:
The objective of the present study was to isolate and characterize most efficient phosphate solubilizing bacteria (PSB) from rice rhizosphere. The study was carried out during the Kharif season’2018 at Department of Soil Science and Agricultural Chemistry, Bihar Agricultural University, Sabour, Bhagalpur, Bihar. The availability of phosphorous to plants for uptake and utilization is limited in soil due to fixation in the form of Fe-P, Al-P and Ca-P. The use of phosphate solubilizing bacteria can prove to be helpful measure to supply phosphorous to the crops to increase the productivity. In the present investigation, a total of 10 isolates were obtained from rice rhizosphere soil samples. All ten isolated isolates were shown phosphorus solubilization. Out of ten isolates BAU3 was found to be most potent phosphate solubilizers showing clear halo zone around its colony. The isolate BAU3 showed 20.00 mm phosphate solubilizing halo zone around its colony. The solubilization index (SI) of the isolate BAU3 was also calculated at the end of the incubation period and observed phosphate solubilization index (SI) of 3.22. The isolate BAU3 showed maximum insoluble phosphate solubilization of 450.24 ?g ml-1 and isolates BAU3 was selected for subsequent studies. The bacterial isolates BAU3 was gram negative, non-spore forming rods shaped. On the basis of the 16SrDNA sequencing, isolate BAU3 was identified as Enterobacter cloacae strain BAU3 (Genebank Accession No. MK033472). The isolated strain of bacterial has potential to solubilize insoluble phosphorus and it can be utilized for preparation of microbial inoculants or biofertilizers.
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Ardila, Alfredo, Byron Bernal, and Monica Rosselli. "How Extended Is Wernicke’s Area? Meta-Analytic Connectivity Study of BA20 and Integrative Proposal." Neuroscience Journal 2016 (February 23, 2016): 1–6. http://dx.doi.org/10.1155/2016/4962562.
Повний текст джерелаАнотація:
Understanding the functions of different brain areas has represented a major endeavor of contemporary neurosciences. The purpose of this paper was to pinpoint the connectivity of Brodmann area 20 (BA20) (inferior temporal gyrus, fusiform gyrus) in language tasks. A meta-analysis was conducted to assess the language network in which BA20 is involved. The DataBase of Brainmap was used; 11 papers corresponding to 12 experimental conditions with a total of 207 subjects were included in this analysis. Our results demonstrated seven clusters of activation including other temporal lobe areas (BA3, BA21), the insula, and the prefrontal cortex; minor clusters in the cingulate gyrus and the occipital lobe were observed; however, the volumes of all the activation clusters were small. Our results suggest that regardless of BA20 having certain participation in language processes it cannot be considered as a core language processing area (Wernicke’s area); nonetheless, it could be regarded as kind of language processing marginal area, participating in “extended Wernicke’s area” or simply “Wernicke’s system.” It is suggested that “core Wernicke’s area” roughly corresponds to BA21, BA22, BA41, and BA42, while a “language associations area” roughly corresponds to BA20, BA37, BA38, BA39, and BA40 (“extended Wernicke’s area” or “Wernicke’s system”).
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Basile, Anna, Nune Darbinian, Rafal Kaminski, Martyn K. White, Antonio Gentilella, Maria Caterina Turco, and Kamel Khalili. "Evidence for modulation of BAG3 by polyomavirus JC early protein." Journal of General Virology 90, no. 7 (July 1, 2009): 1629–40. http://dx.doi.org/10.1099/vir.0.008722-0.
Повний текст джерелаАнотація:
Polyomavirus JC (JCV) infects oligodendrocytes and astrocytes in the brain and is the cause of the demyelinating disease progressive multifocal leukoencephalopathy (PML). In cell culture, JCV infection is characterized by severe damage to cellular DNA, which begins early in infection, and a viral cytopathic effect, which is observed late in infection. Nevertheless, these JCV-infected cells show a low level of apoptosis, at both the early and late stages of infection. This suggests that there is conflicting interplay between viral anti-apoptotic pathways that seek to optimize virus production, e.g. through T antigen (T-Ag)–p53 interaction, and cellular pro-apoptotic pathways that seek to eliminate virally infected cells. The apoptosis regulatory protein BAG3 is a member of the human Bcl-2-associated athanogene (BAG) family of proteins, which function as molecular co-chaperones through their interaction with Hsc70/Hsp70 and function in the regulation of the cellular stress response, proliferation and apoptosis. This study showed that BAG3 protein is downregulated upon JCV infection and that this effect is mediated by JCV T-Ag via repression of the BAG3 promoter. The site of action of T-Ag was mapped to an AP2 site in the BAG3 promoter, and gel shift and chromatin immunoprecipitation assays showed that T-Ag inhibited AP2 binding to this site, resulting in downregulation of BAG3 promoter expression. Using BAG3 and T-Ag expression and BAG3 siRNA, it was found that BAG3 and T-Ag had antagonistic effects on the induction of apoptosis, being anti-apoptotic and pro-apoptotic, respectively. The significance of these interactions to the JCV life cycle is discussed.
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Martin, Thomas G., Sara Tawfik, Christine S. Moravec, Toni R. Pak, and Jonathan A. Kirk. "BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease." American Journal of Physiology-Heart and Circulatory Physiology 320, no. 6 (June 1, 2021): H2339—H2350. http://dx.doi.org/10.1152/ajpheart.00419.2020.
Повний текст джерелаАнотація:
Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3.
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Avinery, Lena, Valid Gahramanov, Arkadi Hesin, and Michael Y. Sherman. "Hsp70–Bag3 Module Regulates Macrophage Motility and Tumor Infiltration via Transcription Factor LITAF and CSF1." Cancers 14, no. 17 (August 28, 2022): 4168. http://dx.doi.org/10.3390/cancers14174168.
Повний текст джерелаАнотація:
The molecular chaperone Hsp70 has been implicated in multiple stages of cancer development. In these processes, a co-chaperone Bag3 links Hsp70 with signaling pathways that control cancer development. Recently, we showed that besides affecting cancer cells, Hsp70 can also regulate the motility of macrophages and their tumor infiltration. However, the mechanisms of these effects have not been explored. Here, we demonstrated that the Hsp70-bound co-chaperone Bag3 associates with a transcription factor LITAF that can regulate the expression of inflammatory cytokines and chemokines in macrophages. Via this interaction, the Hsp70–Bag3 complex regulates expression levels of LITAF by controlling its proteasome-dependent and chaperone-mediated autophagy-dependent degradation. In turn, LITAF regulates the expression of the major chemokine CSF1, and adding this chemokine to the culture medium reversed the effects of Bag3 or LITAF silencing on the macrophage motility. Together, these findings uncover the Hsp70–Bag3–LITAF–CSF1 pathway that controls macrophage motility and tumor infiltration.
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von Strandmann, Elke Pogge, Venkateswara R. Simhadri, Bastian von Tresckow, Stefanie Sasse, Katrin S. Reiners, Hinrich P. Hansen, Achim Rothe, et al. "Tumor Cell-Derived HLA-B-Associated Transkript 3 (BAT3) Is a Ligand for NKp30 and Activates NK Cells." Blood 108, no. 11 (November 16, 2006): 643. http://dx.doi.org/10.1182/blood.v108.11.643.643.
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Abstract Natural-killer (NK)-cells are lymphocytes of the innate immune system, which directly attack tumor and virus-infected cells. They provide a link between innate and adaptive immunity through crosstalk with dendritic cells (DCs) and mediate T-cell activation. Among the activating and inhibitory receptors that regulate NK cell activity, the orphan NKp30 receptor (NCR3, CD337) plays a special role as NKp30 does not only induce target cell lysis but is also crucial for the interaction between NK cells and dendritic cells. However, so far the cellular ligands for NKp30 have remained elusive. Using a yeast two hybrid approach with the extracellular NKp30 sequence as bait we were able to isolate a putative NKp30 ligand from a tumor cDNA library. Sequence analysis revealed that the cDNA encoded for BAT3 (HLA-B-associated transcript 3) which originally had been cloned from the human major histocompatibility complex by chromosome walking and mapped to chromosome 6p21.3 within the HLA complex. BAT3 was described as a nuclear protein characterized by an N-terminal ubiquitin-like region, a polyproline stretch and a highly conserved BAG-(Bcl-2-associated athanogene) domain. Until now, the function of BAT3 in mammals is not clearly defined. With BAT3-specific antibodies and by means of laser scanner microscopy and Western Blotting we demonstrate that tumor cell lines and immature as well as mature DCs express BAT3. Upon co-cultivation with NK cells or exposure to stress signals such as heat shock, we observed that BAT3 translocates from the nucleus to the cell-surface and the protein is released from tumor cells into the extracellular environment. BAT3 binds directly and specifically to NKp30 on NK cells and triggers NK cell-mediated cytokine release and NKp30-dependent cytotoxicity. The inhibition of endogenous BAT3 using polyclonal antibodies prevents tumor rejection in vivo, demonstrating that BAT3 is necessary for the tumor rejection in a xenograft tumor model. Thus, BAT3 is the long sought cellular NKp30 ligand and exhibits a novel mechanism by which a nuclear protein activates NK cells via NKp30-engagement after its release to the cell-surface and the cell environment. The isolation of the first cellular NKp30-ligand provides the basis for a better molecular understanding of NK cell-regulation and allows the development of clinical applications targeting NKp30 for the immunotherapy.
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Sasaki, Toru, Edyta Marcon, Tracy McQuire, Yoichi Arai, Peter B. Moens, and Hitoshi Okada. "Bat3 deficiency accelerates the degradation of Hsp70-2/HspA2 during spermatogenesis." Journal of Cell Biology 182, no. 3 (August 4, 2008): 449–58. http://dx.doi.org/10.1083/jcb.200802113.
Повний текст джерелаАнотація:
Meiosis is critical for sexual reproduction. During meiosis, the dynamics and integrity of homologous chromosomes are tightly regulated. The genetic and molecular mechanisms governing these processes in vivo, however, remain largely unknown. In this study, we demonstrate that Bat3/Scythe is essential for survival and maintenance of male germ cells (GCs). Targeted inactivation of Bat3/Scythe in mice results in widespread apoptosis of meiotic male GCs and complete male infertility. Pachytene spermatocytes exhibit abnormal assembly and disassembly of synaptonemal complexes as demonstrated by abnormal SYCP3 staining and sustained γ-H2AX and Rad51/replication protein A foci. Further investigation revealed that a testis-specific protein, Hsp70-2/HspA2, is absent in Bat3-deficient male GCs at any stage of spermatogenesis; however, Hsp70-2 transcripts are expressed at normal levels. We found that Bat3 deficiency induces polyubiquitylation and subsequent degradation of Hsp70-2. Inhibition of proteasomal degradation restores Hsp70-2 protein levels. Our findings identify Bat3 as a critical regulator of Hsp70-2 in spermatogenesis, thereby providing a possible molecular target in idiopathic male infertility.
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Kakumitsu, Haruko, Kazuya Shimoda, Takashi Haro, Kotaro Shide, Takashi Kumano, Seido Oku, Kenjirou Kamezaki, Akihiko Numata, Katsuto Takenaka, and Mine Harada. "Tyrosine Kinase 2 (Tyk2) Interacts with and Phosphorylates Siva-1, and Auguments the Apoptotic Effect Induced by Siva-1." Blood 108, no. 11 (November 16, 2006): 1726. http://dx.doi.org/10.1182/blood.v108.11.1726.1726.
Повний текст джерелаАнотація:
Abstract Jak-Stat pathway is essential to transduce cytokine signalings. We previously reported that tyrosine kinase 2 (Tyk2), one of the Jak kinases, was essential but Stat1 was dispensable in IFN-alpha-induced B lymphocyte apoptosis. This indicates the existence of other signaling molecules besides Stat1 downstream of activated Tyk2. Therefore, in order to find Tyk2-activated signaling molecules which transduce IFN-alpha signal and induce B lymphocyte apoptosis, we performed a yeast two-hybrid screen for proteins that interact with Tyk2, and identified Siva-1, which had been originally cloned as a CD27 binding protein. Siva-1 has a death domain (DD) homology region and induces apoptosis in various cells through binding CD27, which belongs to the tumor necrosis factor receptor (TNFR) family. We found that Tyk2 interacts with and phosphorylates Siva-1. Two regions of Siva-1, the N-terminus and the middle portion of the protein containing a death domain homology region, contributed to binding to Tyk2, and two tyrosines of Siva-1, Tyr53 and Tyr162, were phosphorylated by Tyk2. Because Siva-1 is so far thought to be a proapoptotic protein, we assessed whether Tyk2 had any effects on Siva-1-mediated apoptosis through the Tyk2-Siva-1 interaction. First, we established BaF3 cell (IL-3 dependent murine proB cell) lines stably expressing either wild-type Tyk2 (BaF3/WT Tyk2) or constitutively activated Tyk2 which Valine678 was replaced by Phenylalanine (BaF3/V678F Tyk2). In BaF3/V678F Tyk2 cells, Tyk2 and Stats are constitutively activated, and they grow in the absence of IL-3. We transiently transfected either GFP-Siva-1 or control GFP vector into BaF3/parent cells, BaF3/WT Tyk2 cells or BaF3/V678F Tyk2 cells. Thirty-six hours after transfection, we measured annexin V positive cells by flow cytometry on GFP-positive cells. Approximately 24% of both BaF3/parent cells and BaF3/WT Tyk2 cells transfected with GFP-Siva-1 fell into apoptosis, whereas only less than 7% of the cells transfected control vector showed apoptosis. The frequency of this Siva-1-induced apoptosis was increased in BaF3/V678F Tyk2 cells (over 43% vs <10% of expressing control vector), suggesting that activated Tyk2 augmented the apoptotic function of Siva-1. In conclusion, we show that Tyk2 associates with and phosphorylates Siva-1 and that this Tyk2-Siva-1 interaction enhances the apoptotic effect induced by Siva-1. This indicates that Siva-1 might be a probable key molecule downstream of Tyk2 which is activated in response to IFN-alpha.
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Kimura, Shinya, Hidekazu Segawa, Junya Kuroda, Takeshi Yuasa, and Taira Maekawa. "CNS-9, a Novel Specific Inhibitor of ABL Tyrosine Kinase Overcomes Resistance Mechanism of Imatinib." Blood 104, no. 11 (November 16, 2004): 761. http://dx.doi.org/10.1182/blood.v104.11.761.761.
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Abstract Imatinib mesylate (also known as STI-571 and Gleevec) has drastically changed the treatment of Philadelphia chromosome positive (Ph+) leukemias. However, the resistance to imatinib has frequently been reported, particularly in patients with advanced-stage disease. A novel orally bioavailable inhibitor of the ABL tyrosine kinase (TK) named CNS-9 was developed from the 2-(phenylamino)pyrimidine class to overcome resistance mechanisms of imatinib. Inhibition of TK phosphorylation (IC50) on wild type (wt) BCR/ABL in 293T cell line by CNS-9 was 22nM, which was 2-log more potent than imatinib. Importantly, CNS-9 inhibited TK phosphorylation of E255K mutant BCR/ABL with IC50 of 98nM, while imatinib could not inhibit it with clinically relevant concentration. The T315I mutant BCR/ABL protein was resistant to CNS-9 and imatinib. CNS-9 also inhibited TK phosphorylation of platelet-derived growth factor receptor (PDGFR) or c-Kit pathways at the very similar observed IC50s when compared with imatinib, in spite of significant higher potency against ABL. The ability of CNS-9 in vitro to inhibit 101 TK molecules was assayed by KinaseProfilerTM (Upstate), showing also more specific inhibitory activity against ABL than imatinib. The growth of BCR/ABL-positive cell lines K562, KU812, BaF3 harboring wt BCR/ABL (BaF3/wt) and E255K (BaF3/E255K) was inhibited by CNS-9 with IC50 of 5, 3, 17, and 110nM, respectively (Table 1). Generally, CNS-9 was 20 to 30-fold more potent on the growth inhibition than imatinib in these same cell lines. We next investigated the in vivo effect on the leukemic growth inhibition of CNS-9. Nude mice were injected subcutaneously with 3x107 KU812 (wt BCR/ABL) on Day 0. CNS-9 or imatinib were orally administrated twice a day from Day 7 to Day 18. The dosages of CNS-9 and imatinib, which inhibited completely tumor growth were 20mg/kg/day and 200mg/kg/day, respectively, indicating that CNS-9 is 10-fold potent than imatinib in vivo. To examine the in vivo effect of CNS-9 against mutant BCR/ABL, BaF3/wt, BaF3/E255K or BaF3/T315I were engrafted to nude mice and treated with CNS-9 or imatinib. CNS-9 was also 10-fold potent than imatinib against BaF3/wt. Intriguingly, mice harboring BaF3/wt or BaF3/E255K showed significantly prolonged survival when treated with CNS-9. Consistent with in vitro assay, CNS-9 had no effect on T315I, and imatinib was not effective against both E255K and T315I. In conclusion, CNS-9 is substantially more inhibitory and more specifically than imatinib toward BCR/ABL-dependent cell growth both in vitro and in vivo Moreover, CNS-9 may be effective for leukemia patients whose leukemic cells harbor E255K mutant. The efficacy and safety of CNS-9 for Ph+ leukemias should be verified in early phase clinical trials. The IC50s values of leukemic cell lines for CNS-9 and imatinib CNS-9 (nM) imatinib (nM) K562 p210 wt BCR/ABL 5 130 KU812 p210 wt BCR/ABL 3 67 U937 BCR/ABL (−) >1000 >1000 BaF3 p190 wt BCR/ABL 17 360 BaF3 p190 E255K BCR/ABL 110 >1000 BaF3 p190 T315I BCR/ABL >1000 >1000
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Berg, Stephanie, Manuel O. Diaz, Sucha Nand, and Jiwang Zhang. "Germline Mutations Predispose to Familial Myeloproliferative Neoplasms." Blood 134, Supplement_1 (November 13, 2019): 2969. http://dx.doi.org/10.1182/blood-2019-124805.
Повний текст джерелаАнотація:
Background: Myeloproliferative neoplasms (MPNs), commonly polycythemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythemia (ET), are a group of malignant hematologic disorders characterized by proliferation and accumulation of terminally differentiated blood cells of erythroid, myeloid and megakaryocytic origin (Cazzola, Blood 2014).Somatic driver mutations, frequently JAK2V617F, MPLW515L/K or mutant CALR in sporadic MPNs affect signaling by the thrombopoietin (THPO) and/or the erythropoietin (EPO) receptor (Pickman, PLoS 2016). MPL is the receptor of THPO and JAK2 is the key downstream mediator of THPO/MPL signaling (Nangalia NEJM 2013). In familial MPNs (families with more than 1 member developing a MPN) a germline mutation predisposes to disease development. These mutations can reveal pathways or processes involved in the pathogenesis of the disease, independent of, or cooperating with, the somatic driver mutations (Rumi, JCO 2007). We identified 3 putative predisposing germline mutations in 1 family, 3 affected generations developed MPN (PMF, ET and PV): RBSN frameshift,JAK2R340Q & PRKAA2Q425P missense variants. RBSN encodes Rabenosyn-5 protein (RBSN) which plays a role in early growth-factor receptor clathrin-dependent endocytosis (Nielsen, J Cell Biol 2000) (Fig.1).We discovered that wild type (WT) Rabenosyn-5 regulates cell surface MPL levels in hematopoietic progenitor cells and predict that MPL levels on the cell surface are negatively associated with WT Rabenosyn-5 levels. We hypothesize that the RBSN mutation predisposes to MPN development in this family, leading to abnormal activation of THPO signaling by reducing MPL turnover. Methods: Peripheral blood DNA from patient samples were analyzed for potential putative mutations using Agilent SureSelect Human ALL Exon V5+UTRs exome capture kit followed by parallel sequencing with Illumina HiSeq 2000. In vitro studies involved using the BaF3 system and CRISPR-Cas9 gene editing technique. We generated BaF3-MPL (BaF3 cells transduced with human CD4-MPL fusion) cell lines that rely on IL3 or human THPO cytokines for growth & proliferation (Fig.2&3). We transduced RBSN into the BaF3-MPL cell lines and produced RBSN heterozygous (HT) and homozygous (HM) mutants. We first generated LentiCRISPRV2GFP-mRBSN vector by inserting RBSN specific guide RNA into the LentiCRISPRV2GFP vector and generated lentivirus expressing both Cas9 and guide RNA by co-transfecting 293T cells with LentiCRISPRV2GFP vector and viral packaging vectors. The final virus was used to infect BaF3-MPL cells. Transduced cells were purified by FACS to select GFP+ cells and individual cells were grown in culture. RBSN gene mutations were examined using PCR and sequenced accordingly. To study whether the RBSN mutation alters the surface MPL levels, we stained BaF3-MPL, HT-RBSN-BaF3 and HM-RBSN-BaF3 cells with APC-CD4 antibody and the surface levels of MPL were detected by FACS by comparing the mean fluorescence intensity (MFI) of APC. Results: We identified several colonies with either HT-RBSN-BaF3 or HM-RBSN-BaF3. The guide RNA we designed specifically targeted the 12th exon of the RBSN gene which best recapitulates the mutations observed in our patients, thus, the frameshift mutations in HT-RBSN-BaF3 and HM-RBSN-BaF3 cell lines we predict will make truncated forms of RBSN which will be verified by Western Blotting for future experiments. Surface levels of MPL in the HT-RBSN-BaF3 and HM-RBSN-BaF3 cells are greater than that in BaF3-MPL cells, suggesting RBSN negatively regulates THPO-MPL signaling by regulating the cell surface MPL levels (Fig. 4). Conclusions: RBSN is a regulator of receptor trafficking, which mediates the fusion of the endocytosed receptor to the early endosome and then lysosome for degradation. We propose that genetic inactivation of RBSN might prevent the endocytosed MPL from endosome-degradation and enhance the reuse of MPL by recycling. Future experiments are planned to include in vivo studies to study whether inactivation of RBSN promoted MPN-like disease development into NSG mice and transducing our established cell lines to label individual cell compartments to study THPO-stimulated signaling. Our findings, if confirmed, will further clarify aspects of familial and somatic MPN pathogenesis and may inform efforts to devise new therapeutic and diagnostic strategies for this disease complex. Disclosures No relevant conflicts of interest to declare.
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Yamamoto, Yukiya, Sachiko Iba, Akihiro Abe, and Nobuhiko Emi. "Elongation of MPL Transmembrane Domain Is a Novel Activating-Mutation in Essential Thrombocythemia." Blood 126, no. 23 (December 3, 2015): 1628. http://dx.doi.org/10.1182/blood.v126.23.1628.1628.
Повний текст джерелаАнотація:
Abstract Essential thrombocythemia (ET) is a clonal disease of hematopoietic stem cell. Somatic gene mutations including JAK2 or CALR are hallmark of diagnosis and molecular targets for developing novel therapies. However, non-mutated ET cases within JAK2 and CALR still exist. The third mutated gene of ET is MPL, which is known as encoding thrombopoietin receptor. MPL W515 and S505 are hot spot for missense mutations leading to constitutive active MPL signaling. These missense mutations are located within transmembrane or juxtamembrane domain of MPL. Here, we present a novel activating-mutation of MPL in an ET patient. The patient was a 54-year-old woman with occasional headache. A full blood count showed a hemoglobin level of 12.2 g/dL, a white blood cell count of 11.2 x 103/mL and a platelet count of 164 x 104/mL. A bone marrow sample was hypercellular, containing increased megakaryocytes. Chromosomal analysis showed normal karyotype. Further genetic analysis did not detect JAK2 V617F or CALR mutation. Finally, we directly sequenced MPL exon 10. The result showed MPL c.1496-1497AT>TGGGCCTCAGCTGGGCG (Figure 1). This mutation has been considered as an in-frame mutation, indicating MPL p.H499LGLSWA (reference: NP_005364). The amino acids insertion in transmembrane domain of MPL belongs to hydrophobic family, suggesting that MPL H499 mutation (H499ins) might construct stable structure. To investigate whether MPL H499ins is functionally active, we established stable BaF3/MPL H499ins cell lines. In contrast to BaF3/MPL wild-type, BaF3/MPL H499ins cells proliferate without WEHI3-conditioned medium as well as BaF3/MPL W515L or S505N. Western blot analysis showed BaF3/MPL H499ins cells constitutionally activate downstream signaling including JAK-STAT, MAPK and AKT. Furthermore, we established stable BaF3 cell lines with MPL H499 LGLSWALGLSWA (H499 insx2), MPL H499del and others. In contrast to BaF3/H499del, H499L, H499LG and H499insx3, BaF3/MPL H499insx2 cells proliferate without WEHI3-conditioned medium. This result suggests that elongation of MPL transmembrane domain is a novel oncogenic mechanism leading to constitutive active MPL signaling. Phosphorylation of MPL Y626 has significant role to transduce MPL signaling. To explore if constitutive activation of MPL H499ins depends on phosphorylation of MPL Y626, we established stable BaF3 cell lines with MPL H499insY626F. The BaF3 cells could not proliferate without WEHI3-conditioned medium. This result clearly shows phosphorylation of MPL Y626 has a pivotal role for constitutive activation of MPL H499ins. Finally, we examined potential effect to inhibit constitutive MPL signaling with JAK1/2 inhibitor, Ruxolitinib. In contrast to K562, growth of BaF3/MPL H499ins cells were inhibited with Ruxolitinib at half maximal effective concentration 113 nM as well as MPL W515L or S505N (Figure 2). In summary, elongation of MPL transmembrane domain is a novel oncogenic mechanism in ET patients. Ruxolitinib is also a potent inhibitor against MPL activating mutations as well as JAK2 V617F-associated myeloproliferative neoplasm. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Ruggiero, Dafne, Stefania Terracciano, Gianluigi Lauro, Michela Pecoraro, Silvia Franceschelli, Giuseppe Bifulco, and Ines Bruno. "Structural Refinement of 2,4-Thiazolidinedione Derivatives as New Anticancer Agents Able to Modulate the BAG3 Protein." Molecules 27, no. 3 (January 20, 2022): 665. http://dx.doi.org/10.3390/molecules27030665.
Повний текст джерелаАнотація:
The multidomain BAG3 protein is a member of the BAG (Bcl-2-associated athanogene) family of co-chaperones, involved in a wide range of protein–protein interactions crucial for many key cellular pathways, including autophagy, cytoskeletal dynamics, and apoptosis. Basal expression of BAG3 is elevated in several tumor cell lines, where it promotes cell survival signaling and apoptosis resistance through the interaction with many protein partners. In addition, its role as a key player of several hallmarks of cancer, such as metastasis, angiogenesis, autophagy activation, and apoptosis inhibition, has been established. Due to its involvement in malignant transformation, BAG3 has emerged as a potential and effective biological target to control multiple cancer-related signaling pathways. Recently, by using a multidisciplinary approach we reported the first synthetic BAG3 modulator interfering with its BAG domain (BD), based on a 2,4-thiazolidinedione scaffold and endowed with significant anti-proliferative activity. Here, a further in silico-driven selection of a 2,4-thiazolidinedione-based compound was performed. Thanks to a straightforward synthesis, relevant binding affinity for the BAG3BD domain, and attractive biological activities, this novel generation of compounds is of great interest for the development of further BAG3 binders, as well as for the elucidation of the biological roles of this protein in tumors. Specifically, we found compound 6 as a new BAG3 modulator with a relevant antiproliferative effect on two different cancer cell lines (IC50: A375 = 19.36 μM; HeLa = 18.67 μM).
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Han, Ziying, Michael Schwoerer, Philip Hicks, Jingjing Liang, Gordon Ruthel, Corbett Berry, Bruce Freedman, et al. "Host Protein BAG3 is a Negative Regulator of Lassa VLP Egress." Diseases 6, no. 3 (July 13, 2018): 64. http://dx.doi.org/10.3390/diseases6030064.
Повний текст джерелаАнотація:
Lassa fever virus (LFV) belongs to the Arenaviridae family and can cause acute hemorrhagic fever in humans. The LFV Z protein plays a central role in virion assembly and egress, such that independent expression of LFV Z leads to the production of virus-like particles (VLPs) that mimic egress of infectious virus. LFV Z contains both PTAP and PPPY L-domain motifs that are known to recruit host proteins that are important for mediating efficient virus egress and spread. The viral PPPY motif is known to interact with specific host WW-domain bearing proteins. Here we identified host WW-domain bearing protein BCL2 Associated Athanogene 3 (BAG3) as a LFV Z PPPY interactor using our proline-rich reading array of WW-domain containing mammalian proteins. BAG3 is a stress-induced molecular co-chaperone that functions to regulate cellular protein homeostasis and cell survival via Chaperone-Assisted Selective Autophagy (CASA). Similar to our previously published findings for the VP40 proteins of Ebola and Marburg viruses, our results using VLP budding assays, BAG3 knockout cells, and confocal microscopy indicate that BAG3 is a WW-domain interactor that negatively regulates egress of LFV Z VLPs, rather than promoting VLP release. Our results suggest that CASA and specifically BAG3 may represent a novel host defense mechanism, whereby BAG3 may dampen egress of several hemorrhagic fever viruses by interacting and interfering with the budding function of viral PPxY-containing matrix proteins.