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Xiao-Tong Wang, Qiu-Yuan Xia, Sheng-Bing Ye, Xuan Wang, Rui Li, Ru Fang, Shan-Shan Shi, Ru-Song Zhang, Xiao Tan, Jie-Yu Chen, Ke Sun, Xiao-Dong Teng, Heng-Hui Ma, Zhen-Feng Lu, Xiao-Jun Zhou, Qiu Rao
Both Xp11 translocation renal cell carcinomas and the corresponding mesenchymal neoplasms are characterized by a variety of gene fusions involving TFE3. It has been known that tumors with different gene fusions may have different clinicopathologic features; however, further in-depth investigations of subtyping Xp11 translocation-associated cancers are needed in order to explore more meaningful clinicopathologic correlations. A total of 22 unusual cases of Xp11 translocation-associated cancers were selected for the current study; 20 cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners...
April 30, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Lisa M Tuttle, Derek Pacheco, Linda Warfield, Jie Luo, Jeff Ranish, Steven Hahn, Rachel E Klevit
Transcription activation domains (ADs) are inherently disordered proteins that often target multiple coactivator complexes, but the specificity of these interactions is not understood. Efficient transcription activation by yeast Gcn4 requires its tandem ADs and four activator-binding domains (ABDs) on its target, the Mediator subunit Med15. Multiple ABDs are a common feature of coactivator complexes. We find that the large Gcn4-Med15 complex is heterogeneous and contains nearly all possible AD-ABD interactions...
March 20, 2018: Cell Reports
Kunyuan Wang, Chenxi Duan, Xuejing Zou, Yang Song, Wenwen Li, Lushan Xiao, Jie Peng, Liheng Yao, Qian Long, Li Liu
Mediator complex subunit 15 (MED15) is a coactivator involved in the regulated transcription of RNA polymerase II-dependent genes and serves an oncogenic role in numerous types of cancer. However, the expression and function of MED15 in hepatocellular carcinoma (HCC) remain unknown. In the present study, the aim was to investigate the expression and clinical significance of MED15 in HCC. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical analysis revealed that MED15 mRNA and protein levels were significantly upregulated in HCC tissues compared with those in the corresponding adjacent non-tumor liver tissues...
April 2018: Oncology Letters
Derek Pacheco, Linda Warfield, Michelle Brajcich, Hannah Robbins, Jie Luo, Jeff Ranish, Steven Hahn
Eukaryotic transcription activation domains (ADs) are intrinsically disordered polypeptides that typically interact with coactivator complexes, leading to stimulation of transcription initiation, elongation, and chromatin modifications. Here we examined the properties of two strong and conserved yeast ADs: Met4 and Ino2. Both factors have tandem ADs that were identified by conserved sequence and functional studies. While the AD function of both factors depended on hydrophobic residues, Ino2 further required key conserved acidic and polar residues for optimal function...
May 15, 2018: Molecular and Cellular Biology
Elien M Doorduijn, Marjolein Sluijter, Bianca J Querido, Ursula J E Seidel, Claudia C Oliveira, Sjoerd H van der Burg, Thorbald van Hall
The HLA-E homolog in the mouse (Qa-1b ) is a conserved MHC class Ib molecule presenting monomorphic peptides to germline-encoded natural killer receptor CD94/NKG2A. Previously, we demonstrated the replacement of this canonical peptide by a diverse peptidome upon deficiency of the TAP peptide transporter. Analysis of this Qa-1b -restricted T cell repertoire against these non-mutated neoantigens revealed characteristics of conventional hypervariable CD8+ T cells, but also of invariant T cell receptor (TCR)αβ T cells...
2018: Frontiers in Immunology
Richard Weiten, Tim Müller, Doris Schmidt, Susanne Steiner, Glen Kristiansen, Stefan C Müller, Jörg Ellinger, Isabella Syring
BACKGROUND/OBJECTIVE: MED15 is a part of the multiprotein Mediator complex which is involved in the transcription of polymerase (Pol) II-dependent genes. Several studies in this field have reported altered expressions of distinct subunits in human malignancy. However, the role of MED15 in renal cell carcinoma (RCC) has not be investigated yet. METHODS: First, we performed an RNA expression and survival analysis of MED15 in RCC by using the database cBioPortal. To confirm these data on the protein level, we executed immunohistochemical (IHC) staining against MED15 on a tissue microarray containing 184 samples of the most common subtypes of the tumour at the various stages...
2018: Cancer Biomarkers: Section A of Disease Markers
Vinay Kumar, Mohd Waseem, Nidhi Dwivedi, Sourobh Maji, Angad Kumar, Jitendra K Thakur
Med15 is an important subunit of Mediator tail module and is characterized by a KIX domain present in the amino terminal. In yeast and metazoans, Med15 KIX domain has been found to interact with various transcription factors, regulating several processes including carbohydrate metabolism, lipogenesis, stress response and multidrug resistance. Mechanism of Med15 functioning in Arabidopsis is largely unknown. In this study, interactome of Arabidopsis Med15, AtMed15a, was characterized. We found 45 proteins that interact with AtMed15a KIX domain, including 11 transcription factors, 3 single strand nucleic acid-binding proteins and 1 splicing factor...
January 17, 2018: Plant Signaling & Behavior
Archana Yadav, Jitendra K Thakur, Gitanjali Yadav
The KIX domain has emerged in the last two decades as a critical site of interaction for transcriptional assembly, regulation and gene expression. Discovered in 1994, this conserved, triple helical globular domain has been characterised in various coactivator proteins of yeast, mammals and plants, including the p300/CBP (a histone acetyl transferase), MED15 (a subunit of the mediator complex of RNA polymerase II), and RECQL5 helicases. In this work, we describe the first rigorous meta analysis of KIX domains across all forms of life, leading to the development of KIXBASE, a predictive web server and global repository for detection and analysis of KIX domains...
November 2, 2017: Scientific Reports
Chenggang Wang, Xuezhu Du, Zhonglin Mou
Mediator is a highly conserved protein complex that functions as a transcriptional coactivator in RNA polymerase II (RNAPII)-mediated transcription. The Arabidopsis Mediator complex has recently been implicated in plant immune responses. Here, we compared salicylic acid (SA)-, methyl jasmonate (MeJA)-, and the ethylene (ET) precursor 1-aminocyclopropane-1-carboxylic acid (ACC)-induced defense and/or wound-responsive gene expression in 14 Arabidopsis Mediator subunit mutants. Our results show that MED14, MED15, and MED16 are required for SA-activated expression of the defense marker gene PATHOEGNESIS-RELATED GENE1, MED25 is required for MeJA-induced expression of the wound-responsive marker gene VEGATATIVE STORAGE PROTEIN1 (VSP1), MED8, MED14, MED15, MED16, MED18, MED20a, MED25, MED31, and MED33A/B (MED33a and MED33B) are required for MeJA-induced expression of the defense maker gene PLANT DEFENSIN1...
2016: Frontiers in Plant Science
Anne Offermann, Ignacija Vlasic, Isabella Syring, Wenzel Vogel, Christian Ruiz, Tobias Zellweger, Cyrill A Rentsch, Susanne Hagedorn, Jochen Behrends, Michael Nowak, Axel Merseburger, Lukas Bubendorf, Jutta Kirfel, Stefan Duensing, Zaki Shaikhibrahim, Sven Perner
Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%...
January 31, 2017: Oncotarget
Yenkai Lim, Yunxia Wan, Dimitrios Vagenas, Dmitry A Ovchinnikov, Chris F L Perry, Melissa J Davis, Chamindie Punyadeera
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumours with a typical 5 year survival rate of <40 %. DNA methylation in tumour-suppressor genes often occurs at an early stage of tumorigenesis, hence DNA methylation can be used as an early tumour biomarker. Saliva is an ideal diagnostic medium to detect early HNSCC tumour activities due to its proximity to tumour site, non-invasiveness and ease of sampling. We test the hypothesis that the surveillance of DNA methylation in five tumour-suppressor genes (RASSF1α, p16 (INK4a) , TIMP3, PCQAP/MED15) will allow us to diagnose HNSCC patients from a normal healthy control group as well as to discriminate between Human Papillomavirus (HPV)-positive and HPV-negative patients...
2016: BMC Cancer
Pradeep Dahiya, Divya S Bhat, Jitendra K Thakur
Mediator, a multiprotein complex involved in transcription of class II genes, was first discovered in yeast and then characterized in many metazoans revealing a striking structural conservation of the complex. However, sequences of Mediator subunits are not well conserved raising a question on the functional conservation of these individual subunits. In this study, expression of Med15 of Arabidopsis (AtMed15) in gal11∆ yeast could not complement the function of ScGal11 in galactose metabolism and resistance against cycloheximide...
June 16, 2016: Scientific Reports
Mi Jung Kim, In-Cheol Jang, Nam-Hai Chua
The Mediator complex is known to be a master coordinator of transcription by RNA polymerase II, and this complex is recruited by transcription factors (TFs) to target promoters for gene activation or repression. The plant-specific TF WRINKLED1 (WRI1) activates glycolysis-related and fatty acid biosynthetic genes during embryogenesis. However, no Mediator subunit has yet been identified that mediates WRI1 transcriptional activity. Promoter-β-glucuronidase fusion experiments showed that MEDIATOR15 (MED15) is expressed in the same cells in the embryo as WRI1...
July 2016: Plant Physiology
Jayamani Anandhakumar, Yara W Moustafa, Surabhi Chowdhary, Amoldeep S Kainth, David S Gross
Mediator is an evolutionarily conserved coactivator complex essential for RNA polymerase II transcription. Although it has been generally assumed that in Saccharomyces cerevisiae, Mediator is a stable trimodular complex, its structural state in vivo remains unclear. Using the "anchor away" (AA) technique to conditionally deplete select subunits within Mediator and its reversibly associated Cdk8 kinase module (CKM), we provide evidence that Mediator's tail module is highly dynamic and that a subcomplex consisting of Med2, Med3, and Med15 can be independently recruited to the regulatory regions of heat shock factor 1 (Hsf1)-activated genes...
July 15, 2016: Molecular and Cellular Biology
Joy L Nishikawa, Andras Boeszoermenyi, Luis A Vale-Silva, Riccardo Torelli, Brunella Posteraro, Yoo-Jin Sohn, Fei Ji, Vladimir Gelev, Dominique Sanglard, Maurizio Sanguinetti, Ruslan I Sadreyev, Goutam Mukherjee, Jayaram Bhyravabhotla, Sara J Buhrlage, Nathanael S Gray, Gerhard Wagner, Anders M Näär, Haribabu Arthanari
Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi...
February 25, 2016: Nature
Malini Nagulapalli, Sourobh Maji, Nidhi Dwivedi, Pradeep Dahiya, Jitendra K Thakur
Mediator, an important component of eukaryotic transcriptional machinery, is a huge multisubunit complex. Though the complex is known to be conserved across all the eukaryotic kingdoms, the evolutionary topology of its subunits has never been studied. In this study, we profiled disorder in the Mediator subunits of 146 eukaryotes belonging to three kingdoms viz., metazoans, plants and fungi, and attempted to find correlation between the evolution of Mediator complex and its disorder. Our analysis suggests that disorder in Mediator complex have played a crucial role in the evolutionary diversification of complexity of eukaryotic organisms...
February 29, 2016: Nucleic Acids Research
Anne Offermann, Zaki Shaikhibrahim, Sven Perner
No abstract text is available yet for this article.
2015: Biomarkers in Medicine
Kati Kämpjärvi, Nam Hee Kim, Salla Keskitalo, Alison D Clark, Pernilla von Nandelstadh, Mikko Turunen, Tuomas Heikkinen, Min Ju Park, Netta Mäkinen, Kati Kivinummi, Susanna Lintula, Kristina Hotakainen, Heli Nevanlinna, Peter Hokland, Tom Böhling, Ralf Bützow, Jan Böhm, Jukka-Pekka Mecklin, Heikki Järvinen, Mika Kontro, Tapio Visakorpi, Jussi Taipale, Markku Varjosalo, Thomas G Boyer, Pia Vahteristo
BACKGROUND: Mediator is a multiprotein interface between eukaryotic gene-specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator-associated kinase activity. MED12 mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer...
January 2016: Prostate
Niklas Klümper, Isabella Syring, Anne Offermann, Zaki Shaikhibrahim, Wenzel Vogel, Stefan C Müller, Jörg Ellinger, Arne Strauß, Heinz Joachim Radzun, Philipp Ströbel, Johannes Brägelmann, Sven Perner, Felix Bremmer
BACKGROUND: Testicular germ cell tumors (TGCT) are the most common cancer entities in young men with increasing incidence observed in the last decades. For therapeutic management it is important, that TGCT are divided into several histological subtypes. MED15 is part of the multiprotein Mediator complex which presents an integrative hub for transcriptional regulation and is known to be deregulated in several malignancies, such as prostate cancer and bladder cancer role, whereas the role of the Mediator complex in TGCT has not been investigated so far...
2015: Diagnostic Pathology
Xuefeng Zhu, Lihua Chen, Jonas O P Carlsten, Qian Liu, Junsheng Yang, Beidong Liu, Claes M Gustafsson
The Med2, Med3 and Med15 proteins form a heterotrimeric subdomain in the budding yeast Mediator complex. This Med15 module is an important target for many gene specific transcription activators. A previous proteome wide screen in yeast identified Med3 as a protein with priogenic potential. In the present work, we have extended this observation and demonstrate that both Med3 and Med15 form amyloid-like protein aggregates under H2O2 stress conditions. Amyloid formation can also be stimulated by overexpression of Med3 or of a glutamine-rich domain present in Med15, which in turn leads to loss of the entire Med15 module from Mediator and a change in stress response...
September 3, 2015: Nucleic Acids Research
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