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Checkpoint kinase 1

Jessica Fletcher, Liam Griffiths, Thomas Caspari
The S. pombe checkpoint kinase, Cds1, protects the integrity of stalled DNA replication forks after its phosphorylation at threonine-11 by Rad3 (ATR). Modified Cds1 associates through its N-terminal forkhead-associated domain (FHA)-domain with Mrc1 (Claspin) at stalled forks. We report here that nutrient starvation results in post-translational changes to Cds1 and the loss of Mrc1. A drop in glucose after a down-shift from 3% to 0.1-0.3%, or when cells enter the stationary phase, triggers a sharp decline in Mrc1 and the accumulation of insoluble Cds1...
February 23, 2018: Cells
Yuqing Shen, John William Sherman, Xuyong Chen, Ruoning Wang
From unicellular to multicellular organisms, cell cycle progression is tightly coupled to biosynthetic and bioenergetic demands. Accumulating evidence has demonstrated the G1/S phase transition as a key checkpoint where cells respond to their metabolic status and commit to replicating the genome. However, the mechanism underlying the coordination of metabolism and the G2/M phase transition in mammalian cells remains unclear. Here we show that the activation of AMP-activated protein kinase (AMPK), a highly conserved cellular energy sensor, significantly delays mitosis entry...
February 21, 2018: Journal of Biological Chemistry
Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, Kirby N Swatek, Jianbin Ruan, Gianmaria Liccardi, Katiuscia Bianchi, Paul R Elliott, Sze Men Choi, Samya Van Coillie, John Bertin, Hao Wu, David Komander, Peter Vandenabeele, John Silke, Pascal Meier
Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation...
February 15, 2018: Molecular Cell
Valentina Restelli, Monica Lupi, Micaela Vagni, Rosaria Chilà, Francesco Bertoni, Giovanna Damia, Laura Carrassa
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton's tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment...
February 13, 2018: Targeted Oncology
Tyler J Lahusen, Seung-Jin Kim, Kai Miao, Zebin Huang, Xiaoling Xu, Chu-Xia Deng
Breast cancer associated gene 1 (BRCA1) function has been shown to be regulated by phosphorylation but the role of acetylation has not been determined. Therefore, we tested whether BRCA1 can be acetylated by the acetyltransferases P300/CBP-associated factor (pCAF), GCN5, and p300. p300 exhibited the highest level of BRCA1 acetylation; however, there was also a decrease in the total level of BRCA1. Therefore, we focused on pCAF and GCN5 because they both acetylated BRCA1 without affecting BRCA1 expression. Further analysis indicated that the acetylated form of BRCA1 is deacetylated by wild-type (WT) SIRT1, but not deacetylase mutant SIRT1, suggesting that SIRT1 is a specific deacetylase of BRCA1...
February 14, 2018: Oncogene
Michael B Atkins, Elizabeth R Plimack, Igor Puzanov, Mayer N Fishman, David F McDermott, Daniel C Cho, Ulka Vaishampayan, Saby George, Thomas E Olencki, Jamal C Tarazi, Brad Rosbrook, Kathrine C Fernandez, Mariajose Lechuga, Toni K Choueiri
BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma...
February 9, 2018: Lancet Oncology
H Richard Alexander, Claire Yue Li, Timothy J Kennedy
PURPOSE: Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. METHODS: The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM...
February 8, 2018: Annals of Surgical Oncology
Manoj B Menon, Julia Gropengießer, Klaus Ruckdeschel, Matthias Gaestel
Complex posttranslational modifications determine the effects of receptor-interacting protein kinase-1 (RIPK1) on cell survival and death. Studies from us and others have revealed a p38MAPK/MK2-dependent checkpoint in RIPK1 signaling. MAPKAP kinase 2 (MK2) phosphorylates RIPK1 to suppress RIPK1-mediated apoptosis and necroptosis in response to diverse stimuli relevant to inflammation, infection, genotoxic stress and chemotherapy.
2018: Molecular & Cellular Oncology
Xin He, Lei Zhu, Shu Li, Zhigang Chen, Xiaoying Zhao
Loperamide, an antidiarrheal agent, is frequently used to treat patients with leukemia with symptoms of diarrhea during treatment. However, the effect of loperamide on leukemia cells is unknown. The MTT assay was used to explore the cytotoxic effect of loperamide on leukemia cells. Morphological analysis and flow cytometry were performed to determine the level of apoptosis in leukemia cells following loperamide treatment. Western blotting was conducted to test the activation of the apoptotic pathway. The comet assay was used to determine the DNA damage induced by loperamide...
January 2018: Oncology Letters
Clément Korenbaum, Laure Pierard, Alicia Thiéry, Fleur Story, Véronique Lindner, Hervé Lang, Jean-Emmanuel Kurtz, Philippe Barthélémy
INTRODUCTION: Metastatic renal cell carcinoma (RCC) with a sarcomatoid component is a rare disease associated with a poor prognosis. We report the outcomes of 47 patients with metastatic sarcomatoid RCC (SRCC) treated with different modalities including chemotherapy, tyrosine kinase inhibitors, or immunotherapy over 2 decades in a French cancer center. Furthermore, we assessed the validity of prognostic scores in this subset of RCC. PATIENTS AND METHODS: Patients were retrospectively identified from the database of the pathology department of the University Hospital of Strasbourg...
December 28, 2017: Clinical Genitourinary Cancer
Linfeng Zheng, Yuping Zhu, Lei Lei, Wenyong Sun, Guoping Cheng, Shifeng Yang
Checkpoint kinase 1 (CHK1) and p53 are involved in cell-cycle checkpoint, and cellular response to DNA damage. CHK1 and p53 are overexpressed in bladder urothelial carcinoma (BUC); however, a clear elucidation on their interaction and influence in the progress of BUC is absent. The aim of the present study was to examine the correlation between CHK1 and p53 in BUC, and analyze their value as therapeutic targets and prognostic indicators in BUC. A clinically annotated cohort of 110 patients with BUC was identified retrospectively...
January 2018: Oncology Letters
Özge Saatci, Simone Borgoni, Özge Akbulut, Selvi Durmuş, Umar Raza, Erol Eyüpoğlu, Can Alkan, Aytekin Akyol, Özgür Kütük, Stefan Wiemann, Özgür Şahin
Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer...
February 2, 2018: Oncogene
Ai Huang, Jing Yao, Tao Liu, Zhenyu Lin, Sheng Zhang, Tao Zhang, Hong Ma
BACKGROUND: This study aimed to investigate the influence of the expression of P53-binding protein 1 (53BP1), a key component in DNA damage repair pathways, on the radiosensitizing effect of icotinib hydrochloride in colorectal cancer and to elucidate the mechanisms underlying this influence. MATERIALS AND METHODS: Real-time RT-PCR and western blotting were performed to verify the gene-knockout effect of 53BP1 small hairpin RNA (siRNA), and colony formation assay was employed to investigate the influence of 53BP1 downregulation on the radiosensitizing effect of icotinib hydrochloride in HCT116 cells...
February 1, 2018: International Journal of Radiation Biology
Liang Shen, Ming Liu, Wei Liu, Jing Cui, Changzhong Li
In the present study, the RNA sequencing (RNA-seq) data of uterine corpus endometrial carcinoma (UCEC) samples were collected and analyzed using bioinformatics tools to identify potential genes associated with the development of UCEC. UCEC RNA-seq data were downloaded from The Cancer Genome Atlas database. Differential analysis was performed using edgeR software. A false discovery rate <0.01 and |log2(fold change)|>1 were set as the cut-off criteria to screen for differentially expressed genes (DEGs)...
January 2018: Oncology Letters
Sunwoo Min, Yong Won Choi, Hansol Yun, Sujin Jo, Jae-Hoon Ji, Hyeseong Cho
Chromatin remodeling factors are involved in many cellular processes such as transcription, replication, and DNA damage response by regulating chromatin structure. As one of chromatin remodeling factors, remodeling and spacing factor 1 (RSF1) is recruited at double strand break (DSB) sites and regulates ataxia telangiectasia mutated (ATM) -dependent checkpoint pathway upon DNA damage for the efficient repair. RSF1 is overexpressed in a variety of cancers, but regulation of RSF1 levels remains largely unknown...
January 31, 2018: Molecules and Cells
John Tat, Céline Loriot, Martha Henze, Charles Spruck, Brunhilde H Felding, Steven I Reed
The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand...
December 29, 2017: Oncotarget
Kai Chen, Wenxiu Duan, Qianqian Han, Xuan Sun, Wenqian Li, Shuangyun Hu, Jiajia Wan, Jiang Wu, Yushu Ge, Dan Liu
Protein kinase monopolar spindle 1 plays an important role in spindle assembly checkpoint at the onset of mitosis. Over expression of MPS1 correlated with a wide range of human tumors makes it an attractive target for finding an effective and specific inhibitor. In this work, we performed molecular dynamics simulations of protein MPS1 itself as well as protein bound systems with the inhibitor and natural substrate based on crystal structures. The reported orally bioavailable 1h-pyrrolo [3,2-c] pyridine inhibitors of MPS1 maintained stable binding in the catalytic site while natural substrate ATP could not stay...
January 30, 2018: Journal of Biomolecular Structure & Dynamics
K L Thu, J Silvester, M J Elliott, W Ba-Alawi, M H Duncan, A C Elia, A S Mer, P Smirnov, Z Safikhani, B Haibe-Kains, T W Mak, D W Cescon
TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
Dipika Gupta, Bo Lin, Ann Cowan, Christopher D Heinen
The mismatch repair pathway (MMR) is essential for removing DNA polymerase errors, thereby maintaining genomic stability. Loss of MMR function increases mutation frequency and is associated with tumorigenesis. However, how MMR is executed at active DNA replication forks is unclear. This has important implications for understanding how MMR repairs O6-methylguanine/thymidine (MeG/T) mismatches created upon exposure to DNA alkylating agents. If MeG/T lesion recognition by MMR initiates mismatch excision, the reinsertion of a mismatched thymidine during resynthesis could initiate futile repair cycles...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
David M Gill, Andrew W Hahn, Peter Hale, Benjamin L Maughan
Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20 years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment...
January 24, 2018: Current Treatment Options in Oncology
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