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https://www.readbyqxmd.com/read/29229926/cell-cycle-dependent-phosphorylation-regulates-recql4-pathway-choice-and-ubiquitination-in-dna-double-strand-break-repair
#1
Huiming Lu, Raghavendra A Shamanna, Jessica K de Freitas, Mustafa Okur, Prabhat Khadka, Tomasz Kulikowicz, Priscella P Holland, Jane Tian, Deborah L Croteau, Anthony J Davis, Vilhelm A Bohr
Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 promotes and coordinates NHEJ and HR in different cell cycle phases. RECQL4 interacts with Ku70 to promote NHEJ in G1 when overall cyclin-dependent kinase (CDK) activity is low. During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs...
December 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29229876/microrna-486-5p-suppresses-tgf-%C3%AE-2-induced-proliferation-invasion-and-epithelial-mesenchymal-transition-of-lens-epithelial-cells-by-targeting-smad2
#2
Bei Liu, Jianhua Sun, Xiaoqin Lei, Zhongqiao Zhu, Cheng Pei, Li Qin
The pathological development of lens epithelial cells (LECs) leads to posterior capsular opacification (PCO). This study was undertaken to investigate the effects of microRNA-486-5p (miR-486-5p) on TGF-β2-induced proliferation, invasion and epithelial-mesenchymal transition (EMT) in the lens epithelial cell line SRA01/04, and to explore the underlying molecular mechanisms. The expression of miR-486-5p in TGF-β2-induced SRA01/04 cells was down-regulated, and the expression of Smad2, p-Smad2 and p-Smad3 was up-regulated...
December 2017: Journal of Biosciences
https://www.readbyqxmd.com/read/29229598/cdkn2a-p16-deletion-in-head-and-neck-cancer-cells-is-associated-with-cdk2-activation-replication-stress-and-vulnerability-to-chk1-inhibition
#3
Mayur A Gadhikar, Jiexin Zhang, Li Shen, Xiayu Rao, Jing Wang, Mei Zhao, Nene N Kalu, Faye M Johnson, Lauren A Byers, John Heymach, Walter N Hittelman, Durga Udayakumar, Raj K Pandita, Tej K Pandita, Curtis R Pickering, Abena Redwood, Helen Piwnica-Worms, Katharina Schlacher, Mitchell J Frederick, Jeffrey N Myers
Checkpoint kinase inhibitors (CHKi) exhibit striking single agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of Chk1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity...
December 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29221147/long-noncoding-rna-linc00673-epigenetically-suppresses-klf4-by-interacting-with-ezh2-and-dnmt1-in-gastric-cancer
#4
Ming-Chen Ba, Hui Long, Shu-Zhong Cui, Yuan-Feng Gong, Zhao-Fei Yan, Yin-Bing Wu, Yi-Nuo Tu
Long non-coding RNAs (lncRNAs), a variety of transcripts without protein coding ability, have recently been reported to play vital roles in gastric cancer (GC) development and progression. However, the biological role of long non-coding RNA LINC00673 in GC is not fully known. In the study, we found that LINC00673 expression was dramatically higher in gastric cancer tissues compared with adjacent normal tissues, and positively associated with lymph node metastasis, distant metastasis and TNM stage in patients...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29215867/direct-substrate-identification-with-an-analog-sensitive-as-viral-cyclin-dependent-kinase-v-cdk
#5
Angie C Umaña, Satoko Iwahori, Robert F Kalejta
Viral cyclin-dependent kinases (v-Cdks) functionally emulate their cellular Cdk counterparts. Such viral mimicry is an established phenomenon that we extend here through chemical genetics. Kinases contain gatekeeper residues that limit the size of molecules that can be accommodated within the enzyme active site. Mutating gatekeeper residues to smaller amino acids allows larger molecules access to the active site. Such mutants can utilize bio-orthoganol ATPs for phosphate transfer and are inhibited by compounds ineffective against the wild type protein, and thus are referred to as analog-sensitive (AS) kinases...
December 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29210005/the-novel-role-of-il-37-in-prostate-cancer-evidence-as-a-promising-radiosensitizer
#6
Vivi A Ding, Ziwen Zhu, Timothy A Steele, Mark R Wakefield, Huaping Xiao, Dean Balabanov, Yujiang Fang
Prostate cancer (PCa) is the most common non-cutaneous cancer in men in the USA. Radiation therapy (RT) is widely considered the standard treatment for PCa. IL-37 is an IL-1 family member, and it has been extensively studied in immunity. However, no studies have been done regarding its potential as a radiosensitizer. This study is designed to investigate the direct effect of IL-37 on growth of DU145 and PC-3, two widely studied PCa cell lines, and to investigate whether IL-37 could be used as a radiosensitizer for PCa...
December 5, 2017: Medical Oncology
https://www.readbyqxmd.com/read/29207130/ethanol-extract-from-cnidium-monnieri-l-cusson-induces-cell-cycle-arrest-and-apoptosis-via-regulation-of-the-p53%C3%A2-independent-pathway-in-hepg2-and-hep3b-hepatocellular-carcinoma-cells
#7
Eun Gyeong Lim, Guen Tae Kim, Bo Min Kim, Eun Ji Kim, Sang-Yong Kim, Young Min Kim
Cnidium monnieri (L.) Cusson is a frequently used traditional Chinese medicine that treats gynecological diseases and carbuncles. However, the mechanism of action of C. monnieri remains to be fully elucidated. The present study examined the cell cycle arrest and apoptotic effects resulting from ethanol extract of C. monnieri (CME) in HepG2 (wild‑type p53) and Hep3B (p53‑null) hepatocellular carcinoma cells. An MTT assay was used to confirm the anti‑proliferative effect of CME. The cells were stained with Hoechst 33342 or propidium iodide...
November 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29203878/atm-and-cdk2-control-chromatin-remodeler-csb-to-inhibit-rif1-in-dsb-repair-pathway-choice
#8
Nicole L Batenburg, John R Walker, Sylvie M Noordermeer, Nathalie Moatti, Daniel Durocher, Xu-Dong Zhu
CSB, a member of the SWI2/SNF2 superfamily, is implicated in DNA double-strand break (DSB) repair. However, how it regulates this repair process is poorly understood. Here we uncover that CSB interacts via its newly identified winged helix domain with RIF1, an effector of 53BP1, and that this interaction mediates CSB recruitment to DSBs in S phase. At DSBs, CSB remodels chromatin by evicting histones, which limits RIF1 and its effector MAD2L2 but promotes BRCA1 accumulation. The chromatin remodeling activity of CSB requires not only damage-induced phosphorylation on S10 by ATM but also cell cycle-dependent phosphorylation on S158 by cyclin A-CDK2...
December 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/29198777/the-cyclin-dependent-kinase-2-cdk2-mediates-hematopoiesis-through-g1-to-s-transition-in-chinese-mitten-crab-eriocheir-sinensis
#9
Bin Yang, Yunke Jia, Zhihao Jia, Weilin Wang, Xiaorui Song, Yannan Li, Qilin Yi, Lingling Wang, Linsheng Song
Cyclin-dependent kinases (CDKs), a family of cell cycle-related serine/threonine kinases, participate in various biological processes, and play crucial roles in the innate immunity. In the present study, a CDK2 (designed as EsCDK2) with a serine/threonine protein kinase catalytic domain was identified from Chinese mitten crab (Eriocheir sinensis). The full-length cDNA sequence of EsCDK2 was of 2405 bp with an open reading frame (ORF) of 909 bp. EsCDK2 shared 66%-81% sequence similarities with previously identified CDK2s...
November 30, 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29188562/methods-of-exploring-protein-ligand-interactions-to-guide-medicinal-chemistry-efforts
#10
Paul Labute
We present a number of techniques to analyze protein-ligand interactions in the context of medicinal chemistry: crystal Contract Preferences, Electrostatic Maps and pharmacophore screening using Hückel Theory. Contact Preferences is a statistical technique to predict hydrophobic and hydrophilic geometry in receptor active sites. Electrostatic Maps use the Poisson-Boltzmann Equation to model solvation effects and are particularly useful for predicting hydrophobic regions. Pharmacophore annotation with Hückel Theory provides finer detail of hydrogen bonding interactions, including CH...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29188531/mir-519d-3p-suppresses-breast-cancer-cell-growth-and-motility-via-targeting-lim-domain-kinase-1
#11
Dengfeng Li, Hongming Song, Tianqi Wu, Dan Xie, Jiashu Hu, Junyong Zhao, Qiang Shen, Lin Fang
Breast cancer is the most common female cancer in women, and its estrogen receptor (ER)-negative subtype (ENBC) and triple-negative subtype (TNBC) have unfavorable prognosis in comparison with ER-positive subtype. MiRNAs are small noncoding RNAs that bind to the 3'-UTR region of targeting mRNAs to regulate gene expression. Mir-519d-3p was found to be associated with breast cancer for its potential role in proliferation and metastasis. To explore its potential role and mechanism of miR-519d-3p in breast carcinogenesis, we determined whether miR-519d-3p regulates breast cancer cell proliferation and motility by performing wound-healing assays and migration-invasion assays...
November 29, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29175378/increased-activity-of-both-cdk1-and-cdk2-is-necessary-for-the-combinatorial-activity-of-wee1-inhibition-and-cytarabine
#12
Tamara B Garcia, Susan P Fosmire, Christopher C Porter
Inhibition of WEE1 is emerging as a promising chemosensitization strategy in many cancers including acute leukemia. Our lab and others have demonstrated that a small-molecule inhibitor of WEE1, AZD1775, sensitizes acute leukemia cells to cytarabine; however, a mechanism of combinatorial activity has remained elusive. Thus, we sought to determine the relative contribution of WEE1 targets CDK1 and CDK2 to the combinatorial activity of AZD1775 and cytarabine. To accomplish this, we expressed "WEE1 resistant" CDK1 (CDK1-AF) and CDK2 (CDK2-AF) constructs in a T-ALL cell line...
November 11, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29175329/inhibition-of-cip2a-attenuates-tumor-progression-by-inducing-cell-cycle-arrest-and-promoting-cellular-senescence-in-hepatocellular-carcinoma
#13
Xue Yang, Kai Qu, Jie Tao, Guozhi Yin, Shaoshan Han, Qingguang Liu, Hao Sun
CIP2A is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of CIP2A, we comprehensively analyzed the CIP2A expression levels in pan-cancer and observed high expression level of CIP2A in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of CIP2A in HCC, and found high CIP2A mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC...
November 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29170395/oncogenic-pik3ca-induces-centrosome-amplification-and-tolerance-to-genome-doubling
#14
Inma M Berenjeno, Roberto Piñeiro, Sandra D Castillo, Wayne Pearce, Nicholas McGranahan, Sally M Dewhurst, Valerie Meniel, Nicolai J Birkbak, Evelyn Lau, Laurent Sansregret, Daniele Morelli, Nnennaya Kanu, Shankar Srinivas, Mariona Graupera, Victoria E R Parker, Karen G Montgomery, Larissa S Moniz, Cheryl L Scudamore, Wayne A Phillips, Robert K Semple, Alan Clarke, Charles Swanton, Bart Vanhaesebroeck
Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling...
November 24, 2017: Nature Communications
https://www.readbyqxmd.com/read/29169421/-mir-503-5p-inhibits-the-proliferation-of-t24-and-ej-bladder-cancer-cells-by-interfering-with-the-rb-e2f-signaling-pathway
#15
Xiaohui Li, Xingtao Han, Jinhui Yang, Jiantao Sun, Pengtao Wei
Objective To observe the effect of microRNA-503-5p (miR-503-5p) on the growth of T24 and EJ bladder cancer cells, and explore the possible molecular mechanism. Methods The miR-504-5p mimics or miR-NC was transfected into T24 and EJ cells. The target gene of miR-503-5p was predicted by bioinformatics. The expressions of E2F transcription factor 3 (E2F3) mRNA and Rb/E2F signaling pathway mRNA were detected by the real-time quantitative PCR (qPCR). The expressions of Rb/E2F signal pathway proteins E2F3, cyclin E, CDK2, Rb and p-Rb were detected by Western blotting...
October 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/29159834/linc00473-antagonizes-the-tumour-suppressor-mir-195-to-mediate-the-pathogenesis-of-wilms-tumour-via-ikk%C3%AE
#16
Shibo Zhu, Wen Fu, Liyu Zhang, Kai Fu, Jinhua Hu, Wei Jia, Guochang Liu
OBJECTIVES: Although dramatic improvements of overall survival has achieved in patients with favourable histology Wilms tumour, disease recurrence is still the main cause of cancer-related death in childhood. Long non-coding RNAs (lncRNAs) as oncogenes or tumour suppressors are dysregulated during carcinogenesis. However, the role of lncRNAs in the pathogenesis of Wilms tumour is unknown. Here, an lncRNA LINC00473 signature that functioned as oncogene was identified in Wilms tumour. METHODS: Wilms tumour (n = 15) and relative normal tissues were collected...
November 20, 2017: Cell Proliferation
https://www.readbyqxmd.com/read/29157894/selective-inhibition-reveals-cyclin-dependent-kinase-2-as-another-kinase-that-phosphorylates-the-androgen-receptor-at-serine-81
#17
Radek Jorda, Zuzana Bučková, Eva Řezníčková, Jan Bouchal, Vladimír Kryštof
Several studies have revealed that cyclin-dependent kinases (CDK) can mediate phosphorylation of steroid receptors at multiple sites, including serine 81 of the androgen receptor (AR). Phosphorylation of S81 is required for AR nuclear translocation in association with chromatin and also regulates endogenous AR-regulated transcription in response to hormones. Up to date, S81-phosphorylation has been studied using different CDK inhibitors. Nevertheless, most inhibitors are non-selective or have unknown selectivity...
November 17, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29156719/the-micrornas-mir-200b-3p-and-mir-429-5p-target-the-limk1-cfl1-pathway-to-inhibit-growth-and-motility-of-breast-cancer-cells
#18
Dengfeng Li, Hong Wang, Hongming Song, Hui Xu, Bingkun Zhao, Chenyang Wu, Jiashu Hu, Tianqi Wu, Dan Xie, Junyong Zhao, Qiang Shen, Lin Fang
Triple-negative breast cancer (TNBC) has the worst prognosis of all subtypes of breast cancer (BC), with limited options for conventional therapy and no targeted therapies. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. In this study, we aimed to determine whether two members of the miR-200 family, miR-200b-3p and miR-429-5p, are involved in BC cell proliferation and motility and to elucidate their target genes and pathways. We performed a meta-analysis that reveals down-regulated expression of miR-200b-3p and miR-429-5p in BC tissues and cell lines, consistent with a lower expression of miR-200b-3p and miR-429-5p in MDA-MB-231 and HCC1937 cells than in MCF-7 and MCF-10 cells...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29147649/knockdown-of-sirt1-suppresses-bladder-cancer-cell-proliferation-and-migration-and-induces-cell-cycle-arrest-and-antioxidant-response-through-foxo3a-mediated-pathways
#19
Qingxuan Hu, Gang Wang, Jianping Peng, Guofeng Qian, Wei Jiang, Conghua Xie, Yu Xiao, Xinghuan Wang
Bladder cancer (BCa) is one of the most common tumors, but its underlying mechanism has not been fully clarified. Our transcriptome analysis suggested a close link of Sirtuins, Peroxisome Proliferator-Activated Receptor (PPAR), cell cycle regulation, reactive oxygen species (ROS) metabolism, and Forkhead Box Class O (FOXO) signaling pathway in BCa. SIRT1 is a key member of Sirtuins, playing important roles in aging and energy metabolism, which has been reported to be involved in various metabolic diseases and tumors...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29144137/design-of-novel-3-pyrimidinylazaindole-based-cdk2-9-inhibitors-with-potent-in-vitro-and-in-vivo-antitumor-efficacy-in-a-triple-negative-breast-cancer-model
#20
Umed Singh, Gousia Chashoo, Sameer U Khan, Priya Mahajan, Amit Nargotra, Girish Mahajan, Amarinder Singh, Anjna Sharma, Mubashir Javeed Mintoo, Santosh Kumar Guru, Hariprasad Aruri, Thanusha Thatikonda, Promod Sahu, Pankaj Chibber, Vikas Kumar, Sameer A Mir, Sonali S Bharate, Sreedhar Madishetti, Utpal Nandi, Gurdarshan Singh, Dilip Manikrao Mondhe, Shashi Bhushan, Fayaz Malik, Serge Mignani, Ram A Vishwakarma, Parvinder Pal Singh
In the present study, novel series of 3-pyrimidinylazaindoles were designed and synthesized using bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in cell-cycle control and regulation of cell transcription. The present approach has given new dimensions to existing SAR and opens the new opportunity for lead optimization from comparatively inexpensive starting materials. The study led to the identification of alternative lead candidate 4ab with nanomolar potency against CDK2 and CDK9 and potent anti-proliferative activities against a panel of tested tumor cell lines along better safety ratio of ~30 in comparison to reported leads...
November 16, 2017: Journal of Medicinal Chemistry
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