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Tp53 and MDM4

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...
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
Hong Huang, Kathryn B H Clancy, Crystal Burhance, Yilliang Zhu, Lorena Madrigal
OBJECTIVES: We examine if there are genetic and environmental differences between mothers of singleton and multiple pregnancies in a sample of African-American mothers. METHODS: We focus on genomic areas suggested to increase or decrease the odds of multiple pregnancies. We computed the odds ratio (OR) and the 95% confidence interval (CI) for each SNP unadjusted or adjusted with smoking. SNPs' allelic differences between mothers of multiple pregnancies and singletons were also tested using Fisher's exact test...
September 2015: American Journal of Human Biology: the Official Journal of the Human Biology Council
Michael J Duffy, Naoise C Synnott, Patricia M McGowan, John Crown, Darran O'Connor, William M Gallagher
TP53 (p53) is the most frequently mutated gene in cancer, being altered in approximately 50% of human malignancies. In most, if not all, cancers lacking mutation, wild-type (WT) p53 is inactivated by interaction with cellular (MDM2/MDM4) or viral proteins, leading to its degradation. Because of its near universal alteration in cancer, p53 is an attractive target for the development of new targeted therapies for this disease. However, until recently, p53 was widely regarded as ‘‘undruggable’’. This situation has now changed, as several compounds have become available that can restore wild-type properties to mutant p53 (e...
December 2014: Cancer Treatment Reviews
Chuanbo Fan, Jinyu Wei, Chenglu Yuan, Xin Wang, Chuanwu Jiang, Changchun Zhou, Ming Yang
As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China. Accumulated evidences demonstrated that oncoprotein MDM4 plays a crucial role in the TP53 tumor suppressor signaling pathway. An rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression. In this study, we examined the association between this polymorphism as well as the TP53 Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population...
2014: PloS One
Daniel J Brat
BACKGROUND: Lower grade gliomas (LGG) are infiltrative brain tumors that include astrocytomas, oligodendrogliomas and oligoastrocytomas, grades II and III. LGGs almost always progress, typically to glioblastoma (GBM, grade IV), and are uniformly fatal. The Cancer Genome Atlas (TCGA) is conducting a comprehensive molecular analysis of LGG, incorporating genetic and genomic alterations, DNA methylation profiles, and RNA and proteomic signatures. The rich, integrated clinical data of TCGA provides an outstanding platform to uncover biomarkers of therapy response and outcome...
July 2014: Neuro-oncology
Jong-Lyel Roh, Jin Young Park, Eun Hye Kim
Head and neck cancer (HNC), one of the most common cancers worldwide, frequently involves mutation of the TP53 gene and dysregulation of the p53 pathway. Overexpression of MDM2 or MDM4 inactivates the tumor-suppressive function of p53. Restoration of p53 function that counteracts these p53 repressors can lead to in vivo tumor regression. Therefore, the present study assessed the ability of the small molecule p53 activator XI-011 (NSC146109) to induce apoptosis in HNC by restoring p53 function. We tested the effects of XI-011 treatment in HNC cell lines, either individually or in combination with cisplatin and assessed growth suppression, cell cycle arrest, and apoptosis...
November 2014: Apoptosis: An International Journal on Programmed Cell Death
Thierry Soussi
Inactivation of TP53 pathways are the most common defects observed in human cancer. Although missense mutations remain the most frequent genetic event, it is now evident that dysfunction of several members of this network such as MDM2, MDM4 (mdmX), or miR-125b can substitute for TP53 mutations. This special issue on TP53 brings the TP53 gene into the post-genomic era. Several fundamental features of wild type and mutant proteins and their modifications are reviewed, as well as animal models and clinical aspects such as recommendations for patient care...
June 2014: Human Mutation
Chi Young Ok, Zijun Y Xu-Monette, Alexandar Tzankov, Dennis P O'Malley, Santiago Montes-Moreno, Carlo Visco, Michael B Møller, Karen Dybkaer, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L Richards, Eric D Hsi, J Han van Krieken, Maurilio Ponzoni, John P Farnen, Miguel A Piris, Jane N Winter, L Jeffrey Medeiros, Ken H Young
BACKGROUND: Cyclin D1 expression has been reported in a subset of patients with diffuse large B-cell leukemia (DLBCL), but studies have been few and generally small, and they have demonstrated no obvious clinical implications attributable to cyclin D1 expression. METHODS: The authors reviewed 1435 patients who were diagnosed with DLBCL as part of the International DLBCL rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) Consortium Program and performed clinical, immunohistochemical, and genetic analyses with a focus on cyclin D1...
June 15, 2014: Cancer
Funda Meric-Bernstam, Garrett M Frampton, Jaime Ferrer-Lozano, Roman Yelensky, Jose A Pérez-Fidalgo, Ying Wang, Gary A Palmer, Jeffrey S Ross, Vincent A Miller, Xiaoping Su, Pilar Eroles, Juan Antonio Barrera, Octavio Burgues, Ana M Lluch, Xiaofeng Zheng, Aysegul Sahin, Philip J Stephens, Gordon B Mills, Maureen T Cronin, Ana M Gonzalez-Angulo
There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases)...
May 2014: Molecular Cancer Therapeutics
Christine M Eischen, Guillermina Lozano
The potent transcriptional activity of p53 (Trp53, TP53) must be kept in check for normal cell growth and survival. Tumors, which drastically deviate from these parameters, have evolved multiple mechanisms to inactivate TP53, the most prevalent of which is the emergence of TP53 missense mutations, some of which have gain-of-function activities. Another important mechanism by which tumors bypass TP53 functions is via increased levels of two TP53 inhibitors, MDM2, and MDM4. Studies in humans and in mice reveal the complexity of TP53 regulation and the exquisite sensitivity of this pathway to small changes in regulation...
June 2014: Human Mutation
Kathleen I Pishas, Susan J Neuhaus, Mark T Clayer, Andreas W Schreiber, David M Lawrence, Michelle Perugini, Robert J Whitfield, Gelareh Farshid, Jim Manavis, Steve Chryssidis, Bronwen J Mayo, Rebecca C Haycox, Kristen Ho, Michael P Brown, Richard J D'Andrea, Andreas Evdokiou, David M Thomas, Jayesh Desai, David F Callen, Paul M Neilsen
Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity...
February 1, 2014: Cancer Research
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