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Tp53 and MDM4

Ivana Jovčevska
The most aggressive brain malignancy, glioblastoma, accounts for 60-70% of all gliomas and is uniformly fatal. According to the molecular signature, glioblastoma is divided into four subtypes (proneural, neural, classical, and mesenchymal), each with its own genetic background. The Cancer Genome Atlas project provides information about the most common genetic changes in glioblastoma. They involve mutations in TP53, TERT, and PTEN, and amplifications in EFGR, PDGFRA, CDK4, CDK6, MDM2, and MDM4. Recently, epigenetics was used to demonstrate the oncogenic roles of miR-124, miR-137, and miR-128...
April 18, 2018: Critical Reviews in Clinical Laboratory Sciences
Ausra Stumbryte, Zivile Gudleviciene, Gabrielis Kundrotas, Daiva Dabkeviciene, Agne Kunickaite, Saulius Cicenas
Lung cancer (LC) is the second common and with the highest mortality oncological disease. Specific biomarkers for its diagnostics, treatment, and prognosis are still under the investigations. Aim of our study was to evaluate the relationship between the polymorphisms of TP53 pathway genes TP53, MDM2, MDM4, the polymorphisms of HPV-associated genes MTHFR, CASP8, CCR5, and HPV infection with survival of LC patients. SNPs were genotyped using PCR-RFLP. qRT-PCR was used to detect, identify, and quantify HPV. No statistically significant differences were detected between individual SNPs and patient survival with stage I-IV LC...
January 9, 2018: Oncotarget
Olaf Merkel, Ninon Taylor, Nicole Prutsch, Philipp B Staber, Richard Moriggl, Suzanne D Turner, Lukas Kenner
The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. After a brief introduction to current knowledge of p53 and its regulation by the ubiquitin-ligases MDM2/MDMX and post-translational modifications, we will discuss small molecules that are able to reactivate specific, frequently observed mutant forms of p53 and their applicability for clinical purposes...
July 2017: Mutation Research
Zdenek Andrysik, Matthew D Galbraith, Anna L Guarnieri, Sara Zaccara, Kelly D Sullivan, Ahwan Pandey, Morgan MacBeth, Alberto Inga, Joaquín M Espinosa
The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the TP53 gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53...
October 2017: Genome Research
Gabriel S Macedo, Igor Araujo Vieira, Fernanda Salles Luiz Vianna, Barbara Alemar, Juliana Giacomazzi, Ana Paula Carneiro Brandalize, Maira Caleffi, Sahlua Miguel Volc, Henrique de Campos Reis Galvão, Edenir Inez Palmero, Maria Isabel Achatz, Patricia Ashton-Prolla
Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186)...
July 29, 2017: Familial Cancer
Ulrike Fischer, Ella Kim, Andreas Keller, Eckart Meese
There is growing evidence that gene amplifications are an attribute of normal cells during development and differentiation. During neural progenitor cell differentiation half of the genome is involved in amplification process. To answer the question how specific amplifications occur at different stages and in different lineages of differentiation we analyzed the genes CDK4, MDM2, EGFR, GINS2, GFAP, TP53, DDB1 and MDM4 in human neural stem cells that were induced to differentiate towards astrocytes, neurons and oligodendrocytes...
April 18, 2017: Oncotarget
Emilie A Chapeau, Agnieszka Gembarska, Eric Y Durand, Emeline Mandon, Claire Estadieu, Vincent Romanet, Marion Wiesmann, Ralph Tiedt, Joseph Lehar, Antoine de Weck, Roland Rad, Louise Barys, Sebastien Jeay, Stephane Ferretti, Audrey Kauffmann, Esther Sutter, Armelle Grevot, Pierre Moulin, Masato Murakami, William R Sellers, Francesco Hofmann, Michael Rugaard Jensen
Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
Leah Zhrebker, Irene Cherni, Lara M Gross, Margaret M Hinshelwood, Merrick Reese, Jessica Aldrich, Joseph M Guileyardo, William C Roberts, David Craig, Daniel D Von Hoff, Robert G Mennel, John D Carpten
BACKGROUND: Primary cardiac angiosarcomas are rare, but they are the most aggressive type of primary cardiac neoplasms. When patients do present, it is with advanced pulmonary and/or cardiac symptoms. Therefore, many times the correct diagnosis is not made at the time of initial presentation. These patients have metastatic disease and the vast majority of these patients die within a few months after diagnosis. Currently the treatment choices are limited and there are no targeted therapies available...
January 5, 2017: BMC Cancer
Ana B Herrero, Elizabeta A Rojas, Irena Misiewicz-Krzeminska, Patryk Krzeminski, Norma C Gutiérrez
The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation...
November 30, 2016: International Journal of Molecular Sciences
James A McCubrey, Kvin Lertpiriyapong, Timothy L Fitzgerald, Alberto M Martelli, Lucio Cocco, Dariusz Rakus, Agnieszka Gizak, Massimo Libra, Melchiorre Cervello, Guiseppe Montalto, Li V Yang, Stephen L Abrams, Linda S Steelman
TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation...
January 2017: Advances in Biological Regulation
Fabiola Moretti
MDM2 (mouse double minute 2 homolog) and MDM4 (double minute 4 human homolog, also known as MDMX) inhibit the activity of tumor protein p53 (TP53, best known as p53) through their heterodimerization. New evidence indicates that under stress conditions the heterodimer is modified, leading to different activities of the single molecules. In particular, following lethal DNA damage, MDM2 and MDM4 dissociate and MDM4 promotes the stabilization of homeodomain-interacting protein kinase 2 (HIPK2) and the phosphorylation of p53, resulting in transcriptional repression of antiapoptotic targets of p53/HIPK2...
March 2016: Molecular & Cellular Oncology
Cynthia R Coffill, Alison P Lee, Jia Wei Siau, Sharon M Chee, Thomas L Joseph, Yaw Sing Tan, Arumugam Madhumalar, Boon-Hui Tay, Sydney Brenner, Chandra S Verma, Farid J Ghadessy, Byrappa Venkatesh, David P Lane
The extant jawless vertebrates, represented by lampreys and hagfish, are the oldest group of vertebrates and provide an interesting genomic evolutionary pivot point between invertebrates and jawed vertebrates. Through genome analysis of one of these jawless vertebrates, the Japanese lamprey (Lethenteron japonicum), we identified all three members of the important p53 transcription factor family--Tp53, Tp63, and Tp73--as well as the Mdm2 and Mdm4 genes. These genes and their products are significant cellular regulators in human cancer, and further examination of their roles in this most distant vertebrate relative sheds light on their origin and coevolution...
February 1, 2016: Genes & Development
Mayakannan Manikandan, Arunagiri Kuha Deva Magendhra Rao, Ganesan Arunkumar, Kottayasamy Seenivasagam Rajkumar, Ramamurthy Rajaraman, Arasambattu Kannan Munirajan
BACKGROUND: Aberrant microRNA expression has been associated with the pathogenesis of a variety of human malignancies including oral squamous cell carcinoma (SCC). In this study, we examined primary oral SCCs for the expression of 6 candidate miRNAs, of which five (miR-34a, miR-143, miR-373, miR-380-5p, and miR- 504) regulate the tumor suppressor TP53 and one (miR-99a) is involved in AKT/mTOR signaling. MATERIALS AND METHODS: Tumor tissues (punch biopsies) were collected from 52 oral cancer patients and as a control, 8 independent adjacent normal tissue samples were also obtained...
2015: Asian Pacific Journal of Cancer Prevention: APJCP
Vanessa Cristina Jacovas, Diego Luiz Rovaris, Orlando Peréz, Soledad de Azevedo, Gabriel Souza Macedo, José Raul Sandoval, Alberto Salazar-Granara, Mercedes Villena, Jean-Michel Dugoujon, Rafael Bisso-Machado, Maria Luiza Petzl-Erler, Francisco Mauro Salzano, Patricia Ashton-Prolla, Virginia Ramallo, Maria Cátira Bortolini
The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed...
2015: PloS One
Vivek Subbiah, Manojkumar Bupathi, Shumei Kato, Andrew Livingston, John Slopis, Pete M Anderson, David S Hong
BACKGROUND: The aggressive biology of cancers arising in adolescent and young adult (AYA; ages 15-39 years) patients is thought to contribute to poor survival outcomes. METHODS: We used clinical next-generation sequencing (NGS) results to examine the molecular alterations and diverse biology of cancer in AYA patients referred to the Phase 1 program at UT MD Anderson Cancer Center. RESULTS: Among the 28 patients analyzed (14 female and 14 male), 12 had pediatric-type cancers, six had adult-type cancers, and ten had orphan cancers...
2015: Oncoscience
John M Furgason, Robert F Koncar, Sharon K Michelhaugh, Fazlul H Sarkar, Sandeep Mittal, Andrew E Sloan, Jill S Barnholtz-Sloan, El Mustapha Bahassi
BACKGROUND: Findings based on recent advances in next-generation sequence analysis suggest that, in some tumors, a single catastrophic event, termed chromothripsis, results in several simultaneous tumorigenic alterations. Previous studies have suggested that glioblastoma (GBM) may exhibit chromothripsis at a higher rate (39%) than other tumors (9%). Primary glioblastoma is an aggressive form of brain cancer that typically appears suddenly in older adults. With aggressive treatment, the median survival time is only 15 months...
2015: Oncoscience
Francisco Navarro, Judy Lieberman
miR-34, a tumor suppressor miRNA family transcriptionally activated by p53, is considered a critical mediator of p53 function. However, knockout of the mouse miR-34 family has little or no effect on the p53 response. The relative contribution of different miR-34 family members to p53 function or how much p53 relies on miR-34 in human cells is unclear. Here we show that miR-34a has a complex effect on the p53 response in human cells. In HCT116 cells miR-34a overexpression enhances p53 transcriptional activity, but the closely related family members, miR-34b and miR-34c, even when over-expressed, have little effect...
2015: PloS One
Kathleen I Pishas, Alaknanda Adwal, Susan J Neuhaus, Mark T Clayer, Gelareh Farshid, Alexander H Staudacher, David F Callen
There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma. XI-006 treatment of Ewing and osteosarcoma cell lines (n = 11) resulted in rapid and potent apoptosis at low micro-molar concentrations specifically in Ewing sarcoma cell lines (48 hr IC50 0...
June 22, 2015: Scientific Reports
Yashashree Joshi, Marília Grando Sória, Giorgia Quadrato, Gizem Inak, Luming Zhou, Arnau Hervera, Khizr I Rathore, Mohamed Elnaggar, Magali Cucchiarini, Cucchiarini Magali, Jeanne Christophe Marine, Radhika Puttagunta, Simone Di Giovanni
Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown...
July 2015: Brain: a Journal of Neurology
Ines Crespo, Ana Louisa Vital, María Gonzalez-Tablas, María del Carmen Patino, Alvaro Otero, María Celeste Lopes, Catarina de Oliveira, Patricia Domingues, Alberto Orfao, Maria Dolores Tabernero
In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types...
July 2015: American Journal of Pathology
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