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https://www.readbyqxmd.com/read/29330306/an-rb-family-independent-e2f3-transcription-factor-variant-impairs-stat5-signaling-and-mammary-gland-remodeling-during-pregnancy-in-mice
#1
Yang Liao, Wei Du
E2F transcription factors are regulated by binding to the retinoblastoma (Rb) tumor suppressor family of proteins. Previously, we reported an E2FLQ mutation that disrupts the binding with Rb proteins without affecting E2F's transcriptional activity. We also showed that mouse embryonic fibroblasts (MEFs) with an E2F3LQ mutation exhibit increased E2F activity and more rapid cell proliferation. In this report, we analyzed E2F3LQ mice to further characterize the in vivo consequences of Rb family-independent E2F3 activity...
January 12, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29326301/prognostic-roles-of-signal-transducers-activators-of-transcription-family-in-human-breast-cancer
#2
Shuntao Wang, Lili Yu, Wei Shi, Xueqin Li, Lixiu Yu
Signal transducer and activator of transcription (STAT) family are critical transcription factors, which have been proved as prognostic predictors for a number of cancers. However, the prognostic roles of STAT family in breast cancer patients remain in dispute. In this study, we mined the 'Kaplan-Meier plotter' (KM plotter) online database to explore the prognostic roles of STAT family mRNA expression in breast cancer including overall survival (OS), progression-free survival (PFS), as well as post-progression survival (PPS)...
January 11, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29321207/aberrantly-high-expression-of-the-cub-and-zona-pellucida-like-domain-containing-protein-1-cuzd1-in-mammary-epithelium-leads-to-breast-tumorigenesis
#3
Janelle Mapes, Lavanya Anandan, Quanxi Li, Alison Neff, Charles V Clevenger, Indrani C Bagchi, Milan K Bagchi
The peptide hormone prolactin (PRL) and certain members of the epidermal growth factor (EGF) family play central roles in mammary gland development and physiology, and their dysregulation has been implicated in mammary tumorigenesis. Our recent studies have revealed that the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) is a critical factor for PRL-mediated activation of the transcription factor STAT5 in mouse mammary epithelium. CUZD1 controls production of a specific subset of the EGF family growth factors and consequent activation of their receptors...
January 10, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29308327/enhancement-of-antibody-dependent-cellular-cytotoxicity-of-cetuximab-by-a-chimeric-protein-encompassing-interleukin-15
#4
Maria Carmen Ochoa, Luna Minute, Ascensión López, Elisabeth Pérez-Ruiz, Celia Gomar, Marcos Vasquez, Susana Inoges, Iñaki Etxeberria, Inmaculada Rodriguez, Saray Garasa, Jan-Peter Andreas Mayer, Peter Wirtz, Ignacio Melero, Pedro Berraondo
Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15Rα, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8+ T cells...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29307521/decreased-cd122-on-cd56dim-nk-associated-with-its-impairment-in-asymptomatic-chronic-hbv-carriers-with-high-levels-of-hbv-dna-hbsag-and-hbeag
#5
Wenzheng Han, Qin Ni, Kezhou Liu, Yunliang Yao, Dejian Zhao, Xia Liu, Yu Chen
AIMS: NK cells play important roles in inhibiting HBV replication and preventing HBV infection. However, NK-cell dysfunction has not been fully studied in asymptomatic chronic HBV carriers (ASC). This study aims to assess decreased expression of CD122 associated with impaired NK cells and the restoration of NK cells with IL-2 and IL-15 stimulation. MAIN METHODS: The experiments were performed by flow cytometer, cytotoxicity assay, ELISA and Western blotting. KEY FINDINGS: The reduced CD122 on CD56+ NK cells and CD56dim NK cells is associated with high levels of HBV DNA, HBsAg or HBeAg in ASCs, in which CD56dim NK-cell impairment is observed...
January 4, 2018: Life Sciences
https://www.readbyqxmd.com/read/29296839/pak2-regulates-myeloid-derived-suppressor-cell-development-in-mice
#6
Yi Zeng, Seongmin Hahn, Jessica Stokes, Emely A Hoffman, Monika Schmelz, Maria Proytcheva, Jonathan Chernoff, Emmanuel Katsanis
Myeloid-derived suppressor cells (MDSCs) are CD11b+Gr1+ cells that induce T-cell hyporesponsiveness, thus impairing antitumor immunity. We have previously reported that disruption of Pak2, a member of the p21-activated kinases (Paks), in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and expansion of CD11bhighGr1high cells in mice. In this study, we confirmed that Pak2-KO CD11bhighGr1high cells suppressed T-cell proliferation, consistent with an MDSC phenotype. Loss of Pak2 function in HSPCs led to (1) increased hematopoietic progenitor cell sensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, (2) increased MDSC proliferation, (3) decreased MDSC sensitivity to both intrinsic and Fas-Fas ligand-mediated apoptosis, and (4) promotion of MDSCs by Pak2-deficient CD4+ T cells that produced more interferon γ, tumor necrosis factor α, and GM-CSF...
October 10, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296749/high-cd123-levels-enhance-proliferation-in-response-to-il-3-but-reduce-chemotaxis-by-downregulating-cxcr4-expression
#7
Nicole L Wittwer, Gabriela Brumatti, Ceilidh Marchant, Jarrod J Sandow, Melanie K Pudney, Mara Dottore, Richard J D'Andrea, Angel F Lopez, Paul G Ekert, Hayley S Ramshaw
High expression of the α chain of the interleukin-3 receptor (IL-3Rα; CD123) is a hallmark of acute myeloid leukemia (AML) leukemic stem cells (LSCs). Elevated CD123 expression is part of the diagnostic immunophenotyping of myeloid leukemia, and higher expression is associated with poor prognosis. However, the biological basis of the poorer prognosis is unclear, and may include heightened IL-3 signaling and non-cell autonomous interactions with the bone marrow (BM) microenvironment. We used TF-1 cells expressing different levels of CD123 and found elevated CD123 levels amplified the proliferative response to exogenous IL-3 and maintained viability in reducing IL-3 concentrations...
June 27, 2017: Blood Advances
https://www.readbyqxmd.com/read/29285262/nuclear-membrane-localised-nox4d-generates-pro-survival-ros-in-flt3-itd-expressing-aml
#8
Jennifer N Moloney, Ashok Kumar Jayavelu, Joanna Stanicka, Sarah L Roche, Rebecca L O'Brien, Sebastian Scholl, Frank-D Böhmer, Thomas G Cotter
Internal tandem duplication of the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3-ITD) is the most prevalent genetic aberration present in 20-30% of acute myeloid leukaemia (AML) cases and is associated with a poor prognosis. FLT3-ITD expressing cells express elevated levels of NADPH oxidase 4 (NOX4)-generated pro-survival hydrogen peroxide (H2O2) contributing to increased levels of DNA oxidation and double strand breaks. NOX4 is constitutively active and has been found to have various isoforms expressed at multiple locations within a cell...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29282311/a-cellular-microrna-facilitates-regulatory-t-lymphocyte-development-by-targeting-the-foxp3-promoter-tata-box-motif
#9
Yiwen Zhang, Weiwei Liu, Yingshi Chen, Jun Liu, Kang Wu, Lishi Su, Wanying Zhang, Yawen Jiang, Xu Zhang, Yijun Zhang, Chao Liu, Liang Tao, Bingfeng Liu, Hui Zhang
The CD4+CD25+FOXP3+ regulatory T cells (Tregs) mediate immunological self-tolerance and suppress various immune responses. FOXP3 is a key transcriptional factor for the generation and development of Tregs. Its expression is regulated by various cytokines including TGF-β, IL-2, and IL-10. It is important to further identify the regulatory factors for Tregs. Given that many microRNAs (miRNAs) could specifically interact with the core promoter region and specifically enhance the transcription of many target genes, we searched for any possible miRNA(s) targeting the core promoter region of the FOXP3 gene...
December 27, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29277631/a-proteomic-clock-of-human-pregnancy
#10
Nima Aghaeepour, Benoit Lehallier, Quentin Baca, Ed A Ganio, Ronald J Wong, Mohammad S Ghaemi, Anthony Culos, Yasser Y El-Sayed, Yair J Blumenfeld, Maurice L Druzin, Virginia D Winn, Ronald S Gibbs, Rob Tibshirani, Gary M Shaw, David K Stevenson, Brice Gaudilliere, Martin S Angst
BACKGROUND: Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome...
December 22, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/29274969/effect-of-17%C3%AE-estradiol-on-milk-production-hormone-secretion-and-mammary-gland-gene-expression-in-dairy-cows
#11
J J Tong, I M Thompson, X Zhao, P Lacasse
Estradiol inhibits milk production in dairy cows. The present study evaluated the effect of 17β-estradiol (E2) injections on prolactin (PRL) secretion and the mammary gland response to this hormone. Eight mid-lactation cows were used in a crossover design. During each experimental period, the cows were injected daily with either E2 (2.5 mg) or soy oil (2.5 mL; control) for 7 d. For each period, blood and milk samples were collected from d -4 to 14 (relative to the first injection) to measure PRL, insulin-like growth factor-1, and cortisol concentrations...
December 20, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/29274275/stat5-phosphorylation-is-responsible-for-the-excessive-potency-of-hb-egf
#12
Jeongyeon Heo, Jae Geun Kim, Sunghwan Kim, Hara Kang
Heparin-binding EGF-like growth factor (HB-EGF) is a potent growth factor involved in wound healing and tumorigenesis. Despite the sequence similarity between HB-EGF and EGF, HB-EGF induces cellular proliferation and migration more potently than EGF. However, the differential regulation by HB-EGF and EGF has not been thoroughly elucidated. In this study, we compared signaling pathways activated by HB-EGF and EGF to understand the details of the molecular mechanism of the high potency induced by HB-EGF. HB-EGF specifically induced the phosphorylation of EGFR-Y1045 and activated Stat5, which is responsible for promoting cell proliferation and migration...
December 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29259155/central-igf1-improves-glucose-tolerance-and-insulin-sensitivity-in-mice
#13
Hao Hong, Zhen-Zhong Cui, Lu Zhu, Shu-Ping Fu, Mario Rossi, Ying-Hong Cui, Bing-Mei Zhu
Insulin-like growth factor 1 (IGF1) is a key factor for tissue growth and fuel metabolism. The potential function of central IGF1 remains unclear. We previously observed that IGF1 expression is increased in the hypothalamus of obese mice lacking STAT5 in the central nervous system (CNS). In this study, we explored the potential metabolic function of central IGF1 by intracerebroventricular (ICV) injection of IGF1, over-expression of central IGF1 by administering an adeno-associated virus (AAV), and ICV injection of an anti-IGF1 antibody...
December 19, 2017: Nutrition & Diabetes
https://www.readbyqxmd.com/read/29259099/il-2r%C3%AE-abundance-differentially-tunes-il-2-signaling-dynamics-in-cd4-and-cd8-t-cells
#14
Geoffrey A Smith, Jack Taunton, Arthur Weiss
Interleukin-2 (IL-2) stimulates both activated CD4+ and CD8+ T cells to proliferate. IL-2 signals through an identical receptor complex and promotes the same dose-dependent phosphorylation of the canonical transcription factor STAT5 in both cell types. Despite this, CD8+ T cells enter the S phase earlier and proliferate to a greater extent than do CD4+ T cells in response to IL-2. We identified distinct IL-2 signaling dynamics in CD4+ and CD8+ T cells. In IL-2-stimulated CD8+ T cells, STAT5 phosphorylation increased rapidly and was sustained for 6 hours...
December 19, 2017: Science Signaling
https://www.readbyqxmd.com/read/29249817/drug-induced-inhibition-of-phosphorylation-of-stat5-overrides-drug-resistance-in-neoplastic-mast-cells
#15
B Peter, S Bibi, G Eisenwort, B Wingelhofer, D Berger, G Stefanzl, K Blatt, H Herrmann, E Hadzijusufovic, G Hoermann, T Hoffmann, J Schwaab, M Jawhar, M Willmann, W R Sperr, J Zuber, K Sotlar, H-P Horny, R Moriggl, A Reiter, M Arock, P Valent
Systemic mastocytosis (SM) is a mast cell (MC) neoplasm with complex pathology and a variable clinical course. In aggressive SM (ASM) and MC leukemia (MCL), responses to conventional drugs are poor and the prognosis is dismal. R763 is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT and FLT3. We examined the effects of R763 on proliferation and survival of neoplastic MC. R763 produced dose-dependent inhibition of proliferation in the human MC lines HMC-1.1 (IC50 5-50 nM), HMC-1...
November 29, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29248227/d-glucose-and-amino-acid-deficiency-inhibits-casein-synthesis-through-jak2-stat5-and-ampk-mtor-signaling-pathways-in-mammary-epithelial-cells-of-dairy-cows
#16
M C Zhang, S G Zhao, S S Wang, C C Luo, H N Gao, N Zheng, J Q Wang
Amino acids and energy deficiency lead to lower milk protein content in dairy cows. However, the known mechanisms involved in this process do not adequately explain the variability of milk protein concentration in the mammary gland. We hypothesized that a deficiency in d-glucose (d-Glc) or AA would inhibit casein synthesis by regulating signaling pathways in mammary epithelial cells. Cow mammary epithelial cells (CMEC) were subjected to combinations of 1 of 3 concentrations of d-Glc (0, 2.50, or 17.5 mM) and 1 of 3 concentrations of AA (0, 1...
December 13, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/29246863/essential-roles-of-stat5-1-stat5b-in-controlling-fish-somatic-growth
#17
Shuting Xiong, Jie Mei, Peipei Huang, Jing Jing, Zhi Li, Jingliang Kang, Jian-Fang Gui
Signal transducer and activator of transcription 5b (STAT5b) has been identified as a key downstream mediator of growth hormone (GH) signaling in somatic growth of mammalian. However, the corresponding homologue gene of Stat5b is unknown in fish species. In this study, we generated loss-of-function mutants in stat5.1 and stat5.2, two stat5 homologues existing in zebrafish. In stat5.1-deficient zebrafish, a significant reduction of body length and body weight was detected in the embryos/larvae and adults compared with the wild-type control fish, and sexual size dimorphism in adult zebrafish was also eliminated...
November 16, 2017: Journal of Genetics and Genomics, Yi Chuan Xue Bao
https://www.readbyqxmd.com/read/29235580/corrigendum-interleukin-7-induces-osteoclast-formation-via-stat5-independent-of-receptor-activator-of-nf-kappab-ligand
#18
Jin-Hee Kim, Ji Hyun Sim, Sunkyung Lee, Min A Seol, Sang-Kyu Ye, Hyun Mu Shin, Eun Bong Lee, Yun Jong Lee, Yun Jung Choi, Wan-Hee Yoo, Jin Hyun Kim, Wan-Uk Kim, Dong-Sup Lee, Jin-Hong Kim, Insoo Kang, Seong Wook Kang, Hang-Rae Kim
[This corrects the article on p. 1376 in vol. 8, PMID: 29104576.].
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29234062/development-of-erasin-a-chromone-based-stat3-inhibitor-which-induces-apoptosis-in-erlotinib-resistant-lung-cancer-cells
#19
Christian Lis, Stefan Rubner, Martin Roatsch, Angela Berg, Tyler Gilcrest, Darwin Fu, Elizabeth Nguyen, Anne-Marie Schmidt, Harald Krautscheid, Jens Meiler, Thorsten Berg
Inhibition of protein-protein interactions by small molecules offers tremendous opportunities for basic research and drug development. One of the fundamental challenges of this research field is the broad lack of available lead structures from nature. Here, we demonstrate that modifications of a chromone-based inhibitor of the Src homology 2 (SH2) domain of the transcription factor STAT5 confer inhibitory activity against STAT3. The binding mode of the most potent STAT3 inhibitor Erasin was analyzed by the investigation of structure-activity relationships, which was facilitated by chemical synthesis and biochemical activity analysis, in combination with molecular docking studies...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29228564/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#20
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
November 14, 2017: Oncotarget
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