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https://www.readbyqxmd.com/read/28439015/mutant-p53-perturbs-dna-replication-checkpoint-control-through-topbp1-and-treslin
#1
Kang Liu, Fang-Tsyr Lin, Joshua D Graves, Yu-Ju Lee, Weei-Chin Lin
Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress...
April 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28436418/oxoaporphine-metal-complexes-co-ii-ni-ii-zn-ii-with-high-antitumor-activity-by-inducing-mitochondria-mediated-apoptosis-and-s-phase-arrest-in-hepg2
#2
Jiao-Lan Qin, Wen-Ying Shen, Zhen-Feng Chen, Li-Fang Zhao, Qi-Pin Qin, Yan-Cheng Yu, Hong Liang
Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1-3 have been synthesized and fully characterized. 1-3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1-3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80-3 and SK-OV-3/DDP cells, with IC50 value of 0.23-4.31 μM. Interestingly, 0.5 μM 1-3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28435396/lentivirus-mediated-knockdown-of-p27rf-rho-inhibits-hepatocellular-carcinoma-cell-growth
#3
Shuli Xie, Guangyi Wang, Guofu Chen, Mingguang Zhu, Guoyue Lv
AIM OF THE STUDY: To investigate the effects of P27RF-Rho on hepatocellular carcinoma (HCC) cell growth and explore the possibility of using it as a novel therapeutic target for liver cancer treatment. MATERIAL AND METHODS: P27RF-Rho in HCC cells was silenced by lentivirus-mediated RNA interference, and the silencing effect was verified by RT-PCR. Cell proliferation was determined by MTT and clone formation assay. Cell cycle phase and apoptosis were detected through FACS...
2017: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/28430399/targeting-conformational-activation-of-cdk2-kinase
#4
Morgan Pellerano, Sergey Tcherniuk, Corine Perals, Thi Nhu Ngoc Van, Elsa Garcin, Florence Mahuteau-Betzer, Marie-Paule Teulade-Fichou, May C Morris
Cyclin-dependent kinases constitute attractive pharmacological targets for cancer therapeutics, yet inhibitors in clinical trials target the ATP-binding pocket of the CDK and therefore suffer from limited selectivity and emergence of resistance. The more recent development of allosteric inhibitors targeting conformational plasticity of protein kinases offers promising perspectives for therapeutics. In particular tampering with T-loop dynamics of CDK2 kinase would provide a selective means of inhibiting this kinase, by preventing its conformational activation...
April 21, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/28420180/synthesis-and-antiproliferative-activity-of-novel-all-trans-retinoic-acid-podophyllotoxin-conjugate-towards-human-gastric-cancer-cells
#5
Lei Zhang, Jing Wang, Lai Liu, Chengyue Zheng, Yang Wang
With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel all-trans-retinoic acid (ATRA) conjugate with podophyllotoxin (PPT) was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell lines using CCK-8 assay. The conjugate, P-A, exhibited significant anticancer activity against MKN-45 and BGC-823 cells with IC50 values of 0.419 ± 0.032 and 0.202 ± 0.055 μM, respectively. Moreover, P-A efficiently triggered cell cycle arrest and induced apoptosis in MKN-45 and BGC-823 cells due to modulation of cell cycle arrest- (CDK1, CDK2, CyclinA and CyclinB1) and apoptosis- (cleaved caspase-3, -8 and -9) related proteins, respectively...
April 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28414550/expression-of-long-noncoding-rna-urothelial-cancer-associated-1-promotes-cisplatin-resistance-in-cervical-cancer
#6
Bi Wang, Zhi Huang, Rui Gao, Zhu Zeng, Weiming Yang, Yuan Sun, Wei Wei, Zhongqing Wu, Lei Yu, Qinshan Li, Shuai Zhang, Fenghu Li, Guoli Liu, Bingjie Liu, Li Leng, Wei Zhan, Yanlong Yu, Guozhen Yang, Shi Zhou
Cisplatin resistance is still one of the main reasons for failure of clinical therapy for cervical cancer. But the underlying molecular mechanisms involved in cisplatin resistance of cervical cancer have still remained unclear. Recent studies reported that long noncoding RNAs (lncRNAs) are novel nonprotein-coding transcripts, which might play a key role in cancer biogenesis and prognosis. One of the lncRNAs, urothelial cancer associated 1 (UCA1), has been shown to promote different types of cancer cell proliferation, migration, and invasion...
April 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28412739/retinoic-acid-receptor-alpha-drives-cell-cycle-progression-and-is-associated-with-increased-sensitivity-to-retinoids-in-t-cell-lymphoma
#7
Xueju Wang, Surendra Dasari, Grzegorz S Nowakowski, Konstantinos N Lazaridis, Eric D Wieben, Marshall E Kadin, Andrew L Feldman, Rebecca L Boddicker
Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with generally poor outcomes following standard therapy. Few candidate therapeutic targets have been identified to date. Retinoic acid receptor alpha (RARA) is a transcription factor that modulates cell growth and differentiation in response to retinoids. While retinoids have been used to treat some cutaneous T-cell lymphomas (CTCLs), their mechanism of action and the role of RARA in CTCL and other mature T-cell lymphomas remain poorly understood...
February 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28402920/mirna-200c-enhances-radiosensitivity-of-esophageal-cancer-by-cell-cycle-arrest-and-targeting-p21
#8
Ruzhen Zheng, Yuehua Liu, Xiaoling Zhang, Pengjun Zhao, Qinghua Deng
Esophageal squamous cancer is one of the most fatal malignancies and often suffer recurrence after radiotherapy. Downregulation of miRNA-200c is associated with radiotolerance. We aim to investigate the role of miRNA-200c in radiosensitivity and develop a systemic treatment strategy for esophageal squamous cancer. Overexpression of miRNA-200c by transfection was determined by RT-PCR. Radiosensitizing effect of miRNA-200c on esophageal squamous cancer cells was determined by clonogenic assay and xenograft model...
April 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28402259/the-design-of-novel-inhibitors-for-treating-cancer-by-targeting-cdc25b-through-disruption-of-cdc25b-cdk2-cyclin-a-interaction-using-computational-approaches
#9
Hong-Lian Li, Ying Ma, Ying Ma, Yu Li, Xiu-Bo Chen, Wei-Li Dong, Run-Ling Wang
Cell division cycle 25B is a key cell cycle regulator and widely considered as potent clinical drug target for cancers. This research focused on identifying potential compounds in theory which are able to disrupt transient interactions between CDC25B and its CDK2/Cyclin A substrate.By using the method of ZDOCK and RDOCK, the most optimized 3D structure of CDK2/Cyclin A in complex with CDC25B was constructed and validated using two methods: 1) the superimposition of proteins; 2) analysis of the hydrogen bond distances of Arg 488(N1)-Asp 206(OD1), Arg 492(NE)-Asp 206(OD1), Arg 492(N1)-Asp 206(OD2) and Tyr 497(NE)-Asp 210(OD1)...
March 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28387346/plk1-regulates-the-repressor-function-of-foxm1b-by-inhibiting-its-interaction-with-the-retinoblastoma-protein
#10
Nishit K Mukhopadhyay, Vaibhav Chand, Akshay Pandey, Dragana Kopanja, Janai R Carr, Yi-Ju Chen, Xiubei Liao, Pradip Raychaudhuri
FoxM1b is a cell cycle-regulated transcription factor, whose over-expression is a marker for poor outcome in cancers. Its transcriptional activation function requires phosphorylation by Cdk1 or Cdk2 that primes FoxM1b for phosphorylation by Plk1, which triggers association with the co-activator CBP. FoxM1b also possesses transcriptional repression function. It represses the mammary differentiation gene GATA3 involving DNMT3b and Rb. We investigated what determines the two distinct functions of FoxM1b: activation and repression...
April 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28386317/alisertib-induces-g2-m-arrest-apoptosis-and-autophagy-via-pi3k-akt-mtor-and-p38-mapk-mediated-pathways-in-human-glioblastoma-cells
#11
Zheng Liu, Feng Wang, Zhi-Wei Zhou, He-Chun Xia, Xin-Yu Wang, Yin-Xue Yang, Zhi-Xu He, Tao Sun, Shu-Feng Zhou
Glioblastoma (GBM) is the most common brain tumor with poor response to current therapeutics. Alisertib (ALS), a second-generation selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects on solid tumors in animal studies. This study aimed to investigate the killing effect of ALS on GBM cell line DAOY and the possible underlying mechanisms using both bioinformatic and cell-based approaches. Our molecular docking showed that ALS preferentially bound AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28384515/pm2-5-induced-alterations-of-cell-cycle-associated-gene-expression-in-lung-cancer-cells-and-rat-lung-tissues
#12
Hui Zhao, Biao Yang, Jia Xu, Dong-Mei Chen, Chun-Ling Xiao
The aim of the current study was to investigate the expression of cell cycle-associated genes induced by fine particulate matter (PM2.5) in lung cancer cell line and tissues. The pulmonary lymph node metastasis cells (H292) were treated with PM2.5in vitro. Wistar rats were used to perform an in vivo study. Rats were randomly assigned to experiment and control groups and those in the experiment group were exposed to PM2.5 once every 15 d, while those in the control group were exposed to normal saline. The cell cycle-associated genes expression was analyzed by real-time PCR...
March 24, 2017: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/28376145/next-generation-cdk2-9-inhibitors-and-anaphase-catastrophe-in-lung-cancer
#13
Masanori Kawakami, Lisa Maria Mustachio, Jaime Rodriguez-Canales, Barbara Mino, Jason Roszik, Pan Tong, Jing Wang, J Jack Lee, Ja Hye Myung, John V Heymach, Faye M Johnson, Seungpyo Hong, Lin Zheng, Shanhu Hu, Pamela Andrea Villalobos, Carmen Behrens, Ignacio Wistuba, Sarah Freemantle, Xi Liu, Ethan Dmitrovsky
Background: The first generation CDK2/7/9 inhibitor seliciclib (CYC202) causes multipolar anaphase and apoptosis in lung cancer cells with supernumerary centrosomes (known as anaphase catastrophe). We investigated a new and potent CDK2/9 inhibitor, CCT68127 (Cyclacel). Methods: CCT68127 was studied in lung cancer cells (three murine and five human) and control murine pulmonary epithelial and human immortalized bronchial epithelial cells. Robotic CCT68127 cell-based proliferation screens were used...
June 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28374118/structural-insight-into-the-mechanism-of-dibenzo-a-l-pyrene-and-benzo-a-pyrene-mediated-cell-proliferation-using-molecular-docking-simulations
#14
M Kalim A Khan, Salman Akhtar, Jamal M Arif
In the proposed work, we have explicated the mechanism of dibenzo[a,l]pyrene (DBP) and benzo[a]pyrene (BP) modulated cell proliferation by assessing the plausible binding with CASPASES, BAX, Bcl-2, MDM2, p53, p21, p16, CylinD1-CDK4 complex, CylinE1-CDK2 complex, H-Ras, K-Ras, BRCA1, and BRCA2 through exploiting the inherent potential of AutoDock Tools 4.0. In silico findings revealed that potent carcinogenic metabolites of DBP (e.g., (-)-anti-DBPDE and (+)-syn-DBPDE) and BP (e.g., (+)-anti-BPDE) exhibited better binding interactions to Caspase-9 than Caspase-8 and Caspase-3...
April 3, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28368432/effect-of-electrostatic-polarization-and-bridging-water-on-cdk2-ligand-binding-affinities-calculated-using-a-highly-efficient-interaction-entropy-method
#15
Lili Duan, Guoqiang Feng, Xianwei Wang, Lizhi Wang, Qinggang Zhang
A new highly efficient interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field is employed to investigate the interaction mechanism of CDK2-ligand binding and the effect of the bridging water. Our result shows that the computed binding free energies for five CDK2-ligand complexes using the IE method have a significantly linear correlation with the experimentally measured values with a correlation coefficient of 0.98 in consideration of the bridging water under the PPC force field...
April 12, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28368414/tgf%C3%AE-engages-mek-erk-to-differentially-regulate-benign-and-malignant-pancreas-cell-function
#16
D R Principe, A M Diaz, C Torres, R J Mangan, B DeCant, R McKinney, M-S Tsao, A Lowy, H G Munshi, B Jung, P J Grippo
While TGFβ signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFβ appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFβ pathway, we first generated mouse models of neoplastic disease with TGFβ receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFβ led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFβ-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFβ-induced EMT...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28356009/ecpirm-a-potential-therapeutic-agent-for-cutaneous-t-cell-lymphoma-inhibits-cell-proliferation-and-promotes-apoptosis-via-a-jak-stat-pathway-the-biological-effect-of-ecpirm-in-ctcl-cell
#17
Hua Yang, Pengcheng Ma, Yuping Cao, Mengli Zhang, Lingjun Li, Jun Wei, Lei Tao, Kun Qian
BACKGROUND: Retinoids are important agents for treatment of cutaneous T-cell lymphomas (CTCL). But side effects and drug resistance caused by activation of RAR/RXR limited their clinical application. So it is urgent to develop new agents fight against CTCL. ECPIRM, a 13-cis retinoic acid derivative, was reported that it inhibited proliferation and induced apoptosis of SCL-1 cells. OBJECTIVE: To evaluated the biological activities and mechanisms of ECPIEM. METHODS: Effect of ECPIRM on cell proliferation was determined by MTT assay and Trypan blue exclusion assay while FACS analysis was used to detect changes of cell cycle and apoptosis in HUT78 cells...
March 27, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28350126/g%C3%A2-protein-subunit-%C3%AE-q-regulates-gastric-cancer-growth-via-the-p53-p21-and-mek-erk-pathways
#18
Yizhuo Wang, Huijie Xiao, Haitao Wu, Cheng Yao, Hua He, Chang Wang, Wei Li
Genetic alterations in G protein subunit α q (GNAQ) have been reported in numerous types of human cancer. However, the role of GNAQ in human gastric cancer (GC) has not been explored. In the present study, we found that GNAQ was highly expressed in GC patient samples and GNAQ expression was related to patient age, GC differentiation status and adjuvant therapy, as determined by immunohistochemical assay. Lentivirus delivery of short hairpin RNA (shRNA) targeting GNAQ was used to explore the function of GNAQ in GC cells...
April 2017: Oncology Reports
https://www.readbyqxmd.com/read/28350089/mir%C3%A2-150-inhibits-proliferation-and-tumorigenicity-via-retarding-g1-s-phase-transition-in-nasopharyngeal-carcinoma
#19
Xiangyong Li, Fumei Liu, Bihua Lin, Haiqing Luo, Meilian Liu, Jinhua Wu, Caihong Li, Ronggang Li, Xin Zhang, Keyuan Zhou, Dong Ren
Cancer cells are characterized by a pathological manifestation of uncontrolled proliferation, which results in tumor formation. Therefore, it is necessary to improve understanding of the underlying mechanism of cell cycle control. Here, we report that miR‑150 is downregulated in nasopharyngeal carcinoma tissues and cells. Upregulation of miR‑150 suppresses nasopharyngeal carcinoma (NPC) cell proliferation and induces G1/S arrest in vitro, and inhibits tumorigenesis in vivo. Conversely, silencing miR‑150 yields the opposite effect...
March 10, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28342204/the-ep4-antagonist-l-161-982-induces-apoptosis-cell-cycle-arrest-and-inhibits-prostaglandin-e2-induced-proliferation-in-oral-squamous-carcinoma-tca8113-cells
#20
Xiaohui Li, Bo Yang, Guoxu Han, Weizhong Li
BACKGROUND: Recent studies suggest that cyclooxygenase 2 (COX-2) inhibitors may enhance the toxic effects of anticancer drugs on tumor cells, including oral squamous cell carcinoma (OSCC), but its long-term use can cause side effects such as stomach ulcers and myocardial infarction. Our aim was to investigate proliferative effects of a downstream product of COX-2, prostaglandin E2 (PGE2), in human oral squamous carcinoma cell line Tca8113 and explore the effects of PGE2 receptors, especially EP4 receptor, on the growth of Tca8113 cells...
March 25, 2017: Journal of Oral Pathology & Medicine
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