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https://www.readbyqxmd.com/read/28214231/mechanisms-of-action-and-structure-activity-relationships-of-cytotoxic-flavokawain-derivatives
#1
Charlotte Thieury, Nicolas Lebouvier, Rémy Le Guével, Yann Barguil, Gaëtan Herbette, Cyril Antheaume, Edouard Hnawia, Yoshinori Asakawa, Mohammed Nour, Thierry Guillaudeux
22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2',3,4',6'-tetramethoxychalcone (FKd 19)...
February 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28212429/the-p53-isoform-delta133p53%C3%A3-regulates-cancer-cell-apoptosis-in-a-rhob-dependent-manner
#2
Nikola Arsic, Alexandre Ho-Pun-Cheung, Crapez Evelyne, Eric Assenat, Marta Jarlier, Christelle Anguille, Manon Colard, Mikaël Pezet, Pierre Roux, Gilles Gadea
The TP53 gene plays essential roles in cancer. Conventionally, wild type (WT) p53 is thought to prevent cancer development and metastasis formation, while mutant p53 has transforming abilities. However, clinical studies failed to establish p53 mutation status as an unequivocal predictive or prognostic factor of cancer progression. The recent discovery of p53 isoforms that can differentially regulate cell cycle arrest and apoptosis suggests that their expression, rather than p53 mutations, could be a more clinically relevant biomarker in patients with cancer...
2017: PloS One
https://www.readbyqxmd.com/read/28211885/the-novel-bmi-1-inhibitor-ptc596-downregulates-mcl-1-and-induces-p53-independent-mitochondrial-apoptosis-in-acute-myeloid-leukemia-progenitor-cells
#3
Y Nishida, A Maeda, M J Kim, L Cao, Y Kubota, J Ishizawa, A AlRawi, Y Kato, A Iwama, M Fujisawa, K Matsue, M Weetall, M Dumble, M Andreeff, T W Davis, A Branstrom, S Kimura, K Kojima
Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization...
February 17, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28211873/the-p53-family-members-have-distinct-roles-during-mammalian-embryonic-development
#4
Jeanine L Van Nostrand, Margot E Bowen, Hannes Vogel, Maria Barna, Laura D Attardi
The p53 tumor suppressor is a member of a multi-protein family, including the p63 and p73 transcription factors. These proteins can bind to the same consensus sites in DNA and activate the same target genes, suggesting that there could be functional redundancy between them. Indeed, double mutant mice heterozygous for any two family member-encoding genes display enhanced cancer phenotypes relative to single heterozygous mutants. However, whether the family members play redundant roles during embryonic development has remained largely unexplored...
February 17, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28208646/recognition-of-local-dna-structures-by-p53-protein
#5
Václav Brázda, Jan Coufal
p53 plays critical roles in regulating cell cycle, apoptosis, senescence and metabolism and is commonly mutated in human cancer. These roles are achieved by interaction with other proteins, but particularly by interaction with DNA. As a transcription factor, p53 is well known to bind consensus target sequences in linear B-DNA. Recent findings indicate that p53 binds with higher affinity to target sequences that form cruciform DNA structure. Moreover, p53 binds very tightly to non-B DNA structures and local DNA structures are increasingly recognized to influence the activity of wild-type and mutant p53...
February 10, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28199986/a-tree-shrew-glioblastoma-model-recapitulates-features-of-human-glioblastoma
#6
Yaohui Tong, Junjun Hao, Qiu Tu, Hualin Yu, Lanzhen Yan, Yuan Li, Longbao Lv, Fei Wang, Antonio Iavarone, Xudong Zhao
Tupaia belangeri (tree shrew), an animal species whose genome has significantly higher similarity to primates than rodents, has been used in biomedical research. To generate animal models that reproduce the human tumors more faithfully than rodents, we present the first report of a cancer model mimicking human tumor genetics in tree shrew. By engineering a lentiviral system for the transduction of mutant H-Ras and a shRNA against tree shrew p53, we successfully generated malignant glioma in tree shrew. The tree shrew glioma exhibited aggressive behavior and a relatively short latency, and markedly reduced animal survival...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28197530/mutant-p53-nrf2-axis-regulates-the-proteasome-machinery-in-cancer
#7
Kamil Lisek, Dawid Walerych, Giannino Del Sal
The proteasome machinery is a common target of gain-of-function p53 missense mutants. Upregulation of the proteasome fosters chemoresistance to proteasome inhibitors. In triple negative breast cancer cells this resistance mechanism, namely the Nrf2-regulated "bounce-back" response to proteasome inhibitors, can be overcome by targeting p53 mutant proteins with APR-246/PRIMA-1Met.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28195154/zinc-finger-protein-zpr9-functions-as-an-activator-of-ampk-related-serine-threonine-kinase-mpk38-melk-involved-in-ask1-tgf-%C3%AE-p53-signaling-pathways
#8
Hyun-A Seong, Ravi Manoharan, Hyunjung Ha
Murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF-β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activator of MPK38. The association of MPK38 and ZPR9 was mediated by cysteine residues present in each of these two proteins, Cys(269) and Cys(286) of MPK38 and Cys(305) and Cys(308) of ZPR9...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28187004/didymin-an-orally-active-citrus-flavonoid-for-targeting-neuroblastoma
#9
REVIEW
Sharad S Singhal, Sulabh Singhal, Preeti Singhal, Jyotsana Singhal, David Horne, Sanjay Awasthi
Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases...
February 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28186976/32-phosphorus-selectively-delivered-by-listeria-to-pancreatic-cancer-demonstrates-a-strong-therapeutic-effect
#10
Dinesh Chandra, Benson Chellakkan Selvanesan, Ziqiang Yuan, Steven K Libutti, Wade Koba, Amanda Beck, Kun Zhu, Arturo Casadevall, Ekaterina Dadachova, Claudia Gravekamp
Our laboratory has developed a novel delivery platform using an attenuated non-toxic and non-pathogenic bacterium Listeria monocytogenes that infects tumor cells and selectively survives and multiplies in metastases and primary tumors with help of myeloid-derived suppressor cells (MDSC) and immune suppression in the tumor microenvironment (TME). 32P was efficiently incorporated into the Listeria bacteria by starvation of the bacteria in saline, and then cultured in phosphorus-free medium complemented with 32P as a nutrient...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28186650/p16-and-p53-in-hpv-positive-versus-hpv-negative-oral-squamous-cell-carcinoma-oscc-do-pathways-differ
#11
Vineeta Singh, Nuzhat Husain, Naseem Akhtar, M Y Khan, Abhinav A Sonkar, Vijay Kumar
BACKGROUND: p16 overexpression and wild-type p53 expression is associated with human papilloma virus (HPV) in cervical and oropharyngeal cancer. Role of HPV-related carcinogenesis in the etiology of oral squamous cell carcinoma (OSCC) is still vague in Indian population. We aimed to explore the expression pattern of p16 and p53 in HPV positive and HPV negative OSCC to elicit differences, if any. Further their effect on survival of patients was studied. METHODS: Thirty-one consecutive HPV positive as well as 31 age and sex matched HPV negative OSCC cases from a case series of 369 histologically diagnosed cases of OSCC were included in this study...
February 10, 2017: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/28171849/dose-responsive-efficacy-of-umbelliferone-on-lipid-peroxidation-anti-oxidant-and-xenobiotic-metabolism-in-dmba-induced-oral-carcinogenesis
#12
Annamalai Vijayalakshmi, Ganapathy Sindhu
This study evaluated the chemopreventive potential of umbelliferone (UMB) on 7,12- dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis. The mechanistic pathway for chemopreventive potential of UMB was evaluated by measuring the status of tumour incidence, tumour volume, and tumour burden as well as by analyzing the status of phase I, phase II detoxification agents, lipid peroxidation, antioxidants, histopathological changes and also expression patterns of cell proliferation (PCNA, Cyclin D1) and apoptotic (p53) markers using immunohistochemistry in DMBA induced hamster buccal pouch carcinogenesis...
February 4, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28166433/pro-metastatic-p53-mutants-control-folding-of-n-glycoproteins
#13
Jean Schneikert, Thorsten Stiewe
No abstract text is available yet for this article.
February 6, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28166194/mutant-p53-oncogenic-functions-in-cancer-stem-cells-are-regulated-by-wip-through-yap-taz
#14
M Escoll, R Gargini, A Cuadrado, I M Anton, F Wandosell
Wild-type p53 (wtp53) is described as a tumour suppressor gene; mutations in this gene occur in many human cancers and promote oncogenic capacity. Here, we establish that the oncogenic activity of mutant p53 (mtp53) is driven by the WASP-interacting protein (WIP). WIP knockdown from mtp53-expressing glioblastoma and breast cancer cells (BCC) greatly reduced proliferation and growth capacity of cancer stem cell (CSC)-like cells and decreased CSC-like markers (CD133, CD44 or YAP/TAZ). mtp53 overexpression in human astrocytes enhanced their proliferative capacity in suspension culture and increased expression of CSC markers and WIP...
February 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28160562/the-tumor-suppressor-capability-of-p53-is-dependent-on-non-muscle-myosin-iia-function-in-head-and-neck-cancer
#15
Sonya D Coaxum, Jessica Tiedeken, Elizabeth Garrett-Mayer, Jeffrey Myers, Steven A Rosenzweig, David M Neskey
Over 300,000 patients develop squamous cell carcinoma of the head and neck (HNSCC) worldwide with 25-30% of patients ultimately dying from their disease. Currently, molecular biomarkers are not used in HNSCC but several genes have been identified including mutant TP53 (mutp53). Our recent work has identified an approach to stratify patients with tumors harboring high or low risk TP53 mutations. Non-muscle Myosin IIA (NMIIA) was recently identified as a tumor suppressor in HNSCC. We now demonstrate that low MYH9 expression is associated with decreased survival in patients with head and neck cancer harboring low-risk mutp53 but not high-risk mutp53...
February 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28160167/histone-deacetylase-inhibitors-vpa-and-tsa-induce-apoptosis-and-autophagy-in-pancreatic-cancer-cells
#16
Maria Saveria Gilardini Montani, Marisa Granato, Claudio Santoni, Paola Del Porto, Nicolò Merendino, Gabriella D'Orazi, Alberto Faggioni, Mara Cirone
PURPOSE: Histone deacetylase inhibitors (HDACi) are anti-neoplastic agents that are known to affect the growth of different cancer types, but their underlying mechanisms are still incompletely understood. Here, we compared the effects of two HDACi, i.e., Trichostatin A (TSA) and Valproic Acid (VPA), on the induction of cell death and autophagy in pancreatic cancer-derived cells that exhibit a high metastatic capacity and carry KRAS/p53 double mutations. METHODS: Cell viability and proliferation tests were carried out using Trypan blue dye exclusion, MTT and BrdU assays...
February 3, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28157690/variant-peptide-detection-utilizing-mass-spectrometry-laying-the-foundations-for-proteogenomic-identification-and-validation
#17
Lampros Dimitrakopoulos, Ioannis Prassas, Els M J J Berns, John A Foekens, Eleftherios P Diamandis, George S Charames
BACKGROUND: Proteogenomics is an emerging field at the intersection of genomics and proteomics. Many variant peptides corresponding to single nucleotide variations (SNVs) are associated with specific diseases. The aim of this study was to demonstrate the feasibility of proteogenomic-based variant peptide detection in disease models and clinical specimens. METHODS: We sought to detect p53 single amino acid variant (SAAV) peptides in breast cancer tumor samples that have been previously subjected to sequencing analysis...
February 3, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/28153791/hdac6-deacetylates-p53-at-lysines-381-382-and-differentially-coordinates-p53-induced-apoptosis
#18
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Junjeong Choi, Gyoonhee Han, Kang Young Lee, So Hee Kwon
HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation...
January 30, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28149884/p53-mutations-and-cancer-a-tight-linkage
#19
COMMENT
Francesco Perri, Salvatore Pisconti, Giuseppina Della Vittoria Scarpati
P53 is often mutated in solid tumors, in fact, somatic changes involving the gene encoding for p53 (TP53) have been discovered in more than 50% of human malignancies and several data confirmed that p53 mutations represent an early event in cancerogenesis. Main p53 functions consist in cell cycle arrest, DNA repair, senescence and apoptosis induction in response to mutagenic stimuli, and, to exert those functions, p53 acts as transcriptional factor. Recent data have highlighted another very important role of p53, consisting in regulate cell metabolism and cell response to oxidative stress...
December 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28148827/mutant-idh1-disrupts-the-mouse-subventricular-zone-and-alters-brain-tumor-progression
#20
Christopher J Pirozzi, Austin B Carpenter, Matthew S Waitkus, Catherine Y Wang, Huishan Zhu, Landon J Hansen, Lee H Chen, Paula K Greer, Jie Feng, Yu Wang, Cheryl B Bock, Ping Fan, Ivan Spasojevic, Roger E McLendon, Darell D Bigner, Yiping He, Hai Yan
: IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell cycle arrest as well as a decreased ability to undergo neuronal differentiation...
February 1, 2017: Molecular Cancer Research: MCR
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