Journal articles on the topic 'P13K signalling'
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1
Mei, Qiyuan, Xiaohu Chen, and Wei Liu. "Protocatechuic Acid Induces Apoptosis in Human Osteosarcoma Cells by Regulating P13K/AKT/ROS Pathway." Sains Malaysiana 51, no. 4 (April 30, 2022): 1167–79. http://dx.doi.org/10.17576/jsm-2022-5104-18.
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Previous investigations have demonstrated that protocatechuic acid (PCA) provides anti-tumour properties in different tumour cell types. It does, however, have an unknown cause on osteosarcoma cells. In this investigation, the underlying mechanism of the effect of PCA on osteosarcoma cells (MNNG or HOS) was investigated and established. The viability of the cell was assessed with the MTT test. Acridine orange/ethidium bromide staining and Western blot analysis were conducted for assessment of cell apoptosis. Western blot analysis was identified for cell cycle progression. In addition to establishing the above findings, the Western blot analysis demonstrated that PCA mediated osteosarcoma cellular apoptosis by triggering the apoptotic pathway of Caspase-9. Additionally, we found that PCA considerably stimulated osteosarcoma cell apoptosis and arrest of cell cycle proliferation by controlling a pathway involving P13K/Akt/ROS signalling. In short, we observed that PCA prevented the advancement of osteosarcoma through the stimulation of apoptosis in osteosarcoma cells. The mechanism underlying this study also showed that PCA generated effective anti-tumour activity on osteosarcoma cells by controlling the signalling pathways of P13K/Akt/ROS.
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Goruppi, S., E. Ruaro, B. Varnum, and C. Schneider. "Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts." Molecular and Cellular Biology 17, no. 8 (August 1997): 4442–53. http://dx.doi.org/10.1128/mcb.17.8.4442.
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Gas6 is a secreted protein previously identified as the ligand of the Axl receptor tyrosine kinase. We have shown that Gas6 is able to induce cell cycle reentry of serum-starved NIH 3T3 cells and to efficiently prevent apoptosis after complete growth factor removal, a survival effect uncoupled from Gas6-induced mitogenesis. Here we report that the mitogenic effect of Gas6 requires phosphatidylinositol 3-kinase (PI3K) activity since it is abrogated both by the specific inhibitor wortmannin and by overexpression of the dominant negative P13K p85 subunit. Consistently, Gas6 activates the P13K downstream targets S6K and Akt, whose activation is abrogated by addition of wortmannin. Moreover, rapamycin treatment blocks Gas6-induced entry into the S phase of serum-starved NIH 3T3 cells. We also demonstrate the requirement of Src tyrosine kinase for Gas6 signalling since stable or transient expression of a catalytically inactive form of Src significantly inhibited Gas6-stimulated entry into the S phase. Accordingly, Gas6 addition to serum-starved NIH 3T3 cells causes activation of the intrinsic Src kinase activity. When specifically analyzed in a survival assay, these elements were found to be required for the survival effect of Gas6. Taken together, the evidence presented here identifies elements involved in the Gas6 transduction pathway that are responsible for its antiapoptotic effect and suggests that Src is involved in the events regulating cell survival.
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Qattan, Malak Yahia, Mohammad Idreesh Khan, Shudayyed Hasham Alharbi, Amit Kumar Verma, Fatimah A. Al-Saeed, Alduwish Manal Abduallah, and Azza A. Al Al Areefy. "Therapeutic Importance of Kaempferol in the Treatment of Cancer through the Modulation of Cell Signalling Pathways." Molecules 27, no. 24 (December 13, 2022): 8864. http://dx.doi.org/10.3390/molecules27248864.
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Plant-derived flavonoids are considered natural nontoxic chemo-preventers and have been widely studied for cancer treatment in recent decades. Mostly all flavonoid compounds show significant anti-inflammatory, anticancer and antioxidant properties. Kaempferol (Kmp) is a well-studied compound and exhibits remarkable anticancer and antioxidant potential. Kmp can regulate various cancer-related processes and activities such as cell cycle, oxidative stress, apoptosis, proliferation, metastasis, and angiogenesis. The anti-cancer properties of Kmp primarily occur via modulation of apoptosis, MAPK/ERK1/2, P13K/Akt/mTOR, vascular endothelial growth factor (VEGF) signalling pathways. The anti-cancer property of Kmp has been recognized in several in-vivo and in-vitro studies which also includes numerous cell lines and animal models. This flavonoid possesses toxic activities against only cancer cells and have restricted toxicity on healthy cells. In this review, we present extensive research investigations about the therapeutic potential of Kmp in the management of different types of cancers. The anti-cancer properties of Kmp are discussed by concentration on its capability to target molecular-signalling pathway such as VEGF, STAT, p53, NF-κB and PI3K-AKT signalling pathways. The anti-cancer property of Kmf has gained a lot of attention, but the accurate action mechanism remains unclear. However, this natural compound has a great pharmacological capability and is now considered to be an alternative cancer treatment.
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Gao, Hui, Hui Wang, and Jianjun Peng. "Hispidulin Induces Apoptosis Through Mitochondrial Dysfunction and Inhibition of P13k/Akt Signalling Pathway in HepG2 Cancer Cells." Cell Biochemistry and Biophysics 69, no. 1 (September 26, 2013): 27–34. http://dx.doi.org/10.1007/s12013-013-9762-x.
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Gauglitz, G. G., S. C. Halder, G. Kulp, F. N. Williams, D. N. Herndon, and M. G. Jeschke. "91. Postburn Hepatic Insulin Resistance is Due to Altered JNK/IRS-1 Activation Leading to Impaired P13K/AKT Signalling." Journal of Surgical Research 151, no. 2 (February 2009): 212. http://dx.doi.org/10.1016/j.jss.2008.11.098.
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Burgos, Sergio A., Stephanie Chevalier, Jose A. Morais, Marie Lamarche, and Errol B. Marliss. "Insulin Stimulates Grb10 Phosphorylation by mTORC1 and Mediates its Feedback Inhibition on P13K/Akt Signalling in Human Skeletal Muscle." Canadian Journal of Diabetes 37 (October 2013): S62—S63. http://dx.doi.org/10.1016/j.jcjd.2013.08.189.
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Werzowa, J., B. Pratscher, D. Cejka, H. Pehamberger, and V. Wacheck. "583 POSTER mTORC1 inhibition with rapamycin leads to activation of P13K/AKT signalling via an mTORC2 dependent mechanism in melanoma cells." European Journal of Cancer Supplements 4, no. 12 (November 2006): 176–77. http://dx.doi.org/10.1016/s1359-6349(06)70588-2.
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Elekofehinti, Olusola Olalekan, Victor Oluwatoyin Oyedokun, Opeyemi Iwaloye, Akeem Olalekan Lawal, and Oluwamodupe Cecilia Ejelonu. "Momordica charantia silver nanoparticles modulate SOCS/JAK/STAT and P13K/Akt/PTEN signalling pathways in the kidney of streptozotocin-induced diabetic rats." Journal of Diabetes & Metabolic Disorders 20, no. 1 (February 5, 2021): 245–60. http://dx.doi.org/10.1007/s40200-021-00739-w.
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Rodgers, J., C. Murray, and N. Leaves. "Comparison of three methods to detect mutations in the PI3K oncogene in FFPE cancer samples." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22212-e22212. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22212.
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e22212 Background: PI3Kinase is an important target for new oncology therapies, since it is central to several cell signalling pathways associated with proliferation and survival. Many pharmaceutical companies have PI3K inhibitors in their drug development pipelines all of which are in early phase trials. Activating mutations in exons 9 and 20 of the PI3KCA oncogene have been observed in a number of important cancer types including: gastrointestinal, breast, liver, lung and genito-urinary cancers. The presence of such mutations may prove useful as companion diagnostic biomarkers for prediction of response to therapy. Methods: Source BioScience (Nottingham, UK) tested three different methods for the detection of PI3K mutations in archival tumour samples, in their CPA and GLP accredited laboratories. Eighty formalin-fixed paraffin-embedded (‘FFPE') samples from histologically confirmed breast cancer samples were tested by the new DxS P13K Mutation Test Kit using real-time PCR, by pyrosequencing (Qiagen), and by conventional bidirectional capillary sequencing. Tumour content was evaluated by pathology review. Results: The results of the comparison showed that the DxS test using rtPCR technology was easy to perform, convenient and robust. The DxS test had a high degree of sensitivity provided there was more than 20% tumour content in the test sample as determined by histology and pathology review. Conclusions: In conclusion, the DxS test is a valuable tool for detecting PI3K mutations in FFPE samples from breast cancer patients. No significant financial relationships to disclose.
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TAKEUCHI, Hiroshi, Masahiro OIKE, Hugh F. PATERSON, Victoria ALLEN, Takashi KANEMATSU, Yushi ITO, Christophe ERNEUX, Matilda KATAN, and Masato HIRATA. "Inhibition of Ca2+ signalling by p130, a phospholipase-C-related catalytically inactive protein: critical role of the p130 pleckstrin homology domain." Biochemical Journal 349, no. 1 (June 26, 2000): 357–68. http://dx.doi.org/10.1042/bj3490357.
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p130 was originally identified as an Ins(1,4,5)P3-binding protein similar to phospholipase C-∆ but lacking any phospholipase activity. In the present study we have further analysed the interactions of p130 with inositol compounds in vitro. To determine which of the potential ligands interacts with p130 in cells, we performed an analysis of the cellular localization of this protein, the isolation of a protein-ligand complex from cell lysates and studied the effects of p130 on Ins(1,4,5)P3-mediated Ca2+ signalling by using permeabilized and transiently or stably transfected COS-1 cells (COS-1p130). In vitro, p130 bound Ins(1,4,5)P3 with a higher affinity than that for phosphoinositides. When the protein was isolated from COS-1p130 cells by immunoprecipitation, it was found to be associated with Ins(1,4,5)P3. Localization studies demonstrated the presence of the full-length p130 in the cytoplasm of living cells, not at the plasma membrane. In cell-based assays, p130 had an inhibitory effect on Ca2+ signalling. When fura-2-loaded COS-1p130 cells were stimulated with bradykinin, epidermal growth factor or ATP, it was found that the agonist-induced increase in free Ca2+ concentration, observed in control cells, was inhibited in COS-1p130. This inhibition was not accompanied by the decreased production of Ins(1,4,5)P3; the intact p130 pleckstrin homology domain, known to be the ligand-binding site in vitro, was required for this effect in cells. These results suggest that Ins(1,4,5)P3 could be the main p130 ligand in cells and that this binding has the potential to inhibit Ins(1,4,5)P3-mediated Ca2+ signalling.
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Flinn, H. M., and A. J. Ridley. "Rho stimulates tyrosine phosphorylation of focal adhesion kinase, p130 and paxillin." Journal of Cell Science 109, no. 5 (May 1, 1996): 1133–41. http://dx.doi.org/10.1242/jcs.109.5.1133.
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The small GTP-binding protein Rho rapidly stimulates the formation of focal adhesions and actin stress fibres when microinjected into serum-starved Swiss 3T3 fibroblasts. This response is inhibited by tyrosine kinase inhibitors. Addition of growth factors such as lysophosphatidic acid and bombesin to Swiss 3T3 cells stimulates a similar response, which is dependent on endogenous Rho proteins. To investigate signalling events regulated by Rho, we have scrape loaded Rho into serum-starved cells. Activated Rho stimulates the tyrosine phosphorylation of a number of proteins, including three proteins known to localise to focal adhesions, pp125FAK, p130 and paxillin. Rho-induced phosphorylation of pp125FAK, p130 and paxillin is observed in the absence of stress fibre formation and is, therefore, independent of Rho-induced actin polymerisation. We propose that the tyrosine kinase, pp125FAK, and the putative adapter proteins, paxillin and p130, are components of a Rho-regulated signal transduction pathway, and that these protein tyrosine phosphorylation events are likely to be important for the regulation of focal adhesion formation.
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Areces, L. B., P. Dello Sbarba, M. Jücker, E. R. Stanley, and R. A. Feldman. "Functional specificity of cytoplasmic and transmembrane tyrosine kinases: identification of 130- and 75-kilodalton substrates of c-fps/fes tyrosine kinase in macrophages." Molecular and Cellular Biology 14, no. 7 (July 1994): 4606–15. http://dx.doi.org/10.1128/mcb.14.7.4606-4615.1994.
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c-fps/fes encodes a 92-kDa protein-tyrosine kinase (NCP92) that is expressed at the highest levels in macrophages. To determine if c-fps/fes can mediate the action of the colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) and to identify potential targets of c-fps/fes in macrophages, we have overexpressed c-fps/fes in a CSF-1-dependent macrophage cell line. A 30- to 50-fold overexpression of c-fps/fes partially released these cells from their factor dependence by a nonautocrine mechanism, and this correlated with the tyrosine phosphorylation of two proteins of 130 and 75 kDa (P130 and P75). c-fps/fes did not cause tyrosine phosphorylation or activation of CSF-1 dependent targets, including CSF-1R, Shc, and phosphatidylinositol 3-kinase, and conversely, CSF-1 did not induce tyrosine phosphorylation of P130 and P75. P75 appears to be a novel phosphotyrosyl protein, whereas P130 cross-reacts with a known substrate of v-src. P130 and P75 may be direct substrates of c-fps/fes: P130 was tightly associated with NCP92, and the src homology 2 domain of NCP92 specifically bound phosphorylated P130 and P75 but not the CSF-1-induced phosphotyrosyl proteins, consistent with the possibility that P130 and P75 are physiological targets of c-fps/fes. We conclude that although c-fps/fes can functionally substitute for CSF-1R to a certain extent, these tyrosine kinases act largely independently of each other and that P130 and P75 are novel targets whose mechanisms of action may be unrelated to the signalling pathways utilized by receptor tyrosine kinases.
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Areces, L. B., P. Dello Sbarba, M. Jücker, E. R. Stanley, and R. A. Feldman. "Functional specificity of cytoplasmic and transmembrane tyrosine kinases: identification of 130- and 75-kilodalton substrates of c-fps/fes tyrosine kinase in macrophages." Molecular and Cellular Biology 14, no. 7 (July 1994): 4606–15. http://dx.doi.org/10.1128/mcb.14.7.4606.
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c-fps/fes encodes a 92-kDa protein-tyrosine kinase (NCP92) that is expressed at the highest levels in macrophages. To determine if c-fps/fes can mediate the action of the colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) and to identify potential targets of c-fps/fes in macrophages, we have overexpressed c-fps/fes in a CSF-1-dependent macrophage cell line. A 30- to 50-fold overexpression of c-fps/fes partially released these cells from their factor dependence by a nonautocrine mechanism, and this correlated with the tyrosine phosphorylation of two proteins of 130 and 75 kDa (P130 and P75). c-fps/fes did not cause tyrosine phosphorylation or activation of CSF-1 dependent targets, including CSF-1R, Shc, and phosphatidylinositol 3-kinase, and conversely, CSF-1 did not induce tyrosine phosphorylation of P130 and P75. P75 appears to be a novel phosphotyrosyl protein, whereas P130 cross-reacts with a known substrate of v-src. P130 and P75 may be direct substrates of c-fps/fes: P130 was tightly associated with NCP92, and the src homology 2 domain of NCP92 specifically bound phosphorylated P130 and P75 but not the CSF-1-induced phosphotyrosyl proteins, consistent with the possibility that P130 and P75 are physiological targets of c-fps/fes. We conclude that although c-fps/fes can functionally substitute for CSF-1R to a certain extent, these tyrosine kinases act largely independently of each other and that P130 and P75 are novel targets whose mechanisms of action may be unrelated to the signalling pathways utilized by receptor tyrosine kinases.
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Garton, A. J., A. J. Flint, and N. K. Tonks. "Identification of p130(cas) as a substrate for the cytosolic protein tyrosine phosphatase PTP-PEST." Molecular and Cellular Biology 16, no. 11 (November 1996): 6408–18. http://dx.doi.org/10.1128/mcb.16.11.6408.
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PTP-PEST is a ubiquitously expressed, cytosolic, mammalian protein tyrosine phosphatase (PTP) which exhibits high specific activity in vitro. We have investigated the substrate specificity of PTP-PEST by a novel substrate-trapping approach in combination with in vitro dephosphorylation experiments. We initially identified a prominent 130-kDa tyrosine-phosphorylated protein in pervanadate-treated HeLa cell lysates which was preferentially dephosphorylated by PTP-PEST in vitro. In order to identify this potential substrate, mutant (substrate-trapping) forms of PTP-PEST were generated which lack catalytic activity but retain the ability to bind substrates. These mutant proteins associated in stable complexes exclusively with the same 130-kDa protein, which was identified as p130(cas) by immunoblotting. This exclusive association was observed in lysates from several cell lines and in transfected COS cells, but was not observed with other members of the PTP family, strongly suggesting that p130(cas) represents a major physiologically relevant substrate for PTP-PEST. Our studies suggest potential roles for PTP-PEST in regulation of p130(cas) function. These functions include mitogen- and cell adhesion-induced signalling events and probable roles in transformation by various oncogenes. These results provide the first demonstration of a PTP having an inherently restricted substrate specificity in vitro and in vivo. The methods used to identify p130(cas) as a specific substrate for PTP-PEST are potentially applicable to any PTP and should therefore prove useful in determining the physiological substrates of other members of the PTP family.
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Lakkakorpi, P. T., I. Nakamura, M. Young, L. Lipfert, G. A. Rodan, and L. T. Duong. "Abnormal localisation and hyperclustering of (alpha)(V)(beta)(3) integrins and associated proteins in Src-deficient or tyrphostin A9-treated osteoclasts." Journal of Cell Science 114, no. 1 (January 1, 2001): 149–60. http://dx.doi.org/10.1242/jcs.114.1.149.
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The non-receptor tyrosine kinase Src was shown to be essential for osteoclast function in vivo. We have previously reported that engagement of (alpha)(v)(beta)(3) integrin in osteoclasts induces tyrosine phosphorylation and activation of the adhesion kinase PYK2 and the adaptor protein p130(Cas) in a Src-dependent manner. The objective of this study was to analyse the role of c-Src in the (alpha)(v)(beta)(3) integrin-dependent recruitment of signalling and cytoskeletal molecules in osteoclasts during bone resorption. Using prefusion osteoclasts (pOCs) obtained from cocultures of osteoblasts and spleen cells isolated from Src(-/-) mice or their normal littermates, we found: (1) similar expression levels and ligand binding affinities of (alpha)(v)(beta)(3) integrins in Src(-/-) and Src(+/?) pOCs, (2) reduced adhesion and spreading of Src(-/-) pOCs, (3) defective organisation of the microfilament proteins, F-actin, vinculin and paxillin, and of PYK2 and p130(Cas) in the sealing zone of Src(-/-)OCLs, and (4) hyperclustering of (alpha)(v)(beta)(3) integrins together with microfilament and signalling proteins in the basal membrane of Src-deficient OCLs. In normal OCLs, the tyrosine kinase inhibitor tyrphostin A9 inhibits actin ring formation, bone resorption and tyrosine phosphorylation of several proteins, including c-Src. Furthermore, tyrphostin A9 induced similar hyperclustering of (alpha)(v)(beta)(3) integrins in osteoclasts as observed in Src(-/-) OCLs. Taken together, these findings suggest that normal localisation of (alpha)(v)(beta)(3) and recruitment of its downstream effectors to the appropriate compartments of the osteoclast during resorption depend on Src kinase activity.
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TAKEUCHI, Hiroshi, Masahiro OIKE, Hugh F. PATERSON, Victoria ALLEN, Takashi KANEMATSU, Yushi ITO, Christophe ERNEUX, Matilda KATAN, and Masato HIRATA. "Inhibition of Ca2+ signalling by p130, a phospholipase-C-related catalytically inactive protein: critical role of the p130 pleckstrin homology domain." Biochemical Journal 349, no. 1 (July 1, 2000): 357. http://dx.doi.org/10.1042/0264-6021:3490357.
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Hoffmann, J., and G. Schwoch. "Co-ordinated changes in the cyclic AMP signalling system and the phosphorylation of two nuclear proteins of Mr 130,000 and 110,000 during proliferative stimulation of the rat parotid gland by isoprenaline. Possible identity of the two proteins with pp135 and nucleolin." Biochemical Journal 263, no. 3 (November 1, 1989): 785–93. http://dx.doi.org/10.1042/bj2630785.
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Parotid glands were stimulated to growth by repeated injection of the beta-agonist isoprenaline into rats. Incubation of intact parotid-gland lobules with [32P]Pi and subsequent analysis of nuclear proteins revealed in the stimulated glands an increased 32P incorporation into two acid-soluble non-histone proteins with apparent Mr values of 110,000 and 130,000 (p110 and p130). After a single injection of isoprenaline, leading to a biphasic increase in DNA synthesis (maximum at 24 h), the same two proteins showed a transiently increased 32P incorporation at 17 h after injection. At this time point at the onset of DNA synthesis the total activity of soluble cyclic AMP-dependent protein kinase decreased. No change in p110/p130 phosphorylation was observed at 0.3 h after stimulation, a time of maximal stimulation of secretion. Administration of the beta-antagonist propranolol 8 h after the injection of isoprenaline suppressed the increase in DNA synthesis, the preceding changes in the concentration of cyclic AMP and in the activity of cyclic AMP-dependent protein kinase, as well as the increased phosphorylation of p110 and p130. Cross-reactivity of p110 and p130 with specific antisera against two nucleolar phosphoproteins of similar molecular mass (nucleolin and pp135), as well as their localization in a nucleolar cell fraction, indicated a possible identity of p110 and p130 with these two proteins. Our results suggest that nucleolin and pp135 are nuclear target proteins of cyclic AMP in the cyclic AMP-influenced regulation of the transition of cells from the G1 to the S phase.
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Murray, James W., Christopher Fegan, and Chris Pepper. "Genetic Analysis of Distinct Phenotypic Subsets within MM1.S Multiple Myeloma Cell Line Reveals the Pre-Existence of MM.1R-like Glucocorticoid Resistance and a Sub-Clone with an Activating PI3-Kinase Delta Mutation That Is Preferentially Sensitive to the Selective PI3-Kinase Inhibitor, Idelalisib." Blood 128, no. 22 (December 2, 2016): 4449. http://dx.doi.org/10.1182/blood.v128.22.4449.4449.
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Abstract Background: Understanding the pathology of Multiple Myeloma and the testing of therapeutic options has relied heavily on isogeneic cell lines due to the inability to sustain myeloma plasma cells in long-term in vitro culture. The cell lines MM.1S and MM.1R are well recognised in the field of myeloma research, providing a model of glucocorticoid drug resistance, primarily believed to be through variable expression of the glucocorticoid receptor NR3C1 but here we found no evidence of a genetic basis for this. Here we set out to examine the phenotype, function and genotype of the MM.1S and MM.1R cell lines in order to explore the origins of glucocorticoid drug resistance manifested by MM.1R cells and establish whether exome analysis could identify sub-clones with preferential sensitivity to molecular targeted inhibitors. Methods: MM.1S and MM.1R cell lines were purchased from ATCC. A 10-colour flow cytometry panel (CD38, CD138, CD19, CD45, CD56, CD49d, CXCR4, MMP-9, Ki-67, IL-6) was analysed on a BD LSR Fortessa flow cytometer and MM.1S subsets were sorted using a FACS Aria III. Telomere length was assessed using Single Telomere Length Analysis (STELA) and drug toxicity assays using Annexin V-FITC/PI staining. Bioinformatics of whole exome sequencing was carried out on the GATK platform and gene list analysis using Enrichr. PI3K isoforms were analysed by quantitative PCR and immunoblotting. Results: The MM.1S cell line demonstrated bimodal CD38 expression, with a 1.5 log difference in CD38 expression (p<0.0001) between the two populations (termed MM.1Sdim and MM.1Sbright). In contrast the MM.1R cell line was uniformly CD38bright, with expression a further 0.5 log higher than MM.1Sbright. When cell sorted subsets of MM.1S cells were subjected to increasing concentrations of Dexamethasone, the MM.1Sbright cells had a significantly higher LC50 than the MM.1Sdim cells (62nM v 29nM respectively; p<0.0001). In contrast, these subsets showed no significant difference in sensitivity to bortezomib (p=0.84. Furthermore, MM.1Sbright cells had a shorter doubling time than both MM.1Sdim (p=0.0001) and MM.1R (p=0.048). This was underscored by an increased proportion of MM.1Sbright cells in S-phase coupled with shorter mean telomere length when compared with MM.1Sdim and MM.1R (2.58 Kb v 3.29Kb v 3.2Kb respectively). We next subjected purified MM.1Sbright, MM.1Sdim and MM.1R cells to whole exome sequencing. The common clonal origin of the three cell lines was evident from the analysis but each line possessed unique genetic lesions. For example, MM.1Sbright had a FIP1L1-PDGFRA fusion mutation that was not present in the MM.1Sdim cells. This was associated with increased expression of the p110d isoform in MM.1Sdim cells. We therefore analysed the effects of the PI3Kd inhibitor, Idelalisib, on the two cell lines and showed that MM.1Sdim cells were more sensitive (p=0.003) to the effects of this agent. The specific nature of this response was confirmed by the fact that the pan p13K inhibitor PKI-402, was equipotent in both MM.1Sbright and MM.1Sdim cells (p=0.89). Conclusion: Analysis of two phenotypically distinct subsets within the MM.1S cell line revealed differences in function and genetics thereby confirming the sub-clonal architecture within this cell line. Intriguingly, our data point to the pre-existence of a dexamethasone resistant sub-clone the MM.1Sbright (CD38+) population. The subsequent production of the dexamethasone resistant cell line (MM.1R) allowed us to perform comparative genomics thereby identifying the genetic origins of dexamethasone resistance (selection) in MM.1Sbright cells and to track the subsequent clonal evolution (induction) in the MM.1R cells. Furthermore, we showed the potential for developing bespoke treatment plans based on the identification of cell signalling pathway mutations via genomic sequencing. By selective targeting of of these genetic lesions it may be possible to remove multiple sub-clones thereby diminishing the potential for clonal tiding and the development of drug resistance. In theory this could result in longer time to relapse and ultimately improved overall survival. Disclosures Fegan: Roche: Honoraria; Gilead Sciences: Honoraria; AbbVie: Honoraria.
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Makowska, Z., M. T. Dill, J. E. Vogt, M. Filipowicz, L. Terraciano, V. Roth, and M. H. Heim. "P139 Continuous exposure to PEG-IFN-Alpha only transiently activates JAK-stat signalling in human liver." Cytokine 59, no. 3 (September 2012): 563–64. http://dx.doi.org/10.1016/j.cyto.2012.06.231.
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KLEINJR, C., T. WUESTEFELD, M. ERNST, F. TACKE, P. HEINRICH, M. MANNS, and C. TRAUTWEIN. "126 The STAT signalling in hepatocytes is responsible for IL6/P130 dependent protection during concanavalin A-induced liver failure." Hepatology 38 (2003): 217. http://dx.doi.org/10.1016/s0270-9139(03)80169-6.
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Tateossian, Hilda, Rachel Hardisty-Hughes, Susan Morse, Maria R. Romero, Helen Hilton, Charlotte Dean, and Steve D. M. Brown. "13-P138 Regulation of TGF beta signalling by Fbxo11, the gene mutated in the Jeff Otitis Media mouse mutant." Mechanisms of Development 126 (August 2009): S236. http://dx.doi.org/10.1016/j.mod.2009.06.611.
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Martínez-Gac, L., B. Álvarez, Z. García, M. Marqués, M. Arrizabalaga, and A. C. Carrera. "Phosphoinositide 3-kinase and Forkhead, a switch for cell division." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 360–61. http://dx.doi.org/10.1042/bst0320360.
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Cell cycle progression is a tightly controlled process. To initiate cell division, mitogens trigger a number of early signals that promote the G0–G1 transition by inducing cell growth and the activation of G1 cyclins. Activation of cyclin E/cdk2 (cyclin-dependent kinase 2) at the end of G1 is then required to trigger DNA synthesis (S phase entry). Among the early signals induced by mitogens, activation of PI3K (phosphoinositide 3-kinase) appears essential to induce cell cycle entry, as it regulates cell growth signalling pathways, which in turn determine the rate of cell cycle progression. Another mechanisms by which PI3K and its downstream effector protein kinase B regulate cell cycle entry is by inactivation of the FOXO (Forkhead Box, subgroup O) transcription factors, which induce expression of quiescence genes such as those encoding p27kip, p130 and cyclin G2. PI3K/FOXO then work as a complementary switch: when PI3K is active, FOXO transcription factors are inactive. The switch is turned on and off at different phases of the cell cycle, thus regulating cell cycle progression.
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Martynoga, B., M. Manuel, J. West, D. Price, and J. Mason. "[P138]: Foxg1 is required cell autonomously for dorso-ventral patterning of the telencephalon, in part by regulating the response to hedgehog signalling." International Journal of Developmental Neuroscience 24, no. 8 (November 16, 2006): 555–56. http://dx.doi.org/10.1016/j.ijdevneu.2006.09.200.
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KANDA, MIMURA, HAMASAKI, YAMAMOTO, YAZAKI, HIRAI, and NOJIMA. "Fyn and Lck tyrosine kinases regulate tyrosine phosphorylation of p105 CasL , a member of the p130 Cas docking protein family, in T‐cell receptor‐mediated signalling." Immunology 97, no. 1 (May 1999): 56–61. http://dx.doi.org/10.1046/j.1365-2567.1999.00753.x.
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Panzer-Gruemayer, Renate, Gerd Krapf, Dominik Beck, Gerhard Fuka, Christian Bieglmayer, Georg Mann, and Andrea Inthal. "Role of Erythropoietin Receptor in t(12;21) Positive Acute Lymphoblastic Leukemia." Blood 110, no. 11 (November 16, 2007): 2792. http://dx.doi.org/10.1182/blood.v110.11.2792.2792.
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Abstract The chromosomal translocation t(12;21)(p13;q22) resulting in the TEL/AML1 (also known as ETV6/ RUNX1) fusion gene is the most frequent translocation in childhood B cell precursor (BCP) ALL. This type of ALL is characterized by a unique molecular signature, which includes the overexpression of the gene for the erythropoietin receptor (EpoR). So far, it is not known what causes the overexpression of the EpoR gene or whether it has any effect on the t(12;21) positive leukemia. We therefore aimed to evaluate potential mechanisms responsible for the upregulation of the EpoR in t(12;21) leukemias and to find out whether signalling via this receptor affects survival or proliferation of leukemic cells. In addition, we planned to explore signalling pathways linked to the respective effects and to elucidate relevant mechanisms that might be essential for cell survival. We first excluded the possibility that the EpoR expression is upregulated as a consequence of high Epo levels in the plasma that are induced by the patients’ low hemoglobin (Hb) levels. While Hb levels from patients with t(12;21)+ ALL were significantly lower compared to those with other subtypes of BCP ALL (median, 6,15g/dL and 7,9g/dL, respectively; p<0.001 Wilcoxon 2- sample test), which correlated with high Epo levels in the plasma, the extent of EpoR mRNA expression of leukemic cells was independent of the respective amount of Epo in the individual patient’s plasma. Next, the influence of Epo on t(12;21) + leukemic cell lines was evaluated and revealed a consistent time and dose dependent increase in proliferation (Epo concentrations 10, 50, 100U/ml for 72 hours) determined by 3H-Thymidine incorporation. This effect was abrogated upon addition of a blocking anti-EpoR antibody thereby confirming the specificity of EpoR signalling. Since Epo may have apoptosis-modulating potential in EpoR expressing malignant cells, we tested its influence on drug-induced apoptosis. For this purpose IC50 concentrations of drugs that are commonly used for the treatment of children with BCP ALL were used. A reduction of glucocorticoid (GC)-induced apoptosis by Epo was demonstrated in t(12;21)+ cell lines while no effect was seen in combination with other drugs or in t(12;21) negative cell lines. Preliminary data indicate that NF-kappa B as well as PI3K/Akt pathways are triggered by Epo, implying that they play a role in this rescue mechanism. Given that cell lines may have intrinsic changes, we are presently evaluating whether the observed results can also be reproduced in primary leukemic cells. In support of this assumption are results in a limited number of primary t(12;21)+ leukemias showing a superior survival (MTT assay) and reduced apoptosis rate to GC when cultured in the presence of Epo. These findings are in contrast to those in t(12;21) negative BCP ALLs. In conclusion, our data indicate that overexpression of EpoR in t(12;21) positive leukemias is not induced by low Hb, a feature that is generally observed in patients with this type of leukemia. Binding of Epo to its receptor in vitro leads to enhanced survival and negatively affects the sensitivity to GCs. Whether these findings have any implications on the treatment and care of patients with t(12;21)+ leukemia needs to be addressed in further studies. Financial support: OENB10720, FWF P17551-B14 and GENAU-CHILD Projekt GZ200.136/1 - VI/1/2005 to RPG.
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Fazio, Grazia, Chiara Palmi, Greta Giordano Attianese, Andrea Biondi, Antonius Rolink, and Giovanni Cazzaniga. "PAX5/TEL Causes down Regulation of CD19 and TGFbeta Resistance in PreBI Cells." Blood 108, no. 11 (November 16, 2006): 1416. http://dx.doi.org/10.1182/blood.v108.11.1416.1416.
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Abstract The PAX5/TEL chimeric gene was cloned from the translocation t(9;12)(q11;p13) in an ALL patient. Recent data indicate that the PAX5/TEL fusion defines the cytogenetic entity dic(9;12)(p13;p13), which accounts for about 1% of childhood ALL, almost exclusively B-progenitor ALL. PAX5/TEL is likely to be an aberrant transcription factor, resulting from joining the 5′ region of PAX5 (a transcription factor essential for B cell development) to the 3′ region of TEL/ETV6, containing the Ets-family DNA binding domain. We have cloned the FLAG-full length chimeric PAX5/TEL cDNA in the retroviral vector pMSCV-IRES-GFP (MigR1) to transduce target cells. We have demonstrated a specific nuclear localization of the chimeric protein in NIH3T3 by immunofluorescence analysis. Moreover, we observed a PAX5/TEL dependent decrease of the cellular growth rate in IL-3 dependent murine proB Ba/F3 cells. We further investigated the function of the PAX5/TEL chimeric protein as a potential oncoprotein in murine preBI cells, as a more physiological model. Murine PAX5 −/− preBI cells and wild type preBI cells were purified as B220+/c-KIT+ cells from mouse fetal liver and they were cultured on OP9 and DL1-OP9 stroma cells in presence of IL-7. The OP9 stroma supports B cell proliferation and survival; the DL1-OP9 stroma expresses Delta-like1, one of the Notch ligands, and it’s important to support T cell development. Both PAX5 −/− preBI cells and wild type preBI cells were transduced with the retroviral construct pMSCV-PAX5/TEL-IRES-GFP to analyze cell proliferation, differentiation and growth-dependence on IL-7. Wild type preBI cells expressing PAX5/TEL showed down modulation of CD19 when cultured on OP9 stroma in presence of IL-7; an inverse correlation was observed between the levels of expression of GFP and of CD19. The down modulation of CD19 can be involved in driving the preBI cell into differentiation block. A possible explanation of CD19 repression can rely on a potential competition between PAX5/TEL and endogenous PAX5 to bind PAX5 consensus region on DNA. On OP9 stroma, PAX5/TEL preBI cells are resistant to TGFbeta anti-proliferative and apoptotic effects, with a three-fold increased growth rate than control cells. Although the specific mechanism of PAX5/TEL disruption of TGFbeta signalling pathway remains to be investigated, we propose the TGFbeta resistance by PAX5/TEL as a way to evade the immunosurveillance. PAX5/TEL-preBI cells cultured on DL1-OP9 showed a different phenotype, with up-regulation of c-KIT and down-regulation of CD44. PAX5−/− preBI cells infected with PAX5TEL and grown on OP9 were CD19 negative even in the presence of PAX5TEL. On DL1-OP9 stroma, PAX5TEL cells were able to differentiate maintaining the developmental plasticity of PAX5 −/− preBI cells. These preliminary results indicate a role of PAX5/TEL as a transcription factor, potentially with a suppressor function, down regulating CD19 expression, thus suggesting a function on B cell differentiation. The chimera is able to interfere with TGFbeta pathway, inducing resistance and conferring an advantage in cell survival, evading the immunosurveillance. PAX5TEL do not replace PAX5 functions in PAX5−/− cells, it cannot activate PAX5 target genes as CD19, important for restoring B cell differentiation. Further analyeis are needed to better evaluate the role of PAX5/TEL protein, both in vivo and in vitro models.
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Iwanski, Gabriela B., Nils Heinrich Thoennissen, PohYeen Lor, Norihiko Kawamata, Daniel Nowak, Grazia Fazio, Andrea Biondi, Giovanni Gazzaniga, and H. Phillip Koeffler. "PAX5/TEL Exhibits a Dominant-Negative Role by Inhibiting the Expression of Genes Involved in BCR Signalling and Suppressing the Binding of Wild Type PAX5 to Its Direct Target Gene CD79A (mb-1) in a human Pre-B ALL Cell Line." Blood 114, no. 22 (November 20, 2009): 3455. http://dx.doi.org/10.1182/blood.v114.22.3455.3455.
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Abstract Abstract 3455 Poster Board III-343 Acute lymphoblastic leukemia (ALL), one of the most common malignancies in childhood, is a heterogeneous disease with individual leukemia subtypes differing in their response to chemotherapy. Recent findings suggest that disruptions of B cell receptor (BCR) signalling pathways may be involved in the development of ALL. The transcription factor PAX5 is essential for the commitment of lymphoid progenitors to the B-lymphocytic lineage. In 30% of childhood B-ALL cases, PAX5 is a frequent target of aberrancies, showing monoallelic loss, point mutations, or chromosomal translocations, whereas the role of these aberrancies is still poorly understood. Using high resolution SNP-chip analysis, we have recently identified several candidate partner genes fused to PAX5 in pediatric ALL, ETV6 (TEL), FOXP1, AUTS2, C20orf112, which bind to PAX5 recognition sequences as strongly as wild-type PAX5 (wt PAX5) suppressing its transcriptional activity in a dominant-negative fashion. In order to study the role of PAX5/TEL in leukemic evolution of B-ALL, we transfected the leukemic BCP cell line Nalm 6, which endogenously expresses PAX5, with a retroviral vector encoding PAX5/TEL and confirmed its expression by Western blotting and RT-PCR. Previously, the fusion gene PAX5/TEL has been cloned into the retroviral vector pMSCV-IRES-GFP (MIGR) from a patient diagnosed with B-cell precursor ALL (BCP) with t(9;12)(q11;p13). This fusion product consists of the 5′-end NH2 terminal region of the PAX5 gene and the almost whole sequence of the TEL gene. PAX5/TEL-MIGR expressing cells were sorted for GFP and analyzed by gene expression profiling on Affymetrix HG-U133 plus 2.0 Array in comparison to cells transfected with vector control (MIGR) and a MIGR vector encoding wt PAX5 (wtPAX5/MIGR). The probes were normalized with the Affymetrix MAS5.0 software. Probes were considered to be differentially expressed with a fold change ≤ 2 or ≥ 2, respectively. We identified a set of about 200 genes that were differentially expressed in the PAX5/TEL expressing cells, most of which were downregulated, compared to the controls. A subset of these genes encodes proteins important for BCR signalling: RAG1, one of two key mediators in the process of V(D)J recombination, VPREB3, which is involved in the early phase of pre-BCR assembly, the Runt domain transcription factor Runx1 (AML1) and FOXP1. The latter two genes are fusion partners of PAX5 in pediatric B-ALL and loss of FOXP1 leads to impaired DH–JH and VH–DJH rearrangement. Additionally, we found BACH2, which plays an important role during B-cell development, as well as protein kinase C-epsilon (PKCe) to be downregulated. PKCe is highly expressed in B cells linking the BCR to the activation of mitogen-activated protein kinases (MAPK). We confirmed the downregulation of the affected genes by RT-PCR. Strikingly, VPREB3 expression showed a significant downregulation of up to 170-fold, and RAG1 up to 90-fold. Loss of the RAG1/2 locus has been found in four precursor B-cell ALL cases, which indicates that defects in this process might contribute to leukemogenesis. We also detected a significant decrease in the expression of wt PAX5 as well as its direct downstream target CD79A (mb-1). CD79A (mb-1) encodes the B cell receptor component Ig-a and its early B cell-specific mb-1 promoter is a target for regulation by early B cell-specific transcription factors like E2A, early B cell factor (EBF), and PAX5. The latter is important for the activation of the mb-1 promoter by recruiting Ets proteins through protein-protein interactions. We investigated the binding efficiency of wt PAX5 to the promoter region of CD79A by chromatin-immunoprecipitation (ChIP). For the ChIP assay, we used a PAX5 antibody detecting the C-terminal region of PAX5 so that the antibody can bind the wt PAX5 but not the fusion product PAX5/TEL of which the C-terminal side is fused to TEL. Binding of wt PAX5 to the promoter region of CD79A was diminished by expression of the PAX5/TEL-fusion protein compared to the controls, leading to repression of CD79A, which we also confirmed by RT-PCR. In conclusion, we show that the expression of PAX5/TEL in a leukemic cell line has a repressor function on the expression of wt PAX5 as well as other genes important in BCR signalling. Also, we demonstrated that PAX5/TEL has a negative impact on the binding affinity of one of the direct downstream target genes of wt PAX5. Our results indicate a repressor role of the fusion gene PAX5/TEL including BCR signalling and point towards its contribution to leukemic transformation. Disclosures No relevant conflicts of interest to declare.
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Williams, Selena Joy, Chunhong Gu, Joelle dela Paz, Rena Buckstein, and Richard A. Wells. "ARNT/HIF-1β: An AML Biomarker?" Blood 116, no. 21 (November 19, 2010): 2903. http://dx.doi.org/10.1182/blood.v116.21.2903.2903.
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Abstract Abstract 2903 Background: Despite improvements in chemotherapy protocols and bone marrow transplantation techniques, AML remains a lethal disease. Although patients with AML typically respond well to initial therapy, the majority relapse and eventually succumb to the disease. This relapse is thought to be the result of the resistance of leukaemic stem cells to the effects of chemotherapy. Some mechanisms have been discovered which contribute to resistance, but this phenomenon remains incompletely understood and is a significant barrier to improving patient outcomes. TEL is a member of the ETS transcription factor gene family and is essential for developmental processes such as haematopoiesis. TEL is frequently targeted by chromosomal translocations in human malignancies, resulting in the expression of oncogenic TEL gene fusions. A TEL-ARNT gene fusion was reported in a single case of AML, FAB subtype M2, in a patient whose leukaemic cells contained the balanced translocation t(1;12)(q21;p13). ARNT (also known as HIF-1β) is a nuclear protein and functions as part of a heterodimer, whose partners include HIF-1α and the aryl hydrocarbon receptor (AhR). HIF-1 expression is commonly deregulated in cancer and AhR signalling has been linked to leukaemogenesis. Materials and Results: Immunoblot analysis of patient bone marrow mononuclear cell lysates revealed that 5 of 29 AML specimens (∼17%) had elevated levels of ARNT protein, whereas 0 of 19 MDS specimens showed ARNT expression. In addition, AML specimens that had elevated ARNT protein levels also had elevated levels of phosphorylated Akt, while AML specimens that did not have elevated ARNT protein expression did not have activation of Akt signaling. Intriguingly, ARNT expression was noted in one patient who had progressed from MDS to AML. We then studied the expression of ARNT in HL60 cells, which are highly sensitive to induction of apoptosis by troglitazone (TG), and in U937 cells, which are TG resistant. In HL60 cells, ARNT mRNA levels remained constant following TG treatment and ARNT protein levels markedly decreased, while in U937 cells, ARNT mRNA levels increased and ARNT protein levels remained constant. We then tested the effect of exogenous expression of ARNT on the sensitivity of HL-60 cells to apoptosis induced by TG, daunorubin and hydrogen peroxide. HL-60 cells transduced with a retrovirus expressing ARNT became resistant to the induction of apoptosis by all these agents. These cells also had constitutive activation of Akt signaling, and treatment of these cells with a specific inhibitor of Akt signaling reversed their resistance to TG-induced apoptosis. Conclusions: The expression of ARNT confers resistance to apoptosis in AML cell lines and activates Akt signalling. In addition, ARNT is overexpressed in a significant subset of AML patients, in whom it activated Akt signaling, and ARNT expression correlates with progression of MDS to AML. ARNT may play an important role in chemoresistance and may be useful as a predictive or prognostic biomarker. Disclosures: No relevant conflicts of interest to declare.
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Chen, Suning, Bjoern Schneider, Stefan Nagel, Robert Geffers, Maren Kaufmann, Hilmar Quentmeier, Hans G. Drexler, and Roderick A. F. MacLeod. "Spliceosomal Targeting in Acute Myeloid Leukemia Cells with ETV6-NTRK3 Fusion." Blood 114, no. 22 (November 20, 2009): 5042. http://dx.doi.org/10.1182/blood.v114.22.5042.5042.
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Abstract Abstract 5042 Background In acute myeloid leukemia (AML) a recurrent chromosome abnormality t(12;15)(p13;q25) fuses ETV6 with NTRK3. This rearrangement uniquely occurs in both solid tumors – including secretory breast cancer where it has been recently shown to target WNT signalling (Li et al., Cancer Cell 2007, 12: 542) - and leukemia, but has yet to be characterized in the hematologic setting. Tyrosine receptor kinases (TRK) play key roles in leukemogenesis and already serve as therapeutic targets. We set out to characterize potential downstream targets of ETV6-NTKR3 in AML cells. Methods and Cells By applying molecular cytogenetics, rapid amplification of c-DNA ends, microarray transcriptional profiling, reverse transcriptase quantitative-PCR, sequencing technology, and pathway analysis we defined and characterized the transcriptosome of a t(12;15) cell line (AP-1060) recently established from a patient with acute promyelocytic leukemia. We also investigated the transcriptional responses of AP-1060 cells to TRKi(nhibitor). For comparison we used, firstly a panel of 12 AML cell lines lacking ETV6-NTRK3 or PML-RARA, followed by NB-4 cells with solo PML-RARA. Results FISH confirmed ETV6 rearrangement, while 3′-RACE and RT-PCR identified and confirmed ETV6-NTRK3 fusion transcripts. Sequencing revealed both ETV6 exon-4 / NTKR3 exon-14, and ETV6 exon-2 / exon-18 of NTKR3 (hematopoietic) transcripts - the former dominating. Comparative transcriptional profiling of AP-1060 and control AML cells with or without PML-RARA showed upregulation of RAS-MAPK and PI3K-AKT related genes, highlighting the involvement of both TRK physiological signaling pathways via ETV6-NTRK3. Top genes upregulated in AP-1060 confer signatures both for AML - CCNA1, CD96, DSU, EVI1, HGF, IL32, LGALS3, MDS1, TLE1, TSPAN2; and lymphocyte development - BSPRY, BST1, CCR6, EMP1, GIMAP1, GZMA, PLEKHG1. Several primitive hematopoietic or stem cell mRNAs were also overexpressed, including PRSS2, CD96, SIPA1L2, and PYHIN1. Prominent downregulated genes also included: ADD3, CD36, HOXA-9/10, LGALS9, MALAT1, PGDS, PLA2G4A (AML signature); HOXB4, KIAA1949, NR2F6, TEAD4 (stem cell); and LY6E, TRIM44 (lymphocyte signature). Growth and proliferation of ETV6-NTKR3 cells was exquisitely sensitive to TRKi treatments which spared control AML and to which NB-4 cells were highly resistant. Accordingly we used pharmacologic modulation of conspicuously expressed genes by small molecule TRKi treatment to highlight likely kinase signaling targets among conspicuously expressed genes. Several candidate target genes thus emerged, notably AWNT1, IL32, and the MDS-EVI1 fusion transcript. Salient pharmacologically unmodulated genes were preferentially stem cell in character highlighting this setting for t(12;15) formation in AP-1060 cells. Bioinformatic pathway analysis (http://david.abcc.ncifcrf.gov/) of both up- and down- conspicuously regulated genes identified “Alternative Splicing” as top category, with respectively 743 and 373 alternate spliceform genes up- and down-regulated. These included several genes whose spliceforms may be differentially expressed in oncogenesis, including MDS1-EVI1/EVI1, MALAT1, and WT1/AWT1. Interestingly, a key pre-mRNA splicing gene, MBNL2 was conspicuously downregulated, while another spliceosomal component THOC5 (C22orf19), recently identified as a leukemic kinase signalling target (Pierce et al., Br J Haematol 2008;141:641), is upregulated. Conclusions We present a human leukemia model and resource for ETV6-NTRK3. Taken together, our findings support spliceosomal targeting by ETV6-NTRK3 and suggest a possible underlying mechanistic framework. Additional targets, e.g. WNT signaling, seem to be shared with solid tumors bearing the same oncogene fusion. Perspectives: Future work includes transcriptosomal analysis of AP-1060 cells after knockdown of ETV6-NTRK3 and key splicesomal genes, such as THOC5, by short-hairpin RNAs, and novel, highly selective 4-aminopyrazolylpyrimidine TRKi (Thress et al., Mol Cancer Therapy 2009;8:1818). Disclosures No relevant conflicts of interest to declare.
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Patkar, Nikhil, Chinmayee Kakirde, Anam Fatima Shaikh, Shrinidhi Nathany, Gaurav Chatterjee, Prashant Tembhare, Dhanlaxmi Lalit Shetty, et al. "A Novel Machine Learning Derived Genomics-Based Scoring System Is Highly Predictive of Outcome in Core Binding Factor Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2710. http://dx.doi.org/10.1182/blood-2019-128500.
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Introduction: Core binding factor acute myeloid leukemia (CBF-AML) is one of the commonest subtypes of AML characterized presence of t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22). It is characterised by a high frequency of somatic mutations especially in RAS and tyrosine kinase signalling pathways. Here we investigated the feasibility of improving risk prediction of CBF-AML using machine learning algorithms. Methods: We developed a next generation sequencing panel that targeted 50 genes implicated in the pathogenesis of myeloid malignancies using single molecule molecular inversion probes. This panel was used to sequence 106 patients of CBF-AML accrued over a six year period (March 2012 - December 2018) treated with conventional "3 + 7" chemotherapy. Post data analysis, we devised a supervised machine learning (ML) approach for identification of mutations most likely to predict for favorable outcome in CBF-AML. We included somatic mutations in genes occurring in CBF-AML at a frequency of >5%. A total of 11 variables were included for feature selection to predict for favorable outcome (including mutations in ASXL2, CSF3R,FLT3, KIT, NF1, NRAS, RAD21, TET2 and WT1 genes as well as mutation burden). Approaches for supervised ML were naïve bayes, generalized linear model, logistic regression, deep learning and random forest methods. Based on the ML results top 6 selected variables were allotted an individual score. A final score for that case was devised as a sum total of the individual scores. These sum were used to generate a genetic risk for a patient. Overall survival (OS) was calculated from date of diagnosis to time of last follow up or death. Relapse free survival (RFS) was calculated from date of CR till time to relapse or death or last follow up if in CR. Results of the genetic risk were analyzed for their impact on OS and RFS using log rank test. Multivariate analysis was performed using cox proportional hazards regression model. Results: The median follow up of the cohort was 27.6 months. A total of 181 somatic mutations were identified in this subset of AML with 86.7% harbouring at least one somatic mutation (median = 2). Based on ML data, a genetic score was formulated that incorporated mutations in RAD21, FLT3, KIT D816, ASXL2, NRAS genes as well as high mutation burden (≥2) into two genetic risk classes (favorable risk and poor ML derived genetic genetic risk). Patients classified as poor genetic risk had a significantly lower OS [median OS: 34.8 months; 95% confidence interval (CI) (14.2-34.8); p=0.0086] and RFS [median RFS: 17.9 months; 95%CI (12.7-33.6); p=0.0043] as compared to patients with favorable genetic risk (median OS and RFS not reached). These results can be seen in Figure 1. On multivariate analysis poor genetic risk was the most important independent risk factor that predicted for inferior OS [hazard ratio(HR), 2.7; 95% CI 1.3 to 5.7] and RFS (HR, 2.6; 95% CI:1.3 to 5.1). Conclusions In a proof of concept, we describe a novel ML derived genomics scoring model that provides a mechanism to risk stratify CBF-AML, a seemingly homogeneous disease entity. This study, to the best of our knowledge represents a novel application of ML to CBF mutated AML. Our data indicates that this scoring system will be useful in identifying CBF mutated AML patients who are at higher risk of relapse and distinguishes them from patients who are truly good risk. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Xu, Xi, Xingchun Gou, Huifang Guo, Peng Chen, Runfan Luo, and Yuting Zhang. "The Roles of Ciliary Neurotrophic Factor —— from Neuronutrition to Energy Metabolism." Protein & Peptide Letters 29 (September 5, 2022). http://dx.doi.org/10.2174/0929866529666220905105800.
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Abstract: Ciliary neurotrophic factor (CNTF) is a pluripotent neurotrophic factor that was originally isolated from chicken embryo ciliary neurons. It has a powerful role in the development and maintenance of the optic nervous system and has been used for many vision-related diseases. It also plays an important role in the neurogenesis, regeneration and survival of other neurons, including neural stem cells, dorsal root ganglion, sensory neurons and motor neurons. CNTF is related to neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. In addition to its role in nervous system, CNTF regulates the balance of energy metabolism and the administration of CNTF induces body weight loss. More CNTF function have been found with the deepening of study, such as protecting and promoting cardiomyocyte proliferation. In addition, CNTF even participate in the mental illness and inflammation suppressing. CNTF exerts multidirectional physiological activity by regulating the transcription of various genes through a variety of signalling pathways (including JAK/STAT, MAPK, and P13K/AKT). This review summarizes the roles and mechanisms of CNTF in the optic nervous system, retinal-related diseases, neuronal protection, and especially nutrition, energy metabolism and other aspects.
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Alobaid, Hussah, Margaritis Voliotis, Krasimira Tsaneva-Atanasova, and Craig McArdle. "Measuring of information transfer via gonadotropin-releasing hormone receptors (GnRHR) shows a remarkable loss of information through signalling." Endocrine Abstracts, November 2, 2018. http://dx.doi.org/10.1530/endoabs.59.p130.
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Julie, Crockett, Das Subhajit, Dignan Cahal, Mellis David, Duthie Angela, Sobacchi Cristina, Schulz Ansgar, and Helfrich Miep. "Rare mutations associated with osteoclast-poor osteopetrosis provide molecular insights into receptor activator of NF[kappa][beta] signalling." Bone Abstracts, June 1, 2013. http://dx.doi.org/10.1530/boneabs.2.p138.
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Javed, Faryal, Summiya Zubair, Hassan Imran, Safia Sultana Munir, Humayun Riaz, Misbah Sultana, Ruqaiya Rasheed Kayani, Saba Manzoor, Saeed Ur Rashid Nazir, and Muhammad Maaz Ali. "Role of Herbal Medicines in Hepatocellular Carcinoma." Journal of Pharmaceutical Research International, September 24, 2022, 42–50. http://dx.doi.org/10.9734/jpri/2022/v34i50b36441.
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Mutation in several factors and pathways leads to the development of hepatic cancer i.e. Mutation in Wnt-β-Catenin Signalling Pathway , activation of the Insulin-Like Growth Factor (IGF) Signalling Pathway, The P13/PTEN/AKT, TP53 Tumour Suppressor Gene. Liver cirrhosis and fatty liver predispose the normal tissues to fibrosis leading to liver cancer. Excessive alcohol intake results in the inflammation of liver proceeding to cirrhosis and ultimately hepatic carcinoma. Hepatocellular Carcinoma (HCC) is multi-centric i.e. has huge variability in its spread which differs from person to person. Four approaches are practiced for treatment of hepatic cancer; surgery, transarterial intervention, percutaneous intervention, and drug approach. Surgery includes liver transplant and tumour resection. Transarterial approach includes chemoembolization and embolization. Percutaneous approach includes radiofrequency thermal ablation (RFTA) and ethanol injection. Drugs are various including herbal plant medicines, herbal formulae, synthetic drugs, immune, and gene therapies. Zingiber officinal, Schinus molle L., Zerumbone, Curcuma longa and Mammea siamensis are some of the plant medicines.
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Olawale, Femi, Opeyemi Iwaloye, Olushola Olalekan Elekofehinti, Babatomiwa Kikiowo, Emmanuel Ayo Oluwarotimi, Kayode Michael Ilesanmi, Isaac Damilola Akinropo, Oluwaseun Benedicta Akinlosotu, Abayomi Emmanuel Adegboyega, and Taiwo Emmanuel Ologuntere. "A multi-target approach for the discovery of Anti Breast Cancer Agents from Plants Secondary Metabolites." Letters in Drug Design & Discovery 18 (May 21, 2021). http://dx.doi.org/10.2174/1570180818666210521111535.
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Background: Cancer is a multifactorial disease with multiple complications involving multiple proteins. Breast cancer is the most prevalent form of cancer among women. The pathophysiology of this cancer form has implicated several genetic alterations in its hallmark. Two of the most studied breast cancer molecular pathways are the cell cycle protein kinases and P13/AKT signalling pathway. Objective: Thus, this study identified novel inhibitors through computational screening of a library of medicinal plants compounds against cyclin-dependent kinase 2 (CDK2), phosphoinositide-3-kinase A (PI3Ka) and protein kinase B (AKT1). Methods: Rigid protein docking via Glide algorithm was applied to identify the hits from 3000 plants compounds screened against three drug targets involved in breast cancer pathogenesis. A more accurate and reliable ligand-protein docking called induced fit docking was adopted to extensively improve the scoring function by ranking favourable binding as top-scoring one. Results: Nine hit compounds were identified and found to interact with essential residues at the proteins’ binding sites. Subsequently, the hits pharmacokinetic parameters and toxicity were predicted to determine their potential as drug candidates and minimise toxic effects. The hit compounds were found to be non-carcinogenic, and five of them showed a desirable drug-like property. The built predictive QSAR models with an R2 value of 0.7684, 0.7973 and 0.5649 for CDK2, AKT1 and PI3Ka, respectively were adopted to determine the hits inhibitory activity (pIC50) against the screened proteins; and the predictions revealed compounds with significant activity. Three thousand (3000) compounds from diverse medicinal plants were docked with CDK2, AKT1 and PI3Ka to identify the top-scoring compounds using Glide algorithm scoring function. The identified compounds with low binding energies against the three targets were subsequently subjected to a more accurate and reliable ligand-protein docking called induced fit docking to extensively improve the compounds binding affinity with the proteins. Nine (9) compounds identified as hits were found to form highly stable complexes with the proteins and interacted with essential residues at the proteins’ binding sites. Prediction of the hit compounds drug-likeness, pharmacokinetic and toxicity properties by online web servers showed that the compounds are non-carcinogenic and showed moderate indices for ADMET parameters. The constructed QSAR models with reliable R2 coefficient value were used to predict the pIC50 of the selected compounds. The results revealed potent compounds with significant activity. Concluson: This study thus provides insight into multi-target protein compounds which could be explored as chemotherapeutic alternatives in breast cancer treatment.