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Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition.
Moyo TK, Wilson CS, Moore DJ, Eischen CM
(2017) Oncogene 36: 4653-4661
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, B-Lymphocytes, CD79 Antigens, Cell Proliferation, Flow Cytometry, Humans, Lymphoma, Non-Hodgkin, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 3, Phosphatidylinositol 3-Kinases, Phospholipase C gamma, Phosphorylation, Precancerous Conditions, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-myc, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Splenic Neoplasms, Syk Kinase
Show Abstract · Added April 6, 2017
Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells. Utilizing the Eμ-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Eμ-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79α, Btk, Plcγ2 and Erk1/2. Notably, Myc-overexpressing B cells maintained elevated BCR signaling despite treatment with ibrutinib, a Bruton's tyrosine kinase inhibitor. Furthermore, PI3K/Akt pathway signaling was also increased in Eμ-myc B cells, and this increase was partially suppressed with ibrutinib. In addition, experiments with Btk-null B cells revealed off-target effects of ibrutinib on BCR signaling. Our data show that in pre-malignant B cells, Myc overexpression is sufficient to activate BCR and PI3K/Akt signaling pathways and further enhances signaling following BCR ligation. Therefore, our results indicate that precancerous B cells have already acquired enhanced survival and growth capabilities before transformation, and that elevated MYC levels confer resistance to pharmacologic inhibitors of BCR signaling, which has significant implications for B-NHL treatment.
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23 MeSH Terms
Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury: Implications for Human Ischemic Cardiomyopathy.
Zhang B, Novitskaya T, Wheeler DG, Xu Z, Chepurko E, Huttinger R, He H, Varadharaj S, Zweier JL, Song Y, Xu M, Harrell FE, Su YR, Absi T, Kohr MJ, Ziolo MT, Roden DM, Shaffer CM, Galindo CL, Wells QS, Gumina RJ
(2017) Circ Heart Fail 10:
MeSH Terms: Adult, Animals, Calcium Channels, L-Type, Calcium Signaling, Calcium-Binding Proteins, Cardiomyopathies, Case-Control Studies, Disease Models, Animal, Female, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium, Oxidative Stress, Phenotype, Potassium Channels, Inwardly Rectifying, Reactive Nitrogen Species, Reactive Oxygen Species, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Tyrosine, Ventricular Dysfunction, Left, Ventricular Function, Left, Ventricular Pressure
Show Abstract · Added April 6, 2017
BACKGROUND - Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM.
METHODS AND RESULTS - RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in expression with ICM. encodes the Kir6.2 subunit of the cardioprotective K channel. Using wild-type mice and -deficient (-null) mice, we examined the effect of expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in -null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in -null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in -null mice. Despite impaired relaxation, -null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca, thereby increasing sarcoendoplasmic reticulum Ca-mediated calcium reuptake. However, -null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca function, thereby contributing to diastolic dysfunction.
CONCLUSIONS - expression is decreased in human ICM. Lack of expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca-ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.
© 2017 American Heart Association, Inc.
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28 MeSH Terms
Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.
Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, Green MR, Trøen G, Liestøl K, Beiske K, Houot R, Delabie J, Alizadeh AA, Irish JM, Levy R
(2017) Blood 129: 759-770
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, CD79 Antigens, Diagnosis, Differential, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin M, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, Receptors, Antigen, B-Cell, STAT1 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Single-Cell Analysis, Syk Kinase, p38 Mitogen-Activated Protein Kinases, src-Family Kinases
Show Abstract · Added December 31, 2016
Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.
© 2017 by The American Society of Hematology.
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26 MeSH Terms
and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.
Li M, Li Y, Weeks O, Mijatovic V, Teumer A, Huffman JE, Tromp G, Fuchsberger C, Gorski M, Lyytikäinen LP, Nutile T, Sedaghat S, Sorice R, Tin A, Yang Q, Ahluwalia TS, Arking DE, Bihlmeyer NA, Böger CA, Carroll RJ, Chasman DI, Cornelis MC, Dehghan A, Faul JD, Feitosa MF, Gambaro G, Gasparini P, Giulianini F, Heid I, Huang J, Imboden M, Jackson AU, Jeff J, Jhun MA, Katz R, Kifley A, Kilpeläinen TO, Kumar A, Laakso M, Li-Gao R, Lohman K, Lu Y, Mägi R, Malerba G, Mihailov E, Mohlke KL, Mook-Kanamori DO, Robino A, Ruderfer D, Salvi E, Schick UM, Schulz CA, Smith AV, Smith JA, Traglia M, Yerges-Armstrong LM, Zhao W, Goodarzi MO, Kraja AT, Liu C, Wessel J, CHARGE Glycemic-T2D Working Group,, CHARGE Blood Pressure Working Group,, Boerwinkle E, Borecki IB, Bork-Jensen J, Bottinger EP, Braga D, Brandslund I, Brody JA, Campbell A, Carey DJ, Christensen C, Coresh J, Crook E, Curhan GC, Cusi D, de Boer IH, de Vries AP, Denny JC, Devuyst O, Dreisbach AW, Endlich K, Esko T, Franco OH, Fulop T, Gerhard GS, Glümer C, Gottesman O, Grarup N, Gudnason V, Hansen T, Harris TB, Hayward C, Hocking L, Hofman A, Hu FB, Husemoen LL, Jackson RD, Jørgensen T, Jørgensen ME, Kähönen M, Kardia SL, König W, Kooperberg C, Kriebel J, Launer LJ, Lauritzen T, Lehtimäki T, Levy D, Linksted P, Linneberg A, Liu Y, Loos RJ, Lupo A, Meisinger C, Melander O, Metspalu A, Mitchell P, Nauck M, Nürnberg P, Orho-Melander M, Parsa A, Pedersen O, Peters A, Peters U, Polasek O, Porteous D, Probst-Hensch NM, Psaty BM, Qi L, Raitakari OT, Reiner AP, Rettig R, Ridker PM, Rivadeneira F, Rossouw JE, Schmidt F, Siscovick D, Soranzo N, Strauch K, Toniolo D, Turner ST, Uitterlinden AG, Ulivi S, Velayutham D, Völker U, Völzke H, Waldenberger M, Wang JJ, Weir DR, Witte D, Kuivaniemi H, Fox CS, Franceschini N, Goessling W, Köttgen A, Chu AY
(2017) J Am Soc Nephrol 28: 981-994
MeSH Terms: Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Son of Sevenless Proteins, Zebrafish
Show Abstract · Added March 14, 2018
Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
Copyright © 2017 by the American Society of Nephrology.
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11 MeSH Terms
Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis.
Toutounchian JJ, Pagadala J, Miller DD, Baudry J, Park F, Chaum E, Morales-Tirado , Yates CR
(2017) Mol Pharmacol 91: 1-13
MeSH Terms: Animals, Benzoxazines, Cell Movement, Cell Proliferation, Disease Models, Animal, Endothelial Cells, Focal Adhesion Protein-Tyrosine Kinases, Humans, Mice, Inbred C57BL, Models, Biological, Oxygen, Paxillin, Retinal Neovascularization, Signal Transduction, Small Molecule Libraries, Vascular Endothelial Growth Factor A, src-Family Kinases
Show Abstract · Added June 11, 2018
Targeting vascular endothelial growth factor (VEGF) is a common treatment strategy for neovascular eye disease, a major cause of vision loss in diabetic retinopathy and age-related macular degeneration. However, the decline in clinical efficacy over time in many patients suggests that monotherapy of anti-VEGF protein therapeutics may benefit from adjunctive treatments. Our previous work has shown that through decreased activation of the cytoskeletal protein paxillin, growth factor-induced ischemic retinopathy in the murine oxygen-induced retinopathy model could be inhibited. In this study, we demonstrated that VEGF-dependent activation of the Src/FAK/paxillin signalsome is required for human retinal endothelial cell migration and proliferation. Specifically, the disruption of focal adhesion kinase (FAK) and paxillin interactions using the small molecule JP-153 inhibited Src-dependent phosphorylation of paxillin (Y118) and downstream activation of Akt (S473), resulting in reduced migration and proliferation of retinal endothelial cells stimulated with VEGF. However, this effect did not prevent the initial activation of either Src or FAK. Furthermore, topical application of a JP-153-loaded microemulsion affected the hallmark features of pathologic retinal angiogenesis, reducing neovascular tuft formation and increased avascular area, in a dose-dependent manner. In conclusion, our results suggest that using small molecules to modulate the focal adhesion protein paxillin is an effective strategy for treating pathologic retinal neovascularization. To our knowledge, this is the first paradigm validating modulation of paxillin to inhibit angiogenesis. As such, we have identified and developed a novel class of small molecules aimed at targeting focal adhesion protein interactions that are essential for pathologic neovascularization in the eye.
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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MeSH Terms
Reply.
Nyhoff LE, Crofford LJ, Kendall PL
(2017) Arthritis Rheumatol 69: 475-477
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Arthritis, Rheumatoid, Humans
Added July 18, 2017
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3 MeSH Terms
Cardiovascular Toxic Effects of Targeted Cancer Therapies.
Moslehi JJ
(2016) N Engl J Med 375: 1457-1467
MeSH Terms: Antineoplastic Agents, Cardiovascular Diseases, Humans, Neoplasms, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Signal Transduction, Vascular Endothelial Growth Factor A
Added March 26, 2017
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8 MeSH Terms
Tyrosine phosphorylation modulates mitochondrial chaperonin Hsp60 and delays rotavirus NSP4-mediated apoptotic signaling in host cells.
Chattopadhyay S, Mukherjee A, Patra U, Bhowmick R, Basak T, Sengupta S, Chawla-Sarkar M
(2017) Cell Microbiol 19:
MeSH Terms: Apoptosis, Cell Line, Chaperonin 60, Glycoproteins, Host-Pathogen Interactions, Humans, Phosphorylation, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Proteolysis, Rotavirus, Signal Transduction, Time Factors, Toxins, Biological, Tyrosine, Viral Nonstructural Proteins
Show Abstract · Added November 3, 2017
Phosphoproteomics-based platforms have been widely used to identify post translational dynamics of cellular proteins in response to viral infection. The present study was undertaken to assess differential tyrosine phosphorylation during early hours of rotavirus (RV) SA11 infection. Heat shock proteins (Hsp60) were found to be enriched in the data set of RV-SA11 induced differentially tyrosine-phosphorylated proteins at 2 hr post infection (hpi). Hsp60 was further found to be phosphorylated by an activated form of Src kinase on 227th tyrosine residue, and tyrosine phosphorylation of mitochondrial chaperonin Hsp60 correlated with its proteasomal degradation at 2-2.5hpi. Interestingly, mitochondrial Hsp60 positively influenced translocation of the rotaviral nonstructural protein 4 to mitochondria during RV infections. Phosphorylation and subsequent transient degradation of mitochondrial Hsp60 during early hours of RV-SA11 infection resulted in inhibition of premature import of nonstructural protein 4 into mitochondria, thereby delaying early apoptosis. Overall, the study highlighted one of the many strategies rotavirus undertakes to prevent early apoptosis and subsequent reduced viral progeny yield.
© 2016 John Wiley & Sons Ltd.
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16 MeSH Terms
Focal adhesions control cleavage furrow shape and spindle tilt during mitosis.
Taneja N, Fenix AM, Rathbun L, Millis BA, Tyska MJ, Hehnly H, Burnette DT
(2016) Sci Rep 6: 29846
MeSH Terms: Animals, Cell Differentiation, Cell Shape, Centrosome, Dogs, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions, HeLa Cells, Humans, Madin Darby Canine Kidney Cells, Mitosis, Spindle Apparatus, Vinculin
Show Abstract · Added April 7, 2017
The geometry of the cleavage furrow during mitosis is often asymmetric in vivo and plays a critical role in stem cell differentiation and the relative positioning of daughter cells during development. Early observations of adhesive cell lines revealed asymmetry in the shape of the cleavage furrow, where the bottom (i.e., substrate attached side) of the cleavage furrow ingressed less than the top (i.e., unattached side). This data suggested substrate attachment could be regulating furrow ingression. Here we report a population of mitotic focal adhesions (FAs) controls the symmetry of the cleavage furrow. In single HeLa cells, stronger adhesion to the substrate directed less ingression from the bottom of the cell through a pathway including paxillin, focal adhesion kinase (FAK) and vinculin. Cell-cell contacts also direct ingression of the cleavage furrow in coordination with FAs in epithelial cells-MDCK-within monolayers and polarized cysts. In addition, mitotic FAs established 3D orientation of the mitotic spindle and the relative positioning of mother and daughter centrosomes. Therefore, our data reveals mitotic FAs as a key link between mitotic cell shape and spindle orientation, and may have important implications in our understanding stem cell homeostasis and tumorigenesis.
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13 MeSH Terms
Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies.
Shaver TM, Lehmann BD, Beeler JS, Li CI, Li Z, Jin H, Stricker TP, Shyr Y, Pietenpol JA
(2016) Cancer Res 76: 4850-60
MeSH Terms: Algorithms, Cell Line, Tumor, Female, Gene Expression Profiling, Gene Rearrangement, Humans, Immunoblotting, Neoplasms, Oncogene Proteins, Fusion, Polymerase Chain Reaction, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Triple Negative Breast Neoplasms, c-Mer Tyrosine Kinase
Show Abstract · Added April 9, 2017
Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between noncoding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1 The over 1,000 genetic alterations we identified highlight the importance of considering noncoding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers. Cancer Res; 76(16); 4850-60. ©2016 AACR.
©2016 American Association for Cancer Research.
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14 MeSH Terms