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https://www.readbyqxmd.com/read/28817638/the-transcriptional-profiling-of-human-in-vivo-generated-plasma-cells-identifies-selective-imbalances-in-monoclonal-gammopathies
#1
Luis M Valor, Beatriz Rodríguez-Bayona, Ana B Ramos-Amaya, José A Brieva, Antonio Campos-Caro
Plasma cells (PC) represent the heterogeneous final stage of the B cells (BC) differentiation process. To characterize the transition of BC into PC, transcriptomes from human naïve BC were compared to those of three functionally-different subsets of human in vivo-generated PC: i) tonsil PC, mainly consisting of early PC; ii) PC released to the blood after a potent booster-immunization (mostly cycling plasmablasts); and, iii) bone marrow CD138+ PC that represent highly mature PC and include the long-lived PC compartment...
2017: PloS One
https://www.readbyqxmd.com/read/28814434/combined-cdk4-6-and-mtor-inhibition-is-synergistic-against-glioblastoma-via-multiple-mechanisms
#2
Inan Olmez, Breanna Brenneman, Aizhen Xiao, Vlad Serbulea, Mouadh Benamar, Ying Zhang, Laryssa Manigat, Tarek Abbas, Jeongwu Lee, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Roger Abounader, Norbert Leitinger, Benjamin Purow
PURPOSE: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. EXPERIMENTAL DESIGN: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed...
August 16, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28813415/cdk4-6-inhibition-triggers-anti-tumour-immunity
#3
Shom Goel, Molly J DeCristo, April C Watt, Haley BrinJones, Jaclyn Sceneay, Ben B Li, Naveed Khan, Jessalyn M Ubellacker, Shaozhen Xie, Otto Metzger-Filho, Jeremy Hoog, Matthew J Ellis, Cynthia X Ma, Susanne Ramm, Ian E Krop, Eric P Winer, Thomas M Roberts, Hye-Jung Kim, Sandra S McAllister, Jean J Zhao
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28812991/the-retinoblastoma-rb-tumor-suppressor-pushing-back-against-genome-instability-on-multiple-fronts
#4
REVIEW
Renier Vélez-Cruz, David G Johnson
The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F family of transcription factors and with chromatin remodelers and modifiers that contribute to the repression of genes important for cell cycle progression. Over the years, studies have shown that RB participates in multiple processes in addition to cell cycle control...
August 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28810933/microrna-152-suppresses-human-osteosarcoma-cell-proliferation-and-invasion-by-targeting-e2f-transcription-factor-3
#5
Chao Ma, Jinfeng Han, Dong Dong, Nanya Wang
MicroRNA-152(miR-152) expression has been reported to be downregulated in osteosarcoma (OS). However, the role of miR-152 in OS is not well documented. In the present study, we aim to explore the function and underlying mechanism of miR-152 in OS. We found that miR-152 was underexpressed in OS tissues and cell lines. Decreased miR-152 was inversely correlated with lymph-node metastasis and advanced clinical stage. Overexpression of miR-152 significantly inhibited cell proliferation, colony formation, migration and invasion of OS cells...
August 15, 2017: Oncology Research
https://www.readbyqxmd.com/read/28800675/discovery-and-pharmacological-characterisation-of-a-novel-series-of-highly-selective-inhibitors-of-cyclin-dependent-kinases-4-and-6-as-anticancer-agents
#6
Solomon Tadesse, Laychiluh Bantie, Khamis Tomusange, Mingfeng Yu, Saiful Islam, Nataliya Bykovska, Benjamin Noll, Ge Zhu, Peng Li, Frankie Lam, Malika Kumarasiri, Robert Milne, Shudong Wang
BACKGROUND AND PURPOSE: Cyclin D dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle, and are actively pursued as therapeutic targets in cancer targets. We sought to discover a novel series of orally bioavailable, and highly selective small molecule inhibitors of CDK4/6. EXPERIMENTAL APPROACH: The discovery of pharmacological inhibitors and optimisation for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis, and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F) regulated gene expression, and in vitro biopharmaceutical and in vivo pharmacokinetic profiling...
August 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28799433/cell-cycle-transcription-control-dream-muvb-and-rb-e2f-complexes
#7
Martin Fischer, Gerd A Müller
The precise timing of cell cycle gene expression is critical for the control of cell proliferation; de-regulation of this timing promotes the formation of cancer and leads to defects during differentiation and development. Entry into and progression through S phase requires expression of genes coding for proteins that function in DNA replication. Expression of a distinct set of genes is essential to pass through mitosis and cytokinesis. Expression of these groups of cell cycle-dependent genes is regulated by the RB pocket protein family, the E2F transcription factor family, and MuvB complexes together with B-MYB and FOXM1...
August 11, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28797103/effects-of-cancer-testis-antigen-tfdp3-on-cell-cycle-regulation-and-its-mechanism-in-l-02-and-hepg2-cell-lines-in-vitro
#8
Yunshen Jiao, Lingyu Ding, Ming Chu, Tieshan Wang, Jiarui Kang, Xiaofan Zhao, Huanhuan Li, Xi Chen, Zirui Gao, Likai Gao, Yuedan Wang
TFDP3, also be known as HCA661, was one of the cancer-testis antigens, which only expressed in human tissues. The recent researches about TFDP3 mostly focused on its ability to control the drug resistance and apoptosis of tumor cells. However, the role of TFDP3 in the progress of the cell cycle is rarely involved. In this study, we examined the expression of TFDP3 in human liver tissues firstly. After that, we detect the expression of TFDP3 at the RNA level and protein level in L-02 cell line and HepG2 cell line, and the location of TFDP3 was defined by immunofluorescence technique...
2017: PloS One
https://www.readbyqxmd.com/read/28794284/genomic-profiling-of-er-breast-cancers-after-short-term-estrogen-suppression-reveals-alterations-associated-with-endocrine-resistance
#9
Jennifer M Giltnane, Katherine E Hutchinson, Thomas P Stricker, Luigi Formisano, Christian D Young, Monica V Estrada, Mellissa J Nixon, Liping Du, Violeta Sanchez, Paula Gonzalez Ericsson, Maria G Kuba, Melinda E Sanders, Xinmeng J Mu, Eliezer M Van Allen, Nikhil Wagle, Ingrid A Mayer, Vandana Abramson, Henry Gόmez, Monica Rizzo, Weiyi Toy, Sarat Chandarlapaty, Erica L Mayer, Jason Christiansen, Danielle Murphy, Kerry Fitzgerald, Kai Wang, Jeffrey S Ross, Vincent A Miller, Phillip J Stephens, Roman Yelensky, Levi Garraway, Yu Shyr, Ingrid Meszoely, Justin M Balko, Carlos L Arteaga
Inhibition of proliferation in estrogen receptor-positive (ER(+)) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER(+)/human epidermal growth factor receptor 2-negative (HER2(-)) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28794159/p63%C3%AE-protein-upregulates-heat-shock-protein-70-expression-via-e2f1-transcription-factor-1-promoting-wasf3-wave3-mmp9-signaling-and-bladder-cancer-invasion
#10
Honglei Jin, Qipeng Xie, Xirui Guo, Jiheng Xu, Annette Wang, Jingxia Li, Junlan Zhu, Xue-Ru Wu, Haishan Huang, Chuanshu Huang
Bladder cancer (BC) is the sixth most common cancer in the United States and is the number one cause of death among patients with urinary system malignancies. This makes the identification of invasive regulator(s)/effector(s) as the potential therapeutic targets for managing BC a high priority. p63 is a member of the p53 family of tumor suppressor genes/proteins, plays a role in the differentiation of epithelial tissues, and is believed to function as a tumor suppressor. However, whether and how p63 functions in BC cell invasion after tumorigenesis remains unclear...
August 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28775339/unraveling-a-tumor-type-specific-regulatory-core-underlying-e2f1-mediated-epithelial-mesenchymal-transition-to-predict-receptor-protein-signatures
#11
Faiz M Khan, Stephan Marquardt, Shailendra K Gupta, Susanne Knoll, Ulf Schmitz, Alf Spitschak, David Engelmann, Julio Vera, Olaf Wolkenhauer, Brigitte M Pützer
Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial-mesenchymal transition in bladder and breast cancer...
August 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/28754846/overexpression-of-the-e2f-target-gene-cenpi-promotes-chromosome-instability-and-predicts-poor-prognosis-in-estrogen-receptor-positive-breast-cancer
#12
Pulari U Thangavelu, Cheng-Yu Lin, Srividya Vaidyanathan, Thu H M Nguyen, Eloise Dray, Pascal H G Duijf
During cell division, chromosome segregation is facilitated by the mitotic checkpoint, or spindle assembly checkpoint (SAC), which ensures correct kinetochore-microtubule attachments and prevents premature sister-chromatid separation. It is well established that misexpression of SAC components on the outer kinetochores promotes chromosome instability (CIN) and tumorigenesis. Here, we study the expression of CENP-I, a key component of the HIKM complex at the inner kinetochores, in breast cancer, including ductal, lobular, medullary and male breast carcinomas...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28751617/cdk4-6-inhibition-is-more-active-against-the-glioblastoma-proneural-subtype
#13
Ming Li, Aizhen Xiao, Desiree Floyd, Inan Olmez, Jeongwu Lee, Jakub Godlewski, Agnieszka Bronisz, Krishna P L Bhat, Erik P Sulman, Ichiro Nakano, Benjamin Purow
Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17~92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM...
July 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28751448/association-of-fgfr1-with-er%C3%AE-maintains-ligand-independent-er-transcription-and-mediates-resistance-to-estrogen-deprivation-in-er-breast-cancer
#14
Luigi Formisano, Kimberly Mae Stauffer, Christian D Young, Neil E Bhola, Angel L Guerrero-Zotano, Valerie M Jansen, Monica M Estrada, Katherine E Hutchinson, Jennifer M Giltnane, Luis J Schwarz, Yao Lu, Justin M Balko, Olivier Deas, Stefano Cairo, Jean-Gabriel Judde, Ingrid A Mayer, Melinda Sanders, Teresa C Dugger, Roberto Bianco, Thomas Stricker, Carlos L Arteaga
FGFR1 amplification occurs in ~15% of ER+ human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer.<br /><br />Experimental Design: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 immunohistochemistry, FGFR1 FISH, and RNA-sequencing. ER+/FGFR1 amplified breast cancer cells and patient-derived xenografts (PDXs) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib...
July 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28742236/xylem-nac-domain1-an-angiosperm-nac-transcription-factor-inhibits-xylem-differentiation-through-conserved-motifs-that-interact-with-retinoblastoma-related
#15
Chengsong Zhao, Theres Lasses, Laszlo Bako, Danyu Kong, Bingyu Zhao, Bidisha Chanda, Aureliano Bombarely, Alfredo Cruz-Ramírez, Ben Scheres, Amy M Brunner, Eric P Beers
The Arabidopsis thaliana gene XYLEM NAC DOMAIN1 (XND1) is upregulated in xylem tracheary elements. Yet overexpression of XND1 blocks differentiation of tracheary elements. The molecular mechanism of XND1 action was investigated. Phylogenetic and motif analyses indicated that XND1 and its homologs are present only in angiosperms and possess a highly conserved C-terminal region containing linear motifs (CKII-acidic, LXCXE, E2F(TD) -like and LXCXE-mimic) predicted to interact with the cell cycle and differentiation regulator RETINOBLASTOMA-RELATED (RBR)...
July 25, 2017: New Phytologist
https://www.readbyqxmd.com/read/28740578/clinical-performance-of-e2fs-1-3-in-kidney-clear-cell-renal-cancer-evidence-from-bioinformatics-analysis
#16
Bin Liang, Jianying Zhao, Xuan Wang
Extensive research on the E2F transcription factor family has led to numerous insights that E2Fs were involved not only in proliferation and tumorigenesis but also in apoptosis and differentiation. In the present study, we analyzed the differential expression of E2Fs1-3 genes, and also evaluated the impact of E2Fs 1-3 genes expression on clinical outcome from the Cancer Genome Atlas (TCGA) database. The results showed that E2F1, E2F2 and E2F3 expression was increased in KIRC tissues than matched normal tissues (E2F1, P < 0...
May 2017: Genes & Cancer
https://www.readbyqxmd.com/read/28740501/hac1-and-haf1-histone-acetyltransferases-have-different-roles-in-uv-b-responses-in-arabidopsis
#17
Julieta P Fina, Fiorella Masotti, Sebastián P Rius, Franco Crevacuore, Paula Casati
Arabidopsis has 12 histone acetyltransferases grouped in four families: the GNAT/HAG, the MYST/HAM, the p300/CBP/HAC and the TAFII250/HAF families. We previously showed that ham1 and ham2 mutants accumulated higher damaged DNA after UV-B exposure than WT plants. In contrast, hag3 RNA interference transgenic plants showed less DNA damage and lower inhibition of plant growth by UV-B, and increased levels of UV-B-absorbing compounds. These results demonstrated that HAM1, HAM2, and HAG3 participate in UV-B-induced DNA damage repair and signaling...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28723554/hypoxia-sensitive-commd1-integrates-signaling-and-cellular-metabolism-in-human-macrophages-and-suppresses-osteoclastogenesis
#18
Koichi Murata, Celestia Fang, Chikashi Terao, Eugenia G Giannopoulou, Ye Ji Lee, Min Joon Lee, Se-Hwan Mun, Seyeon Bae, Yu Qiao, Ruoxi Yuan, Moritoshi Furu, Hiromu Ito, Koichiro Ohmura, Shuichi Matsuda, Tsuneyo Mimori, Fumihiko Matsuda, Kyung-Hyun Park-Min, Lionel B Ivashkiv
Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-κB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis...
July 18, 2017: Immunity
https://www.readbyqxmd.com/read/28701722/asxl1-deficiency-in-embryonic-fibroblasts-leads-to-cellular-senescence-via-impairment-of-the-akt-e2f-pathway-and-ezh2-inactivation
#19
Hye Sook Youn, Tae-Yoon Kim, Ui-Hyun Park, Seung-Tae Moon, So-Jung An, Yong-Kyu Lee, Jin-Taek Hwang, Eun-Joo Kim, Soo-Jong Um
Although ASXL1 mutations are frequently found in human diseases, including myeloid leukemia, the cell proliferation-associated function of ASXL1 is largely unknown. Here, we explored the molecular mechanism underlying the growth defect found in Asxl1-deficient mouse embryonic fibroblasts (MEFs). We found that Asxl1, through amino acids 371 to 655, interacts with the kinase domain of AKT1. In Asxl1-null MEFs, IGF-1 was unable to induce AKT1 phosphorylation and activation; p27Kip1, which forms a ternary complex with ASXL1 and AKT1, therefore remained unphosphorylated...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698574/an-e2f1-mir-17-92-negative-feedback-loop-mediates-proliferation-of-mouse-palatal-mesenchymal-cells
#20
Ling Li, Bing Shi, Jin Chen, Chunhua Li, Shaoxin Wang, Zhaohui Wang, Guiquan Zhu
Normal cell cycle progression and proliferation of palatal mesenchymal cells are important for palatal development. As targets of miR-17-92, E2F transcription factors family has been suggested to induce the transcription of miR-17-92 in several cell types. In the present study, we sought to investigate whether this negative feedback loop exists in mouse PMCs and what the function of this negative feedback loop would be in palatal mesenchymal cells. Using GeneMANIA, we revealed that the most important function of experimentally verified targets of miR-17-92 is cell cycle regulation...
July 11, 2017: Scientific Reports
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