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https://www.readbyqxmd.com/read/28445466/human-pluripotent-stem-cells-recurrently-acquire-and-expand-dominant-negative-p53-mutations
#1
Florian T Merkle, Sulagna Ghosh, Nolan Kamitaki, Jana Mitchell, Yishai Avior, Curtis Mello, Seva Kashin, Shila Mekhoubad, Dusko Ilic, Maura Charlton, Genevieve Saphier, Robert E Handsaker, Giulio Genovese, Shiran Bar, Nissim Benvenisty, Steven A McCarroll, Kevin Eggan
Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use...
April 26, 2017: Nature
https://www.readbyqxmd.com/read/28442503/molecular-pathways-targeting-the-protein-kinase-wee1-in-cancer
#2
Jill J J Geenen, Jan H M Schellens
Wee1 is a protein kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDKs) are a family of 14 serine/threonine protein kinases, which coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G2 into mitosis. There are two mechanisms by which the G2 checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of Wee1 kinase, which phosphorylates Cdc2. Blockade at the G2 checkpoint is especially important for p53 mutant cells because these tumors mainly rely on DNA repair at the G2 checkpoint...
April 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28442502/ribonucleotide-reductase-large-subunit-rrm1-as-a-novel-therapeutic-target-in-multiple-myeloma
#3
Morihiko Sagawa, Hiroto Ohguchi, Takeshi Harada, Mehmet K Samur, Yu-Tzu Tai, Nikhil C Munshi, Masahiro Kizaki, Teru Hideshima, Kenneth C Anderson
Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival...
April 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28440909/roles-of-the-pdz-binding-motif-of-hpv-16-e6-protein-in-oncogenic-transformation-of-human-cervical-keratinocytes
#4
Yuki Yoshimatsu, Tomomi Nakahara, Katsuyuki Tanaka, Yuki Inagawa, Mako Narisawa-Saito, Takashi Yugawa, Shin-Ichi Ohno, Masatoshi Fujita, Hitoshi Nakagama, Tohru Kiyono
The high-risk human papillomavirus E6 proteins have been shown to interact with and lead degradation of PDZ-domain-containing proteins through its carboxy-terminal motif. This PDZ-binding motif plays important roles in transformation of cultured cells and carcinogenesis of E6-transgenic mice. However, its biological effects on the natural host cells have not been elucidated. We have examined its roles in an in vitro carcinogenesis model for cervical cancer, in which E6 and E7 together with activated HRAS (HRAS(G)(12V) ) can induce tumorigenic transformation of normal human cervical keratinocytes...
April 25, 2017: Cancer Science
https://www.readbyqxmd.com/read/28440661/morphological-features-and-prognostic-significance-of-arid1a-deficient-esophageal-adenocarcinomas
#5
Michael G Drage, Mingkhwan Tippayawong, Agoston T Agoston, Yifan Zheng, Raphael Bueno, Jason L Hornick, Robert D Odze, Amitabh Srivastava
CONTEXT: - The clinicopathologic and prognostic significance of ARID1A mutation in esophageal adenocarcinoma (EAC) is unknown. OBJECTIVE: - To determine the morphological correlates and prognostic significance of ARID1A-deficient EAC. DESIGN: - One hundred twenty cases of primary EAC were evaluated for a predetermined set of histologic features and immunohistochemistry for ARID1A, p53, and MLH1 performed on EAC, as well as adjacent Barrett esophagus and Barrett esophagus-associated dysplasia, when feasible...
April 25, 2017: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/28440416/fuca1-is-induced-by-wild-type-p53-and-expressed-at-different-levels-in-thyroid-cancers-depending-on-p53-status
#6
Nobuo Tsuchida, Masa-Aki Ikeda, Υoshizumu Ιshino, Michele Grieco, Giancarlo Vecchio
Fucose residues of cell surface glycans, which play important roles in growth, invasion and metastasis, are added by fucosyltransferases (FUTs) and removed by α-L-fucosidases (FUCAs). By the differential display method, we isolated a 3' non-coding region of α-L-fucosidase-1 (FUCA1) (a gene coding for the lysosomal fucosidase-1 enzyme) as a wild-type p53-inducible gene: 18S and 20S FUCA1 mRNA species were induced in Saos-2 cells transfected with a temperature-sensitive p53 mutant at the permissive temperature...
April 20, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28439015/mutant-p53-perturbs-dna-replication-checkpoint-control-through-topbp1-and-treslin
#7
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/28435405/establishment-and-characterization-of-6-novel-patient-derived-primary-pancreatic-ductal-adenocarcinoma-cell-lines-from-korean-pancreatic-cancer-patients
#8
Mi-Ju Kim, Min-Sun Kim, Sung Joo Kim, Soyeon An, Jin Park, Hosub Park, Jae Hoon Lee, Ki-Byung Song, Dae Wook Hwang, Suhwan Chang, Kyu-Pyo Kim, Seong-Yun Jeong, Song Cheol Kim, Seung-Mo Hong
BACKGROUND: Pancreatic ductal adenocarcinomas are among the most malignant neoplasms and have very poor prognosis. Our understanding of various cancers has recently improved the survival of patients with cancer, except for pancreatic cancers. Establishment of primary cancer cell lines of pancreatic ductal adenocarcinomas will be useful for understanding the molecular mechanisms of this disease. METHODS: Eighty-one surgically resected pancreatic ductal adenocarcinomas were collected...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28432551/partial-p53-dependence-of-anisomycin-induced-apoptosis-in-pc12-cells
#9
R Schipp, J Varga, J Bátor, M Vecsernyés, Z Árvai, M Pap, József Szeberényi
The bacterial antibiotic anisomycin is known to induce apoptosis by activating several mitogen-activated protein kinases and by inhibiting protein synthesis. In this study, the influence of p53 protein on the apoptosis-inducing effect of anisomycin was investigated. The effect of protein synthesis-inhibiting concentration of anisomycin on apoptotic events was analyzed using Western blot, DNA fragmentation, and cell viability assays in wild-type PC12 and in mutant p53 protein expressing p143p53PC12 cells. Anisomycin stimulated the main apoptotic pathways in both cell lines, but p143p53PC12 cells showed lower sensitivity to the drug than their wild-type counterparts...
April 21, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28427200/idh1-r132h-mutation-regulates-glioma-chemosensitivity-through-nrf2-pathway
#10
Kaishu Li, Leping Ouyang, Mingliang He, Ming Luo, Wangqing Cai, Yalin Tu, Rongbiao Pi, Anmin Liu
PURPOSE: Numerous studies have reported that glioma patients with isocitrate dehydrogenase 1(IDH1) R132H mutation are sensitive to temozolomide treatment. However, the mechanism of IDH1 mutations on the chemosensitivity of glioma remains unclear. In this study, we investigated the role and the potential mechanism of Nrf2 in IDH1 R132H-mediated drug resistance. METHODS: Wild type IDH1 (R132H-WT) and mutant IDH1 (R132H) plasmids were constructed. Stable U87 cells and U251 cells overexpressing IDH1 were generated...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423660/progerin-impairs-vascular-smooth-muscle-cell-growth-via-the-dna-damage-response-pathway
#11
Daisuke Kinoshita, Ayako Nagasawa, Ippei Shimizu, Takashi K Ito, Yohko Yoshida, Masanori Tsuchida, Atsushi Iwama, Toshiya Hayano, Tohru Minamino
Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK)...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423230/gain-of-function-p53-activates-multiple-signaling-pathways-to-induce-oncogenicity-in-lung-cancer-cells
#12
Catherine A Vaughan, Shilpa Singh, Steven R Grossman, Brad Windle, Swati P Deb, Sumitra Deb
Gain of function (GOF) mutants of p53 upregulate genes implicated in cell proliferation and oncogenesis. Here we report that GOF p53 induces tumorigenicity through simultaneous activation of key oncogenic pathways including those controlling putative tumor-initiating cell functions. We determined that in cells expressing p53-R273H, GOF p53 simultaneously up-regulates genes from multiple signaling pathways by recognizing promoters containing distinct transcription factor binding sites. Our analytical data support a model in which GOF p53 complexes with two transcription factors on the promoter - a mediator protein, Med17, and a histone acetyl transferase, activating histone acetylation - and enhances gene expression to signal cell proliferation and oncogenesis...
April 18, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28420165/impact-of-acetazolamide-a-carbonic-anhydrase-inhibitor-on-the-development-of-intestinal-polyps-in-min-mice
#13
Nobuharu Noma, Gen Fujii, Shingo Miyamoto, Masami Komiya, Ruri Nakanishi, Misato Shimura, Sei-Ichi Tanuma, Michihiro Mutoh
Colorectal cancer is a common cancer worldwide. Carbonic anhydrase (CA) catalyzes the reversible conversion of carbon dioxide to bicarbonate ion and a proton, and its inhibitor is reported to reduce cancer cell proliferation and induce apoptosis. Therefore, we asked whether acetazolamide, a CA inhibitor, could inhibit intestinal carcinogenesis. Five-week-old male Apc-mutant mice, Min mice, were fed a AIN-76A diet containing 200 or 400 ppm acetazolamide. As a result, acetazolamide treatment reduced the total number of intestinal polyps by up to 50% compared to the control group...
April 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28415769/aurora-kinase-b-dependent-phosphorylation-of-53bp1-is-required-for-resolving-merotelic-kinetochore-microtubule-attachment-errors-during-mitosis
#14
Haibo Wang, Bin Peng, Raj K Pandita, David A Engler, Risë K Matsunami, Xingzhi Xu, Pavana M Hegde, Brian E Butler, Tej K Pandita, Sankar Mitra, Bo Xu, Muralidhar L Hegde
Defects in resolving kinetochore-microtubule attachment mistakes during mitosis is linked to chromosome instability associated with carcinogenesis as well as resistance to cancer therapy. Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores. Furthermore, 53BP1 staining normally localized on the outer kinetochore, extended to the whole kinetochore when it is merotelically-attached, in concert with mitotic centromere-associated kinesin...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414315/the-emt-activator-zeb1-is-a-key-factor-for-cell-plasticity-and-promotes-metastasis-in-pancreatic-cancer
#15
Angela M Krebs, Julia Mitschke, María Lasierra Losada, Otto Schmalhofer, Melanie Boerries, Hauke Busch, Martin Boettcher, Dimitrios Mougiakakos, Wilfried Reichardt, Peter Bronsert, Valerie G Brunton, Christian Pilarsky, Thomas H Winkler, Simone Brabletz, Marc P Stemmler, Thomas Brabletz
Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis...
April 17, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28412249/the-t-lak-cell-originated-protein-kinase-signal-pathway-promotes-colorectal-cancer-metastasis
#16
Tatyana A Zykova, Feng Zhu, Lei Wang, Haitao Li, Ruihua Bai, Do Young Lim, Ke Yao, Ann M Bode, Zigang Dong
Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. Metastasis is the most lethal attribute of colorectal cancer. New data regarding the molecules contributing to the metastatic phenotype, the pathways they control and the genes they regulate are very important for understanding the processes of metastasis prognosis and prevention in the clinic. The purpose of this study was to investigate the role of T-LAK cell-originated protein kinase (TOPK) in the promotion of colorectal cancer metastasis...
April 6, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28401189/p53-gain-of-function-mutations-promote-metastasis-via-entpd5-upregulation-and-enhanced-n-glycoprotein-folding
#17
Oleg Timofeev, Thorsten Stiewe
Mutations in cancer abolish normal tumor suppressive functions of tumor protein p53 (TP53, best known as p53) and convert it into an oncogene. We recently reported the identification of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a transcriptional target of mutant p53 that enhances folding of N-glycosylated proteins required for cancer cell migration, invasion, and metastasis.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28401005/chk1-inhibition-potentiates-the-therapeutic-efficacy-of-parp-inhibitor-bmn673-in-gastric-cancer
#18
Yuping Yin, Qian Shen, Peng Zhang, Ruikang Tao, Weilong Chang, Ruidong Li, Gengchen Xie, Weizhen Liu, Lihong Zhang, Prabodh Kapoor, Shumei Song, Jaffer Ajani, Gordon B Mills, Jianying Chen, Kaixiong Tao, Guang Peng
Globally, gastric cancer is the second leading cause of cancer deaths because of the lack of effective treatments for patients with advanced tumors when curative surgery is not possible. Thus, there is an urgent need to identify molecular targets in gastric cancer that can be used for developing novel therapies and prolonging patient survival. Checkpoint kinase 1 (Chk1) is a crucial regulator of cell cycle transition in DNA damage response (DDR). In our study, we report that Chk1 plays an important role in promoting gastric cancer cell survival and growth, which serves as an effective therapeutic target in gastric cancer...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28397142/mutations-in-the-tp53-gene-affected-recruitment-of-53bp1-protein-to-dna-lesions-but-level-of-53bp1-was-stable-after-%C3%AE-irradiation-that-depleted-mdc1-protein-in-specific-tp53-mutants
#19
Jana Suchánková, Soňa Legartová, Eva Ručková, Bořivoj Vojtěšek, Stanislav Kozubek, Eva Bártová
53BP1 is a very well-known protein that is recruited to DNA lesions. The focal accumulation of p53 binding protein, 53BP1, is a main feature indicating the repair of spontaneous or irradiation-induced foci (IRIF). Thus, here, we addressed the question of whether mutations in the TP53 gene, which often affect the level of p53 protein, can change the recruitment of 53BP1 to γ- or UVA-irradiated chromatin. In various TP53 mutants, we observed a distinct accumulation of 53BP1 protein to UV-induced DNA lesions: in R273C mutants, 53BP1 appeared transiently at DNA lesions, during 10-30 min after irradiation; the mutation R282W was responsible for accumulation of 53BP1 immediately after UVA-damage; and in L194F mutants, the first appearance of 53BP1 protein at the lesions occurred during 60-70 min...
April 10, 2017: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/28394357/loss-of-lzap-inactivates-p53-and-regulates-sensitivity-of-cells-to-dna-damage-in-a-p53-dependent-manner
#20
J J Wamsley, C Gary, A Biktasova, M Hajek, G Bellinger, R Virk, N Issaeva, W G Yarbrough
Chemotherapy and radiation, the two most common cancer therapies, exert their anticancer effects by causing damage to cellular DNA. However, systemic treatment damages DNA not only in cancer, but also in healthy cells, resulting in the progression of serious side effects and limiting efficacy of the treatment. Interestingly, in response to DNA damage, p53 seems to play an opposite role in normal and in the majority of cancer cells-wild-type p53 mediates apoptosis in healthy tissues, attributing to the side effects, whereas mutant p53 often is responsible for acquired cancer resistance to the treatment...
April 10, 2017: Oncogenesis
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