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TP53 disruption

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https://www.readbyqxmd.com/read/28153010/targeting-muc1-c-inhibits-the-akt-s6k1-elf4a-pathway-regulating-tigar-translation-in-colorectal-cancer
#1
Rehan Ahmad, Maroof Alam, Masanori Hasegawa, Yasumitsu Uchida, Omar Al-Obaid, Surender Kharbanda, Donald Kufe
BACKGROUND: Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 heterodimeric protein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. Here, we investigate the effects of the MUC1-C subunit inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on human colorectal cancer cells. METHODS: TIGAR mRNA level was determined using qRT-PCR. Western blotting was used to measure TIGAR protein level and AKT-mTOR-S6K1 pathways...
February 2, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28068922/functional-changes-in-mrna-expression-and-alternative-pre-mrna-splicing-associated-with-the-effects-of-nutrition-on-apoptosis-and-spermatogenesis-in-the-adult-testis
#2
Yongjuan Guan, Guanxiang Liang, Graeme B Martin, Le Luo Guan
BACKGROUND: The effects of nutrition on testis mass in the sexually mature male have long been known, however, the cellular and molecular processes of the testis response to nutrition was not fully understood. METHODS: We tested whether the defects in spermatogenesis and increases in germ cell apoptosis in the testis that are induced by under-nutrition are associated with changes in mRNA expression and pre-mRNA alternative splicing using groups of 8 male sheep fed for a 10% increase or 10% decrease in body mass over 65 days...
January 10, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28000777/bach1-promotes-temozolomide-resistance-in-glioblastoma-through-antagonizing-the-function-of-p53
#3
Er Nie, Xin Jin, Weining Wu, Tianfu Yu, Xu Zhou, Tongle Zhi, Zhumei Shi, Junxia Zhang, Ning Liu, Yongping You
The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo...
December 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27959929/histological-transformation-and-progression-in-follicular-lymphoma-a-clonal-evolution-study
#4
Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew Mungall, Richard Moore, Ryan D Morin, Nathalie A Johnson, Laurie H Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M Connors, David W Scott, Christian Steidl, Marco A Marra, Randy D Gascoyne, Sohrab P Shah
BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27869650/inhibiting-mitochondrial-respiration-prevents-cancer-in-a-mouse-model-of-li-fraumeni-syndrome
#5
Ping-Yuan Wang, Jie Li, Farzana L Walcott, Ju-Gyeong Kang, Matthew F Starost, S Lalith Talagala, Jie Zhuang, Ji-Hoon Park, Rebecca D Huffstutler, Christina M Bryla, Phuong L Mai, Michael Pollak, Christina M Annunziata, Sharon A Savage, Antonio Tito Fojo, Paul M Hwang
Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism in patients. However, the implications of altered mitochondrial function for tumorigenesis in LFS are unclear. Here, we have reported that genetic or pharmacologic disruption of mitochondrial respiration improves cancer-free survival in a mouse model of LFS that expresses mutant p53. Mechanistically, inhibition of mitochondrial function increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27866339/recurrent-tp53-missense-mutation-in-cancer-patients-of-arab-descent
#6
Aviad Zick, Luna Kadouri, Sherri Cohen, Michael Frohlinger, Tamar Hamburger, Naama Zvi, Morasha Plaser, Eilat Avital, Shani Breuier, Firase Elian, Azzam Salah, Yael Goldberg, Tamar Peretz
Hereditary cancer comprises more than 10% of all breast cancer cases. Identification of germinal mutations enables the initiation of a preventive program that can include early detection or preventive treatment and may also have a major impact on cancer therapy. Several recurrent mutations were identified in the BRCA1/2 genes in Jewish populations however, in other ethnic groups in Israel, no recurrent mutations were identified to date. Our group established panel sequencing in cancer patients to identify recurrent, founder, and new mutations in the heterogeneous and diverse populations in Israel, We evaluated five breast cancer patients of Arab descent diagnosed with cancer before the age of 50 years and identified the previously described TP53 mutation, c...
November 19, 2016: Familial Cancer
https://www.readbyqxmd.com/read/27821812/karyotypic-complexity-rather-than-chromosome-8-abnormalities-aggravates-the-outcome-of-chronic-lymphocytic-leukemia-patients-with-tp53-aberrations
#7
Gonzalo Blanco, Anna Puiggros, Panagiotis Baliakas, Anastasia Athanasiadou, MªDolores García-Malo, Rosa Collado, Aliki Xochelli, María Rodríguez-Rivera, Margarita Ortega, Mª José Calasanz, Elisa Luño, MªTeresa Vargas, Javier Grau, Carolina Martínez-Laperche, Alberto Valiente, José Cervera, Achilles Anagnostopoulos, Eva Gimeno, Eugènia Abella, Evangelia Stalika, Jesús Mª Hernández-Rivas, Francisco José Ortuño, Diego Robles, Ana Ferrer, David Ivars, Marcos González, Francesc Bosch, Pau Abrisqueta, Kostas Stamatopoulos, Blanca Espinet
Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14...
December 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27758891/signal-oriented-pathway-analyses-reveal-a-signaling-complex-as-a-synthetic-lethal-target-for-p53-mutations
#8
Songjian Lu, Chunhui Cai, Gonghong Yan, Zhuan Zhou, Yong Wan, Vicky Chen, Lujia Chen, Gregory F Cooper, Lina M Obeid, Yusuf A Hannun, Adrian V Lee, Xinghua Lu
Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for cancer pathway discovery in this context. We applied our bipartite graph-based functional module discovery algorithm to identify transcriptomic modules abnormally expressed in multiple tumors, such that the genes in a module were likely regulated by a common, perturbed signal. For each transcriptomic module, we applied our weighted k-path merge algorithm to search for a set of somatic genome alterations (SGA) that likely perturbed the signal, that is, the candidate members of the pathway that regulate the transcriptomic module...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27755861/association-of-egf-igfbp-3-and-tp53-gene-polymorphisms-with-major-depressive-disorder-in-slovak-population
#9
Silvia Mahmood, Andrea Evinová, Mária Škereňová, Igor Ondrejka, Ján Lehotský
BACKGROUND: Major depressive disorder (MDD) is a main public health concern worldwide. Despite extensive investigations, the exact mechanisms responsible for MDD have not been identified. Epidermal growth factor (EGF) and insulin growth factor binding protein-3 (IGFBP-3) are involved in brain function. Tumour suppressor protein p53 is widely involved in neuronal death in response to different forms of acute insults and neurological disorders. The present study focuses on the possible associations of the single-nucleotide polymorphisms (SNP) of EGF A61G (rs4444903), IGFBP-3 C32G (rs2854746) and TP53 G72C (rs1042522) genes with MDD risk in the Slovak population...
September 2016: Central European Journal of Public Health
https://www.readbyqxmd.com/read/27751354/mutant-tp53-disrupts-age-related-accumulation-patterns-of-somatic-mutations-in-multiple-cancer-types
#10
Wensheng Zhang, Erik K Flemington, Kun Zhang
Most cancers are driven by somatic mutations in proto-oncogenes and tumor suppressor genes. Genetic changes in a tumor may accumulate in the tissue self-renewal phase prior to neoplasm. The risk of sporadic mutations increases with age. In this regard, a positive association between patient age and the accumulated mutation burden in tumors exists for many cancer types. However, the reported lines of evidence for such a connection are still limited. TP53 is the most frequently mutated cancer gene. The encoded p53 protein plays crucial roles in DNA repair...
September 2016: Cancer Genetics
https://www.readbyqxmd.com/read/27713038/validation-of-recently-proposed-colorectal-cancer-susceptibility-gene-variants-in-an-analysis-of-families-and-patients-a-systematic-review
#11
Peter Broderick, Sara E Dobbins, Daniel Chubb, Ben Kinnersley, Malcolm G Dunlop, Ian Tomlinson, Richard S Houlston
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene...
January 2017: Gastroenterology
https://www.readbyqxmd.com/read/27678008/major-prognostic-value-of-complex-karyotype-in-addition-to-tp53-and-ighv-mutational-status-in-first-line-chronic-lymphocytic-leukemia
#12
Yannick Le Bris, Stéphanie Struski, Romain Guièze, Caroline Rouvellat, Naïs Prade, Xavier Troussard, Olivier Tournilhac, Marie C Béné, Eric Delabesse, Loïc Ysebaert
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder of remarkable heterogeneity as demonstrated by cytogenetics and molecular analyses. Complex karyotype (CK), TP53 deletions and/or mutations (TP53 disruption), IGVH mutational status, and, more recently, recurrent somatic mutations have been identified as prognostic markers in CLL. On a cohort of 110 patients with CLL treated with first-line fludarabin, cyclophosphamide, and rituximab treatment compared with 33 untreated (watch and wait) patients with CLL, we report more frequent complex karyotypes (34 vs 15%; P = ...
September 28, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27633522/extensive-next-generation-sequencing-analysis-in-chronic-lymphocytic-leukemia-at-diagnosis-clinical-and-biological-correlations
#13
Gian Matteo Rigolin, Elena Saccenti, Cristian Bassi, Laura Lupini, Francesca Maria Quaglia, Maurizio Cavallari, Sara Martinelli, Luca Formigaro, Enrico Lista, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Antonio Urso, Francesco Cavazzini, Massimo Negrini, Antonio Cuneo
BACKGROUND: In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations. METHODS: We performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression...
September 15, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27633013/genetic-ablation-of-smoothened-in-pancreatic-fibroblasts-increases-acinar-ductal-metaplasia
#14
Xin Liu, Jason R Pitarresi, Maria C Cuitiño, Raleigh D Kladney, Sarah A Woelke, Gina M Sizemore, Sunayana G Nayak, Onur Egriboz, Patrick G Schweickert, Lianbo Yu, Stefan Trela, Daniel J Schilling, Shannon K Halloran, Maokun Li, Shourik Dutta, Soledad A Fernandez, Thomas J Rosol, Gregory B Lesinski, Reena Shakya, Thomas Ludwig, Stephen F Konieczny, Gustavo Leone, Jinghai Wu, Michael C Ostrowski
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM...
September 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27619989/mutational-analysis-of-tp53-gene-in-tunisian-familial-hematological-malignancies-and-sporadic-acute-leukemia-cases
#15
Walid Sabri Hamadou, Sawsen Besbes, Violaine Bourdon, Yosra Ben Youssef, Mohamed Adnène Laatiri, Testsuro Noguchi, Abderrahim Khélif, Hagay Sobol, Zohra Soua
Mutations are responsible for familial cancer syndromes which account for approximately 5-10 % of all types of cancers. Familial cancers are often caused by genetic alterations occurring either in tumor suppressor or genomic stability genes such as TP53. In this study, we have analyzed the TP53 gene by direct sequencing approach, in a panel of 18 Tunisian familial hematological malignancies cases including several forms of leukemia, lymphoma and myeloid syndrome and 22 cases of sporadic acute leukemia. In one familial case diagnosed with acute lymphoblastic leukemia, we reported an intronic substitution 559+1 G>A which may disrupt the splice site and impact the normal protein function...
January 2017: Familial Cancer
https://www.readbyqxmd.com/read/27617643/zeb1-induces-epb41l5-in-the-cancer-mesenchymal-program-that-drives-arf6-based-invasion-metastasis-and-drug-resistance
#16
A Hashimoto, S Hashimoto, H Sugino, A Yoshikawa, Y Onodera, H Handa, T Oikawa, H Sabe
Onset of the cancer mesenchymal program is closely associated with cancer malignancy and drug resistance. Among the different epithelial-mesenchymal transition (EMT)-associated transcriptional factors, ZEB1 has a key role in inducing the mesenchymal phenotypes and stem cell-like properties of different breast cancer cells. ARF6 and its effector AMAP1 are frequently overexpressed in breast cancer cells, and promote invasion, metastasis and drug resistance. EPB41L5 is induced during EMT, and mediates the disruption of E-cadherin-based cell-cell adhesion and the promotion of focal adhesion dynamics...
2016: Oncogenesis
https://www.readbyqxmd.com/read/27556692/chk1-inhibition-significantly-potentiates-activity-of-nucleoside-analogs-in-tp53-mutated-b-lymphoid-cells
#17
Jana Zemanova, Ondrej Hylse, Jana Collakova, Pavel Vesely, Alexandra Oltova, Marek Borsky, Kristina Zaprazna, Marie Kasparkova, Pavlina Janovska, Jan Verner, Jiri Kohoutek, Marta Dzimkova, Vitezslav Bryja, Zuzana Jaskova, Yvona Brychtova, Kamil Paruch, Martin Trbusek
Treatment options for TP53-mutated lymphoid tumors are very limited. In experimental models, TP53-mutated lymphomas were sensitive to direct inhibition of checkpoint kinase 1 (Chk1), a pivotal regulator of replication. We initially tested the potential of the highly specific Chk1 inhibitor SCH900776 to synergize with nucleoside analogs (NAs) fludarabine, cytarabine and gemcitabine in cell lines derived from B-cell malignancies. In p53-proficient NALM-6 cells, SCH900776 added to NAs enhanced signaling towards Chk1 (pSer317/pSer345), effectively blocked Chk1 activation (Ser296 autophosphorylation), increased replication stress (p53 and γ-H2AX accumulation) and temporarily potentiated apoptosis...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27535981/cell-intrinsic-determinants-of-ibrutinib-induced-apoptosis-in-chronic-lymphocytic-leukemia
#18
Nisar A Amin, Sriram Balasubramanian, Kamlai Saiya-Cork, Kerby Shedden, Nan Hu, Sami N Malek
Purpose: Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) and CLL with del17p. Mechanistically, ibrutinib interferes with B-cell receptor (BCR) signaling as well as multiple CLL cell-to-microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted.Experimental Design: We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole-exome sequencing and SNP 6...
February 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27533246/sensitivity-to-prima-1met-is-associated-with-decreased-mgmt-in-human-glioblastoma-cells-and-glioblastoma-stem-cells-irrespective-of-p53-status
#19
Mariia Patyka, Zeinab Sharifi, Kevin Petrecca, Jose Mansure, Bertrand Jean-Claude, Siham Sabri
Alterations of the TP53 tumor suppressor gene occur in ~30% of primary glioblastoma (GBM) with a high frequency of missense mutations associated with the acquisition of oncogenic "gain-of-function" (GOF) mutant (mut)p53 activities. PRIMA-1MET/APR-246, emerged as a promising compound to rescue wild-type (wt)p53 function in different cancer types. Previous studies suggested the role of wtp53 in the negative regulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), a major determinant in resistance to therapy in GBM treatment...
September 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27486974/telomere-status-in-chronic-lymphocytic-leukemia-with-tp53-disruption
#20
Romain Guièze, Mélanie Pages, Lauren Véronèse, Patricia Combes, Richard Lemal, Mathilde Gay-Bellile, Martine Chauvet, Mary Callanan, Fabrice Kwiatkowski, Bruno Pereira, Philippe Vago, Jacques-Olivier Bay, Olivier Tournilhac, Andreï Tchirkov
In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients...
30, 2016: Oncotarget
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