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p53 cancer mutation

Thomas R Pisanic, Shiho Asaka, Shiou-Fu Lin, Ting-Tai Yen, Hanru Sun, Asli Bahadirli-Talbott, Tza-Huei Wang, Kathleen H Burns, Tian-Li Wang, Ie-Ming Shih
There is growing evidence that the majority of high-grade serous ovarian carcinomas likely arise from local dissemination of precursor lesions of the fallopian tube. Evolution of these lesions from early "p53 signatures" to latter-stage, serous tubal intraepithelial carcinomas (STICs) is characterized by cytologic atypia, accumulation of somatic mutations, and genomic instability, the etiologies of which remain unclear. Long interspersed element 1 (LINE-1) retrotransposon is expressed in many carcinomas, including high-grade serous ovarian carcinoma, where it contributes to genomic instability; however, the timing of LINE-1 activation during this evolution has yet to be elucidated...
December 13, 2018: American Journal of Pathology
Amit Gupta, Karan Shah, Manisha J Oza, Tapan Behl
Cancer is an uncontrolled and abnormal growth of cells in the body. Gene that guards the cell cycle and function as tumor suppressor is p53 (also called as the guardian of the genome) which is encoded by the TP53 gene. Various events like DNA damage, heat shock, hypoxia and oncogene over expression, results in activation of p53.Thus, it plays a major role as a regulatory protein which regulates various diverse biological responses, responsible for genetic stability by preventing genome mutation. More than 50% mutations in human cancers along with the increase in expression of murine double minute 2 gene (mdm2), has been found as one of the reason for cancer progression...
January 2019: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Manzar Alam, Tanushree Kashyap, Prajna Mishra, Aditya K Panda, Siddavaram Nagini, Rajakishore Mishra
BACKGROUND: Bax, a proapoptotic protein but its regulation during oral cancer progression and resistance remains elusive. METHODS: A total of 127 samples including adjacent normal, primary tumor, and resistance to chemoradiation therapy (RCRT) samples from oral squamous cell carcinoma (OSCC) patients were used. The status of Bax was analyzed at DNA/mRNA/protein levels and the results were correlated with p53 and Akt expression in tissue samples/cisplatin-resistant oral tongue SCC (SCC9/SCC4-CisR) cell line...
December 14, 2018: Head & Neck
Morgan Pellerano, Delphine Naud-Martin, Florence Mahuteau-Betzer, Marie Morille, May Catherine Morris
The p53 tumour suppressor and guardian of the genome undergoes missense mutations which lead to functional inactivation in 50% human cancers. These mutations occur mostly in the DNA-binding domain of the protein and several of these induce conformational changes which lead to amyloid-like protein aggregation. Here we describe a fluorescent biosensor that reports on the R248Q mutant of p53 in vitro and in living cells, engineered through conjugation of an environmentally-sensitive probe onto a peptide derived from the primary aggregation segment of p53...
December 13, 2018: Chembiochem: a European Journal of Chemical Biology
Katarzyna Skonieczna, Arkadiusz Jawień, Andrzej Marszałek, Tomasz Grzybowski
BACKGROUND: p53 is a tumour suppressor protein that is involved in many cancer-related processes. Growing evidence suggests that p53 also plays an important role in mtDNA maintenance. Somatic mitogenome mutations are frequently observed in colorectal cancer cells. Thus, it was important to verify whether somatic mtDNA changes are associated with TP53 mutational status. METHODS: Here, we analysed the TP53 gene in 67 colorectal cancer patients, for whom mitogenome haplotypes were previously described...
December 10, 2018: Journal of Gene Medicine
Maria Mrakovcic, Lauren Bohner, Marcel Hanisch, Leopold F Fröhlich
Tumor development and progression is the consequence of genetic as well as epigenetic alterations of the cell. As part of the epigenetic regulatory system, histone acetyltransferases (HATs) and deacetylases (HDACs) drive the modification of histone as well as non-histone proteins. Derailed acetylation-mediated gene expression in cancer due to a delicate imbalance in HDAC expression can be reversed by histone deacetylase inhibitors (HDACi). Histone deacetylase inhibitors have far-reaching anticancer activities that include the induction of cell cycle arrest, the inhibition of angiogenesis, immunomodulatory responses, the inhibition of stress responses, increased generation of oxidative stress, activation of apoptosis, autophagy eliciting cell death, and even the regulation of non-coding RNA expression in malignant tumor cells...
December 8, 2018: International Journal of Molecular Sciences
Tasleem Arif, Avijit Paul, Yakov Krelin, Anna Shteinfer-Kuzmine, Varda Shoshan-Barmatz
Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231)...
December 8, 2018: Cancers
Victor D Li, Karen H Li, John T Li
PURPOSE: Mutations in the tumor suppressor gene TP53 are associated with a variety of cancers. Therefore, it is important to know the occurrence and prognostic effects of TP53 mutations in certain cancers. METHODS: Over 29,000 cases from the April 2016 release of the International Agency for Research on Cancer (IARC) TP53 Database were analyzed to determine the distribution of germline and somatic mutations in the TP53 gene. Subsequently, 7,893 cancer cases were compiled in cBioPortal for Cancer Genomics from the 33 most recent The Cancer Genome Atlas (TCGA) studies to determine the prevalence of TP53 mutations in cancers and their effects on survival and disease-free survival times...
December 12, 2018: Journal of Cancer Research and Clinical Oncology
Ying-Jian Song, Juan Tan, Xin-Huai Gao, Li-Xin Wang
Background: Lung cancer is one of the most common malignant tumors. Despite advances in lung cancer therapies, prognosis of non-small-cell lung cancer is still unfavorable. The aim of this study was to identify the prognostic value of key genes in lung tumorigenesis. Methods: Differentially expressed genes (DEGs) were screened out by GEO2R from three Gene Expression Omnibus cohorts. Common DEGs were selected for Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology enrichment analysis...
2018: Cancer Management and Research
Fiamma Mantovani, Licio Collavin, Giannino Del Sal
Forty years of research have established that the p53 tumor suppressor provides a major barrier to neoplastic transformation and tumor progression by its unique ability to act as an extremely sensitive collector of stress inputs, and to coordinate a complex framework of diverse effector pathways and processes that protect cellular homeostasis and genome stability. Missense mutations in the TP53 gene are extremely widespread in human cancers and give rise to mutant p53 proteins that lose tumor suppressive activities, and some of which exert trans-dominant repression over the wild-type counterpart...
December 11, 2018: Cell Death and Differentiation
Joshua Heyza, Wen Lei, Donovan Watza, Hao Zhang, Wei Chen, Jessica B Back, Ann G Schwartz, Gerold Bepler, Steve M Patrick
PURPOSE: ERCC1/XPF is a DNA endonuclease with variable expression in primary tumor specimens, and has been investigated as a predictive biomarker for efficacy of platinum-based chemotherapy. The failure of clinical trials utilizing ERCC1 expression to predict response to platinum-based chemotherapy suggests additional mechanisms underlying the basic biology of ERCC1 in the response to interstrand crosslinks (ICLs) remain unknown. We aimed to characterize a panel of ERCC1 knockout (D) cell lines where we identified a synthetic viable phenotype in response to ICLs with ERCC1 deficiency...
December 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Suk-Chul Bae, Arun Mouli Kolinjivadi, Yoshiaki Ito
RUNX genes belong to a three-membered family of transcription factors, which are well established as master regulators of development. Of them, aberrations in RUNX3 expression are frequently observed in human malignancies primarily due to epigenetic silencing which is often overlooked. At the G1 phase of the cell cycle, RUNX3 regulates the restriction (R)-point, a mechanism that decides cell cycle entry. Deregulation at the R-point or loss of RUNX3 results in premature entry into S phase, leading to a proliferative advantage...
December 11, 2018: Journal of Molecular Cell Biology
Boya Liu, Jingjie Yi, Xin Yang, Lu Liu, Xinlin Lou, Zeyuan Zhang, Hao Qi, Zhe Wang, Junhua Zou, Wei-Guo Zhu, Wei Gu, Jianyuan Luo
MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro...
December 7, 2018: Oncogene
Veronica V Rossato, Daner A Silveira, Shantanu Gupta, José Carlos M Mombach
The transforming growth factor-beta (TGF-β) pathway is involved in the regulation of cell growth and differentiation. In normal cells or in the early stages of cancer, this pathway can control proliferation stimuli by inducing cell cycle arrest or apoptosis (through the MAP-kinase protein p38MAPK), while in late stages it seems to act as a tumor promoter. This feature is known as the TGF-β dual role in cancer and it is not completely explained. This seems to arise through the accumulation of mutations in cancer development that affect the normal function of these pathways...
December 3, 2018: Computers in Biology and Medicine
Hakim Echchannaoui, Jutta Petschenka, Edite Antunes Ferreira, Beate Hauptrock, Carina Lotz-Jenne, Ralf-Holger Voss, Matthias Theobald
Genetic engineering of T cells with a T cell receptor (TCR) targeting tumor antigen is a promising strategy for cancer immunotherapy. Inefficient expression of the introduced TCR due to TCR mispairing may limit the efficacy and adversely affect the safety of TCR gene therapy. Here, we evaluated the safety and therapeutic efficiency of an optimized single-chain TCR (scTCR) specific for an HLA-A2.1-restricted (non-mutated) p53(264-272) peptide in adoptive T cell transfer (ACT) models using our unique transgenic mice expressing human p53 and HLA-A2...
November 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Soo Youn Bae, Seung Pil Jung, Se Kyung Lee, Jonghan Yu, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam
Mutations of the p53 gene are the most common genomic alterations associated with triple-negative breast cancer (TNBC) and are reported in 60-88% cases. Despite the high incidence of such mutations, there is no consensus about the clinical application of p53 detection in breast cancer management. This study investigates the prognostic value of immunohistochemically detected p53 in TNBC patients who received adjuvant chemotherapy. We reviewed the clinicopathologic features of 1088 TNBC patients who received curative surgery and adjuvant chemotherapy...
December 2018: Kaohsiung Journal of Medical Sciences
Elizabeth R Smith, Callinice D Capo-Chichi, Xiang-Xi Xu
Aneuploidy, loss or gain of whole chromosomes, is a prominent feature of carcinomas, and is generally considered to play an important role in the initiation and progression of cancer. In high-grade serous ovarian cancer, the only common gene aberration is the p53 point mutation, though extensive genomic perturbation is common due to severe aneuploidy, which presents as a deviant karyotype. Several mechanisms for the development of aneuploidy in cancer cells have been recognized, including chromosomal non-disjunction during mitosis, centrosome amplification, and more recently, nuclear envelope rupture at interphase...
2018: Frontiers in Oncology
Jasmin Quandt, Christoph Schlude, Michael Bartoschek, Rainer Will, Angel Cid-Arregui, Sebastian Schölch, Christoph Reissfelder, Jürgen Weitz, Martin Schneider, Stefan Wiemann, Frank Momburg, Philipp Beckhove
Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28-35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential...
2018: Oncoimmunology
Timothy J Humpton, Andreas K Hock, Oliver D K Maddocks, Karen H Vousden
Background: In response to oncogenic stress, the tumour suppressor protein p53 can induce the elimination of cells through induction of cell death or senescence, helping to restrain malignant progression. Conversely, under nutrient stress, p53 can protect cells by supporting metabolic adaptation. Many cancers express mutant p53 proteins that have lost the cell-elimination properties of wild-type p53. However, a previous report showed that a tumour-derived mutant can retain the ability to support cells under glutamine starvation...
2018: Cancer & Metabolism
Aline Talhouk, Heather Derocher, Pascal Schmidt, Samuel Leung, Katy Milne, Blake Gilks, Michael S Anglesio, Brad H Nelson, Jessica N McAlpine
PURPOSE: Tumors with high mutation load are thought to engender stronger immune responses which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TIL) and immunosuppressive factors across the four molecular subtypes of endometrial cancer (EC), which have characteristic mutation rates ranging from low to ultra-high. EXPERIMENTAL DESIGN: 460 ECs were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into four molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wildtype (p53wt)...
December 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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