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https://www.readbyqxmd.com/read/29789497/treating-p53-mutant-aggregation-associated-cancer
#1
REVIEW
Mathumai Kanapathipillai
p53 is a tumor suppressor protein. Under stressful conditions, p53 tightly regulates cell growth by promoting apoptosis and DNA repair. When p53 becomes mutated, it loses its function, resulting in abnormal cell proliferation and tumor progression. Depending on the p53 mutation, it has been shown to form aggregates leading to negative gain of function of the protein. p53 mutant associated aggregation has been observed in several cancer tissues and has been shown to promote tumor growth. Recent studies show correlation between p53 mutant aggregation, functional loss, and tumor growth...
May 23, 2018: Cancers
https://www.readbyqxmd.com/read/29786075/tp53-gain-of-function-mutation-promotes-inflammation-in-glioblastoma
#2
Seok Won Ham, Hee-Young Jeon, Xiong Jin, Eun-Jung Kim, Jun-Kyum Kim, Yong Jae Shin, Yeri Lee, Se Hoon Kim, Seon Yong Lee, Sunyoung Seo, Min Gi Park, Hye-Mi Kim, Do-Hyun Nam, Hyunggee Kim
Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations...
May 21, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29783721/azd1775-increases-sensitivity-to-olaparib-and-gemcitabine-in-cancer-cells-with-p53-mutations
#3
Xiangbing Meng, Jianling Bi, Yujun Li, Shujie Yang, Yuping Zhang, Mary Li, Haitao Liu, Yiyang Li, Megan E Mcdonald, Kristina W Thiel, Kuo-Kuang Wen, Xinhao Wang, Meng Wu, Kimberly K Leslie
Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function...
May 19, 2018: Cancers
https://www.readbyqxmd.com/read/29778960/rapid-colorimetric-detection-of-p53-protein-function-using-dna-gold-nanoconjugates-with-applications-for-drug-discovery-and-cancer-diagnostics
#4
Enock Assah, Walter Goh, Xin Ting Zheng, Ting Xiang Lim, Jun Li, David Lane, Farid Ghadessy, Yen Nee Tan
The tumor suppressor protein p53 plays a central role in preventing cancer through interaction with DNA response elements (REs) to regulate target gene expression in cells. Due to its significance in cancer biology, relentless efforts have been directed toward understanding p53-DNA interactions for the development of cancer therapeutics and diagnostics. In this paper, we report a rapid, label-free and versatile colorimetric assay to detect wildtype p53 DNA-binding function in complex solutions. The assay design is based on a concept that alters interparticle-distances between RE-AuNPs from a crosslinking effect induced through tetramerization of wildtype p53 protein (p53-WT) upon binding to canonical DNA motifs modified on gold nanoparticles (RE-AuNPs)...
May 5, 2018: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/29774132/natural-products-a-hope-for-glioblastoma-patients
#5
REVIEW
Raghupathy Vengoji, Muzafar A Macha, Surinder K Batra, Nicole A Shonka
Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB)...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29773887/varacin-1-a-novel-analog-of-varacin-c-induces-p53-independent-apoptosis-in-cancer-cells-through-ros-mediated-reduction-of-xiap
#6
Jing Zhou, Wen-Li Li, Zi-Xuan Wang, Nai-Yuan Chen, Yue Tang, Xiao-Xiao Hu, Jing-Huan Deng, Yixin Lu, Guo-Dong Lu
Varacin C is a promising anticancer agent and possesses acid-promoted and photo-induced DNA-damaging activities. In this study, we synthesized an analog varacin-1 (VCA-1) and examined its anticancer potentials. The results demonstrated that VCA-1 caused dose-dependent apoptotic cell death in cancer cells. Note that this action is independent of p53 status, because VCA-1 induced similar levels of apoptosis in two different panels of cell lines (HCT116 p53- wild-type vs. HCT116 p53-knockout colon cancer cells, and p53-expressing U2OS vs...
May 17, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29769406/spindle-assembly-disruption-and-cancer-cell-apoptosis-with-a-cltc-binding-compound
#7
Michael J Bond, Marina Bleiler, Lauren E Harrison, Eric W Scocchera, Masako Nakanishi, Narendran G-Dayanandan, Santosh Keshipeddy, Daniel W Rosenberg, Dennis L Wright, Charles Giardina
AK3 compounds are mitotic-arrest agents that induce high levels of γH2AX during mitosis and apoptosis following release from arrest. We synthesized a potent AK3 derivative, AK306, that induced arrest and apoptosis of the HCT116 colon cancer cell line with an EC50 of ~50 nM. AK306 was active on a broad spectrum of cancer cell lines with total growth inhibition values ranging from ~25 nM to 25 µM. Using biotin and BODIPY-linked derivatives of AK306, binding to clathrin heavy chain (CLTC/CHC) was observed, a protein with roles in endocytosis and mitosis...
May 16, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29769307/orally-bioavailable-and-blood-brain-barrier-penetrating-atm-inhibitor-az32-radiosensitizes-intracranial-gliomas-in-mice
#8
Jeremy Karlin, Jasmine Allen, Syed F Ahmad, Gareth Hughes, Victoria Sheridan, Rajesh Odedra, Paul Farrington, Elaine B Cadogan, Lucy C Riches, Antonio Garcia-Trinidad, Andrew G Thomason, Bhavika Patel, Jennifer Vincent, Alan Lau, Kurt G Pike, Thomas A Hunt, Amrita Sule, Nicholas C K Valerie, Laura Biddlestone-Thorpe, Jenna Kahn, Jason M Beckta, Nitai Mukhopadhyay, Bernard Barlaam, Sebastien L Degorce, Jason Kettle, Nicola Colclough, Joanne Wilson, Aaron Smith, Ian P Barrett, Li Zheng, Tianwei Zhang, Yingchun Wang, Kan Chen, Martin Pass, Stephen T Durant, Kristoffer Valerie
Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited CNS bioavailability, thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain...
May 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29767258/pd-l1-mrna-expression-in-egfr-mutant-lung-adenocarcinoma
#9
Kazutoshi Isobe, Atsushi Kakimoto, Tetuo Mikami, Kyohei Kaburaki, Hiroshi Kobayashi, Takahiro Yoshizawa, Yuta Nakano, Takashi Makino, Hajime Otsuka, Go Sano, Keishi Sugino, Susumu Sakamoto, Yujiro Takai, Naobumi Tochigi, Akira Iyoda, Sakae Homma
Molecular mechanisms of programmed death-ligand 1 (PD-L1) mRNA expression and roles of apoptosis and biomarkers are poorly understood in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients. Thirty-three patients with recurrent postoperative EGFR-mutant lung adenocarcinoma (exon 19 deletion in 16, L858R in 15, G719C in 2 patients) treated with gefitinib were studied. PD-L1 mRNA expression of formalin-fixed paraffin-embedded paratumoral and intratumoral tissues was quantified by PCR. Correlations of PD-L1 mRNA expression with BIM, p53 upregulated modular of apoptosis (PUMA), human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition (MET), EGFR, and vascular endothelial growth factor A (VEGFA) were determined...
May 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29765555/a-protein-folding-molecular-imaging-biosensor-monitors-the-effects-of-drugs-that-restore-mutant-p53-structure-and-its-downstream-function-in-glioblastoma-cells
#10
Ramasamy Paulmurugan, Rayhaneh Afjei, Thillai V Sekar, Husam A Babikir, Tarik F Massoud
Misfolding mutations in the DNA-binding domain of p53 alter its conformation, affecting the efficiency with which it binds to chromatin to regulate target gene expression and cell cycle checkpoint functions in many cancers, including glioblastoma. Small molecule drugs that recover misfolded p53 structure and function may improve chemotherapy by activating p53-mediated senescence. We constructed and optimized a split Renilla luciferase (RLUC) complementation molecular biosensor (NRLUC-p53-CRLUC) to determine small molecule-meditated folding changes in p53 protein...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29760279/histone-h3k27-methylation-is-required-for-nhej-and-genome-stability-by-modulating-the-dynamics-of-fancd2-on-chromatin
#11
Ye Zhang, Jian-Feng Chang, Jin Sun, Lu Chen, Xiao-Mei Yang, Huan-Yin Tang, Yuan-Ya Jing, Xuan Kang, Zhi-Min He, Jun-Yu Wu, Hui-Min Wei, Da-Liang Wang, Rong-Gang Xu, Rui-Bao Zhu, Ying Shen, Shi-Yang Zeng, Chen Wang, Kui-Nan Liu, Yong Zhang, Zhi-Ying Mao, Ci-Zhong Jiang, Fang-Lin Sun
Dysregulation of homeostatic balance in di- and tri-methyl H3K27 levels or that caused by mis-sense mutations of histone H3 (H3K27M) was reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in DIPG patients, dramatically attenuated the presence of 53BP1 foci and NHEJ repair capability in HDF cells. H3.1K27M cells showed increased rates of genomic insertions/deletions (In/Dels) and copy number variations (CNVs), as well as augmented p53-dependent apoptotic cells...
May 14, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29755668/mutant-p53-tunes-the-nrf2-dependent-antioxidant-response-to-support-survival-of-cancer-cells
#12
Kamil Lisek, Elena Campaner, Yari Ciani, Dawid Walerych, Giannino Del Sal
NRF2 (NFE2L2) is one of the main regulators of the antioxidant response of the cell. Here we show that in cancer cells NRF2 targets are selectively upregulated or repressed through a mutant p53-dependent mechanism. Mechanistically, mutant p53 interacts with NRF2, increases its nuclear presence and resides with NRF2 on selected ARE containing gene promoters activating the transcription of a specific set of genes while leading to the transcriptional repression of others. We show that thioredoxin ( TXN) is a mutant p53-activated NRF2 target with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 ( HMOX1) is a mutant p53-repressed target displaying opposite effects...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29754823/pol%C3%AE%C2%B5-instability-drives-replication-stress-abnormal-development-and-tumorigenesis
#13
Roberto Bellelli, Valerie Borel, Clare Logan, Jennifer Svendsen, Danielle E Cox, Emma Nye, Kay Metcalfe, Susan M O'Connell, Gordon Stamp, Helen R Flynn, Ambrosius P Snijders, François Lassailly, Andrew Jackson, Simon J Boulton
DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1...
May 3, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29751559/insights-of-crosstalk-between-p53-protein-and-the-mkk3-mkk6-p38-mapk-signaling-pathway-in-cancer
#14
REVIEW
Lorenzo Stramucci, Angelina Pranteda, Gianluca Bossi
TP53 is universally recognized as a pivotal protein in cell-cycle fate and apoptotic induction and, unsurprisingly, it is one of the most commonly hijacked control mechanisms in cancer. Recently, the kinase MKK3 emerged as a potential therapeutic target in different types of solid tumor being linked to mutant p53 gain-of-function. In this review, we summarize the delicate relationship among p53 mutational status, MKK3/MKK6 and the downstream activated master kinase p38MAPK, dissecting a finely-tuned crosstalk, in a potentially cell-context dependent scenario that urges towards a deeper characterization of the different molecular players involved in this signaling cascade and their interactions...
May 3, 2018: Cancers
https://www.readbyqxmd.com/read/29750295/endogenous-leu332gln-mutation-in-p53-disrupts-the-tetramerization-ability-in-a-canine-mammary-gland-tumor-cell-line
#15
Kazuhiko Ochiai, Daigo Azakami, Masami Morimatsu, Hinako Hirama, Shota Kawakami, Takayuki Nakagawa, Masaki Michishita, Ai S Egusa, Takanori Sasaki, Masami Watanabe, Toshinori Omi
Mutations in the p53 gene are associated with more than half of all human cancers. These mutations often cause a disruption of the tumor-suppressor function of p53 and induce genomic instabilities. Wild‑type p53 requires tetramerization to function as an initiator of cell cycle arrest and apoptosis. Although alterations in p53 tetramerization caused by mutation have been well studied, there are few cell lines containing an endogenous mutation in the tetramerization domain of p53. Here, we report the discovery of a canine mammary gland tumor cell line CTB‑m2, which contains the Leu332Gln (L332Q) mutation corresponding to Leu344 in the tetramerization domain of human p53...
May 2, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29743236/idh1-r132-mutant-promotes-tumor-formation-through-downregulating-p53
#16
Bin Jiang, Wentao Zhao, Minggang Shi, Jia Zhang, Ai Chen, Huanhuan Ma, Muhammad Suleman, Furong Lin, Lin Zhou, Jinyang Wang, Yan Zhang, Mengjue Liu, Shixiong Wen, Cong Ouyang, Huihui Wang, Xiumin Huang, Huamin Zhou, Qinxi Li
Resistance to apoptosis and uncontrolled proliferation are two hallmarks of cancer cells. p53 is crucial for apoptosis triggered by a broad range of stresses and a well known gatekeeper for neoplastic transformation. Here we show that oncogenic IDH1 R132H/Q mutants robustly inhibit p53 expression and such an effect is attributed to 2-HG production. Mechanistically, 2-HG stabilizes hypoxia-inducible factor-2α which in turn activates the expression of miR-380-5p, a characterized microRNA against p53 expression...
May 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29740875/evaluation-of-epithelial-dysplasia-adjacent-to-lip-squamous-cell-carcinoma-indicates-that-the-degree-of-dysplasia-is-not-associated-to-the-occurrence-of-invasive-carcinoma-in-this-site
#17
Gabriela Nagata, Thalita Santana, Aline Queiroz, Renata Helena Caramez, Marília Trierveiler
BACKGROUND: We analyzed the different grades of dysplasia in the epithelium adjacent to lip squamous cell carcinoma (LSCC), as a parallel to actinic cheilitis (AC) that suffered malignant transformation. METHODS: Forty samples of epithelium adjacent to LSCC were histologically graded according to the World Health Organization (WHO) and the binary systems. The expression of mutated p53 was evaluated through immunohistochemistry. RESULTS: According to WHO system, 37...
May 8, 2018: Journal of Cutaneous Pathology
https://www.readbyqxmd.com/read/29740540/signaling-pathways-regulating-redox-balance-in-cancer-metabolism
#18
REVIEW
Maria Chiara De Santis, Paolo Ettore Porporato, Miriam Martini, Andrea Morandi
The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29739757/evidence-of-inter-tissue-differences-in-the-dna-damage-response-and-the-pro-oncogenic-role-of-nf%C3%AE%C2%BAb-in-mice-with-disengaged-brca1-palb2-interaction
#19
Amar Hekmat Mahdi, Yanying Huo, Yongmei Tan, Srilatha Simhadri, Gabriele Vincelli, Jie Gao, Shridar Ganesan, Bing Xia
The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair (HRR), defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here we analyzed several aspects of the DNA damage response in multiple tissues of Palb2 mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage...
May 8, 2018: Cancer Research
https://www.readbyqxmd.com/read/29734785/the-guardian-of-the-genome-revisited-p53-downregulates-genes-required-for-telomere-maintenance-dna-repair-and-centromere-structure
#20
REVIEW
Eléonore Toufektchan, Franck Toledo
The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia...
May 6, 2018: Cancers
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