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https://www.readbyqxmd.com/read/28821558/defective-cyclin-b1-induction-in-trastuzumab-emtansine-t-dm1-acquired-resistance-in-her2-positive-breast-cancer
#1
MohammadA Sabbaghi, Gabriel Gil-Gómez, Cristina Guardia, Sonia Servitja, Oriol Arpi, Sara García-Alonso, Silvia Menéndez, Montserrat Arumi-Uria, Laia Serrano, Marta Salido, Aura Muntasell, Maria Martinez-Garcia, Sandra Zazo, Cristina Chamizo, Paula González-Alonso, Juan Madoz-Gúrpide, Pilar Eroles, Joaquin Arribas, Ignasi Tusquets, Ana Lluch, Atanasio Pandiella, Federico Rojo, Ana Rovira, Joan Albanell
Purpose: Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2 positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance. <p>Experimental Design: HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3 and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28820331/polo-like-kinase-1-plk1-dependent-phosphorylation-of-methylenetetrahydrofolate-reductase-mthfr-regulates-replication-via-histone-methylation
#2
Xueyan Li, Shanshan Nai, Yuehe Ding, Qizhi Geng, Bingtao Zhu, Kai Yu, Wei-Guo Zhu, Meng-Qiu Dong, Xiao-Dong Su, Xingzhi Xu, Jing Li
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the folate cycle and its genetic variations have been associated with various human diseases. Previously we identified that MTHFR is phosphorylated by cyclin-dependent kinase 1 (CDK1) at T34 and MTHFR underlies heterochromatin maintenance marked by H3K9me3 levels. Herein we demonstrate that pT34 creates a binding motif that docks MTHFR to the polo-binding domain (PBD) of polo-like kinase 1 (PLK1), a fundamental kinase that orchestrates many cell cycle events...
August 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28817102/anticancer-activity-of-ramalin-a-secondary-metabolite-from-the-antarctic-lichen-ramalina-terebrata-against-colorectal-cancer-cells
#3
Sung-Suk Suh, Tai Kyoung Kim, Jung Eun Kim, Ju-Mi Hong, Trang Thu Thi Nguyen, Se Jong Han, Ui Joung Youn, Joung Han Yim, Il-Chan Kim
Colorectal cancer is a leading cause of death worldwide and occurs through the highly complex coordination of multiple cellular pathways, resulting in carcinogenesis. Recent studies have increasingly revealed that constituents of lichen extracts exhibit potent pharmaceutical activities, including anticancer activity against various cancer cells, making them promising candidates for new anticancer therapeutic drugs. The main objective of this study was to evaluate the anticancer capacities of ramalin, a secondary metabolite from the Antarctic lichen Ramalina terebrata, in the human colorectal cancer cell line HCT116...
August 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28815566/maturation-promoting-factor-destabilization-mediates-human-chorionic-gonadotropin-induced-meiotic-resumption-in-rat-oocytes
#4
Meenakshi Tiwari, Shail K Chaube
Human chorionic gonadotropin (hCG) mimics the action of luteinizing hormone (LH) and triggers meiotic maturation and ovulation in mammals. The mechanism by which hCG triggers meiotic resumption in mammalian oocytes remains poorly understood. We aimed to find out the impact of hCG surge on morphological changes, adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), cell division cycle 25B (Cdc25B), Wee1, early mitotic inhibitor 2 (Emi2), anaphase-promoting complex/cyclosome (APC/C), meiotic arrest deficient protein 2 (MAD2), phosphorylation status of cyclin-dependent kinase 1 (Cdk1), its activity and cyclin B1 expression levels during meiotic resumption from diplotene as well as metaphase-II (M-II) arrest in cumulus oocyte complexes (COCs)...
August 16, 2017: Development, Growth & Differentiation
https://www.readbyqxmd.com/read/28808311/antitumor-properties-of-coenzyme-q0-against-human-ovarian-carcinoma-cells-via-induction-of-ros-mediated-apoptosis-and-cytoprotective-autophagy
#5
You-Cheng Hseu, Tai-Jung Tsai, Mallikarjuna Korivi, Jer-Yuh Liu, Hui-Jye Chen, Chung-Ming Lin, Yi-Chun Shen, Hsin-Ling Yang
Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone) has been reported to exert anticancer properties against human breast/lung cancer cells. This study investigated the in vitro and in vivo anticancer properties of CoQ0 on human ovarian carcinoma (SKOV-3) cells and xenografted nude mice, and revealed the underlying molecular mechanism. CoQ0 induced G2/M arrest through downregulation of cyclin B1/A and CDK1/K2 expressions. CoQ0-induced autophagy as a survival mechanism was evidenced by increased accumulation of LC3-II, GFP-LC3 puncta, AVOs formation and Beclin-1/Bcl-2 dysregulation...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808045/fighting-tubulin-targeting-anticancer-drug-toxicity-and-resistance
#6
REVIEW
Roberta Visconti, Domenico Grieco
Tubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti-microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD efficacy, reducing the acquisition of resistance by the tumor and side effects from the drug and/or its vehicle...
September 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28804952/evaluation-of-cytotoxicity-of-propofol-and-its-related-mechanism-in-glioblastoma-cells-and-astrocytes
#7
Shu-Shong Hsu, Chung-Ren Jan, Wei-Zhe Liang
Propofol (2,6-diisopropylphenol), one of the extensively and commonly used anesthetic agents, has been shown to affect the biological behavior of various models. Previous researches have shown that propofol-induced cytotoxicity might cause anticancer effect in different cells. However, the mechanisms underlying the effect of propofol on cytotoxicity is still elusive in human glioblastoma cells. The aims of this study were to evaluate effects of propofol on cytotoxicity, cell cycle distribution and ROS production, and establish the relationship between oxidative stress and cytotoxicity in GBM 8401 human glioblastoma cells and DI TNC1 rat astrocytes...
August 14, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/28792760/structural-basis-of-wee-kinases-functionality-and-inactivation-by-diverse-small-molecule-inhibitors
#8
Jin-Yi Zhu, Rebecca Ann Duenes Cuellar, Norbert Berndt, Hee Eun Lee, Sanne H Olesen, Mathew P Martin, Jeffrey T Jensen, Gunda I Georg, Ernst Schönbrunn
Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure-function relationship of human Wee1, Wee2 and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency suggesting complex mechanisms of activation. A series of crystal structures revealed unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775...
August 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28790110/replication-stress-leading-to-apoptosis-within-the-s-phase-contributes-to-synergism-between-vorinostat-and-azd1775-in-hnscc-harboring-high-risk-tp53-mutation
#9
Noriaki Tanaka, Ameeta A Patel, Lin Tang, Natalie L Silver, Antje Lindemann, Hideaki Takahashi, Roman Jaksik, Xiayu Rao, Nene N Kalu, Tseng-Cheng Chen, Jiping Wang, Mitchell J Frederick, Faye M Johnson, Frederico Gleber-Netto, Siqing Fu, Marek Kimmel, Jing Wang, Walter N Hittelman, Curtis R Pickering, Jeffrey N Myers, Abdullah A Osman
Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. Since mutation of TP53 in HNSCC occurs in 60-80% of non-HPV associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. <p>Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28780319/cdk1-mediated-mitotic-phosphorylation-of-pbk-is-involved-in-cytokinesis-and-inhibits-its-oncogenic-activity
#10
Seth Stauffer, Yongji Zeng, Jiuli Zhou, Xingcheng Chen, Yuanhong Chen, Jixin Dong
PDZ-binding kinase (PBK) plays a major role in proliferation and in safeguarding mitotic fidelity in cancer cells. Frequently upregulated in many cancers, PBK drives tumorigenesis and metastasis. PBK has been shown to be phosphorylated in mitosis by cyclin-dependent kinase 1 (CDK1)/cyclin B, however, no studies have been done examining PBK mitotic phosphorylation in oncogenesis. Additionally to the previously identified Threonine-9 phosphorylation, we found that Threonine-24, Serine-32, and Serine-59 of PBK are also phosphorylated...
August 3, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28776765/s-cerevisiae-gle2-rae1-is-involved-in-septin-organization-essential-for-cell-cycle-progression
#11
Gesa Zander, Wilfried Kramer, Anika Seel, Heike Krebber
Gle2/Rae1 is highly conserved from yeast to humans and described as an mRNA export factor. Additionally, it is implicated in the anaphase-promoting complex (APC)-mediated cell cycle regulation in higher eukaryotes. Here we identified an involvement for S. cerevisiae Gle2 in septin organization, which is crucial for cell cycle progression and cell division. Gle2 genetically and physically interacts with components of the septin-ring. Importantly, deletion of GLE2 leads to elongated buds, severe defects in septin-assembly and their cellular mislocalization...
August 4, 2017: Yeast
https://www.readbyqxmd.com/read/28774892/dialogue-between-centrosomal-entrance-and-exit-scaffold-pathways-regulates-mitotic-commitment
#12
Kuan Yoow Chan, Marisa Alonso-Nuñez, Agnes Grallert, Kayoko Tanaka, Yvonne Connolly, Duncan L Smith, Iain M Hagan
The fission yeast scaffold molecule Sid4 anchors the septum initiation network to the spindle pole body (SPB, centrosome equivalent) to control mitotic exit events. A second SPB-associated scaffold, Cut12, promotes SPB-associated Cdk1-cyclin B to drive mitotic commitment. Signals emanating from each scaffold have been assumed to operate independently to promote two distinct outcomes. We now find that signals from Sid4 contribute to the Cut12 mitotic commitment switch. Specifically, phosphorylation of Sid4 by NIMA(Fin1) reduces Sid4 affinity for its SPB anchor, Ppc89, while also enhancing Sid4's affinity for casein kinase 1δ (CK1δ)...
August 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28771906/cdk1-interacting-protein-cip1-is-regulated-by-the-s%C3%A2-phase-checkpoint-in-response-to-genotoxic-stress
#13
Ze Zhang, Ping Ren, Ajay A Vashisht, James A Wohlschlegel, David G Quintana, Fanli Zeng
In eukaryotic cells, a surveillance mechanism, the S phase checkpoint, detects and responds to insults that challenge chromosomal replication, arresting cell cycle progression and triggering appropriate events to prevent genomic instability. In the budding yeast Saccharomyces cerevisiae, Mec1/ATM/ATR, and its downstream kinase, Rad53/Chk2, mediate the response to genotoxic stress. In this study, we place Cip1, a recently identified Cdk1 inhibitor (CKI), under the regulation of Mec1 and Rad53 in response to genotoxic stress...
August 3, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28763745/carbenoxolone-reduces-cyclic-nucleotides-level-destabilizes-maturation-promoting-factor-and-induces-meiotic-exit-from-diplotene-arrest-in-rat-cumulus-oocytes-complexes-cultured-in-vitro
#14
Meenakshi Tiwari, Shail K Chaube
BACKGROUND: Disruption of gap junction and transfer of cyclic nucleotides to the oocyte lead to meiotic exit from diplotene arrest (EDA) in mammals. In the present study, we examined whether a gap junction blocker, carbenoxolone (CBX) could induce EDA by reducing cyclic nucleotides level and destabilizing maturation promoting factor (MPF) in rat oocytes cultured in vitro. METHODS: Diplotene-arrested cumulus oocyte complexes (COCs) were collected from ovary of immature female rats after 20 IU pregnant mare's serum gonadotropins (PMSG) for 48h...
July 29, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28761362/targeted-tpx2-increases-chromosome-missegregation-and-suppresses-tumor-cell-growth-in-human-prostate-cancer
#15
Hung-Wei Pan, Hsing-Hao Su, Chao-Wen Hsu, Guan-Jin Huang, Tony Tong-Lin Wu
Prostate cancer is a complex disease that can be relatively harmless or extremely aggressive. Although androgen-deprivation therapy is a commonly used treatment for men with prostate cancer, the adverse effects can be detrimental to patient health and quality of life. Therefore, identifying new target genes for tumor growth will enable the development of novel therapeutic intervention. TPX2 plays a critical role in chromosome segregation machinery during mitosis. Low rates of chromosome missegregation can promote tumor development, whereas higher levels might promote cell death and suppress tumorigenesis...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28757065/design-and-synthesis-of-piperazine-acetate-podophyllotoxin-ester-derivatives-targeting-tubulin-depolymerization-as-new-anticancer-agents
#16
Wen-Xue Sun, Ya-Jing Ji, Yun Wan, Hong-Wei Han, Hong-Yan Lin, Gui-Hua Lu, Jin-Liang Qi, Xiao-Ming Wang, Yong-Hua Yang
In this paper, a series of podophyllotoxin piperazine acetate ester derivatives were synthesized and investigated due to their antiproliferation activity on different human cancer cell lines. Among the congeners, C5 manifested prominent cytotoxicity towards the cancer cells, without causing damage on the non-cancer cells through inhibiting tubulin assembly and having high selectively causing damage on the human breast (MCF-7) cell line (IC50=2.78±0.15μM). Treatments of MCF-7 cells with C5 resulted in cell cycle arrest in G2/M phase and microtubule network disruption...
July 20, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28747658/a-single-amino-acid-substitution-confers-b-cell-clonogenic-activity-to-the-hiv-1-matrix-protein-p17
#17
Cinzia Giagulli, Pasqualina D'Ursi, Wangxiao He, Simone Zorzan, Francesca Caccuri, Kristen Varney, Alessandro Orro, Stefania Marsico, Benoît Otjacques, Carlo Laudanna, Luciano Milanesi, Riccardo Dolcetti, Simona Fiorentini, Wuyuan Lu, Arnaldo Caruso
Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha)...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28740209/novel-risk-genes-for-systemic-lupus-erythematosus-predicted-by-random-forest-classification
#18
Jonas Carlsson Almlöf, Andrei Alexsson, Juliana Imgenberg-Kreuz, Lina Sylwan, Christofer Bäcklin, Dag Leonard, Gunnel Nordmark, Karolina Tandre, Maija-Leena Eloranta, Leonid Padyukov, Christine Bengtsson, Andreas Jönsen, Solbritt Rantapää Dahlqvist, Christopher Sjöwall, Anders A Bengtsson, Iva Gunnarsson, Elisabet Svenungsson, Lars Rönnblom, Johanna K Sandling, Ann-Christine Syvänen
Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28739725/high-efficient-screening-method-for-identification-of-key-genes-in-breast-cancer-through-microarray-and-bioinformatics
#19
Zihao Liu, Gehao Liang, Luyuan Tan, A N Su, Wenguo Jiang, Chang Gong
BACKGROUND/AIM: The aim of the present study was to identify key pathways and genes in breast cancer and develop a new method for screening key genes with abnormal expression based on bioinformatics. MATERIALS AND METHODS: Three microarray datasets GSE21422, GSE42568 and GSE45827 were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were analyzed using GEO2R. The gene ontology (GO) and pathway enrichment analysis were established through DAVID database...
August 2017: Anticancer Research
https://www.readbyqxmd.com/read/28723571/emi2-is-essential-for-mouse-spermatogenesis
#20
Lakshmi Gopinathan, Radoslaw Szmyd, Diana Low, M Kasim Diril, Heng-Yu Chang, Vincenzo Coppola, Kui Liu, Lino Tessarollo, Ernesto Guccione, Ans M M van Pelt, Philipp Kaldis
The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated knockout mice to determine the in vivo functions of Emi2-in particular, its functions in the testis, where Emi2 is expressed at high levels. Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions...
July 18, 2017: Cell Reports
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