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Érica Aparecida de Oliveira, Diogenes Saulo de Lima, Lucas Esteves Cardozo, Garcia Ferreira de Souza, Nayane de Souza, Debora Kristina Alves-Fernandes, Fernanda Faião-Flores, José Agustín Pablo Quincoces, Silvia Berlanga de Moraes Barros, Helder I Nakaya, Gisele Monteiro, Silvya Stuchi Maria-Engler
Melanoma is a highly invasive and metastatic cancer with high mortality rates and chemoresistance. Around 50% of melanomas are driven by activating mutations in BRAF that has led to the development of potent anti-BRAF inhibitors. However resistance to anti-BRAF therapy usually develops within a few months and consequently there is a need to identify alternative therapies that will bypass BRAF inhibitor resistance. The curcumin analogue DM-1 (sodium 4-[5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) has substantial anti-tumor activity in melanoma, but its mechanism of action remains unclear...
September 4, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
De-Chen Lin, Huy Q Dinh, Jian-Jun Xie, Anand Mayakonda, Tiago Chedraoui Silva, Yan-Yi Jiang, Ling-Wen Ding, Jian-Zhong He, Xiu-E Xu, Jia-Jie Hao, Ming-Rong Wang, Chunquan Li, Li-Yan Xu, En-Min Li, Benjamin P Berman, H Phillip Koeffler
OBJECTIVES: Oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance. DESIGN: Previously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures...
August 31, 2017: Gut
Yu Liu, John Easton, Ying Shao, Jamie Maciaszek, Zhaoming Wang, Mark R Wilkinson, Kelly McCastlain, Michael Edmonson, Stanley B Pounds, Lei Shi, Xin Zhou, Xiaotu Ma, Edgar Sioson, Yongjin Li, Michael Rusch, Pankaj Gupta, Deqing Pei, Cheng Cheng, Malcolm A Smith, Jaime Guidry Auvil, Daniela S Gerhard, Mary V Relling, Naomi J Winick, Andrew J Carroll, Nyla A Heerema, Elizabeth Raetz, Meenakshi Devidas, Cheryl L Willman, Richard C Harvey, William L Carroll, Kimberly P Dunsmore, Stuart S Winter, Brent L Wood, Brian P Sorrentino, James R Downing, Mignon L Loh, Stephen P Hunger, Jinghui Zhang, Charles G Mullighan
Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN)...
August 2017: Nature Genetics
Christopher B Ball, Amanda C Solem, Rita M Meganck, Alain Laederach, Silvia B V Ramos
ZFP36L2 (L2) destabilizes AU-rich element (ARE)-containing transcripts and has been implicated in female fertility. We have shown that only one of three putative AREs within the 3' UTR of murine luteinizing hormone receptor mRNA, ARE2197 (UAUUUAU), is capable of interacting with L2. To assess whether structural elements of ARE2197 could explain this unique binding ability, we performed whole-transcript SHAPE-MaP (selective 2' hydroxyl acylation by primer extension-mutational profiling) of the full-length mLHR mRNA...
August 2017: RNA
Keiichi Yonemori, Naohiko Seki, Hiroshi Kurahara, Yusaku Osako, Tetsuya Idichi, Takayuki Arai, Keiichi Koshizuka, Yoshiaki Kita, Kosei Maemura, Shoji Natsugoe
Due to its aggressive nature, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and hard-to-treat malignancies. Recently developed targeted molecular strategies have contributed to remarkable improvements in the treatment of several cancers. However, such therapies have not been applied to PDAC. Therefore, new treatment options are needed for PDAC based on current genomic approaches. Expression of microRNA-375 (miR-375) was significantly reduced in miRNA expression signatures of several types of cancers, including PDAC...
January 2017: Cancer Science
Katharina U Vogel, Lewis S Bell, Alison Galloway, Helena Ahlfors, Martin Turner
The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly to enforce the β-selection checkpoint during thymopoiesis, yet their molecular targets remain largely unknown. In this study, we identify these targets on a genome-wide scale in primary mouse thymocytes and show that Zfp36l1/l2 regulate DNA damage response and cell cycle transcripts to ensure proper β-selection. Double-negative 3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with postselected double-negative 3b cells despite the absence of intracellular TCRβ and reduced IL-7 signaling...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Frauke Prenzler, Annunziata Fragasso, Angelika Schmitt, Barbara Munz
The ZFP36 family of zinc finger proteins, including ZFP36, ZFP36L1, and ZFP36L2, regulates the production of growth factors and cytokines via destabilization of the respective mRNAs. We could recently demonstrate that in cultured keratinocytes, expression of the ZFP36, ZFP36L1, and ZFP36L2 genes is induced by growth factors and cytokines and that ZFP36L1 is a potent regulator of keratinocyte VEGF production. We now further analyzed the localization and function of ZFP36 proteins in the skin, specifically in epidermal keratinocytes...
August 2016: European Journal of Cell Biology
Alison Galloway, Alexander Saveliev, Sebastian Łukasiak, Daniel J Hodson, Daniel Bolland, Kathryn Balmanno, Helena Ahlfors, Elisa Monzón-Casanova, Sara Ciullini Mannurita, Lewis S Bell, Simon Andrews, Manuel D Díaz-Muñoz, Simon J Cook, Anne Corcoran, Martin Turner
Progression through the stages of lymphocyte development requires coordination of the cell cycle. Such coordination ensures genomic integrity while cells somatically rearrange their antigen receptor genes [in a process called variable-diversity-joining (VDJ) recombination] and, upon successful rearrangement, expands the pools of progenitor lymphocytes. Here we show that in developing B lymphocytes, the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 are critical for maintaining quiescence before precursor B cell receptor (pre-BCR) expression and for reestablishing quiescence after pre-BCR-induced expansion...
April 22, 2016: Science
Timothy J Gingerich, Deborah J Stumpo, Wi S Lai, Thomas A Randall, Scott J Steppan, Perry J Blackshear
In most mammals, the Zfp36 gene family consists of three conserved members, with a fourth member, Zfp36l3, present only in rodents. The ZFP36 proteins regulate post-transcriptional gene expression at the level of mRNA stability in organisms from humans to yeasts, and appear to be expressed in all major groups of eukaryotes. In Mus musculus, Zfp36l3 expression is limited to the placenta and yolk sac, and is important for overall fecundity. We sequenced the Zfp36l3 gene from more than 20 representative species, from members of the Muridae, Cricetidae and Nesomyidae families...
January 2016: Molecular Phylogenetics and Evolution
Kuan-Ting Wang, Hsin-Hui Wang, Yan-Yun Wu, Yu-Lun Su, Pei-Yu Chiang, Nien-Yi Lin, Shun-Chang Wang, Geen-Dong Chang, Ching-Jin Chang
BACKGROUND: The tristetraprolin (TTP) family of mRNA-binding proteins contains three major members, Ttp, Zfp36l1, and Zfp36l2. Ttp down-regulates the stability of AU-rich element-containing mRNAs and functions as an anti-inflammation regulator. METHODS: To examine whether other TTP family proteins also play roles in the inflammatory response, their expression profiles and the possible mRNA targets were determined in the knockdown cells. RESULTS: Ttp mRNA and protein were highly induced by lipopolysaccharide (LPS), whereas Zfp36l1 and Zfp36l2 mRNAs were down-regulated and their proteins were phosphorylated during early lipopolysaccharide stimulation...
2015: Journal of Inflammation
Siriluck Ponsuksili, Puntita Siengdee, Yang Du, Nares Trakooljul, Eduard Murani, Manfred Schwerin, Klaus Wimmers
Understanding the genetic contributions behind skeletal muscle composition and metabolism is of great interest in medicine and agriculture. Attempts to dissect these complex traits combine genome-wide genotyping, expression data analyses and network analyses. Weighted gene co-expression network analysis (WGCNA) groups genes into modules based on patterns of co-expression, which can be linked to phenotypes by correlation analysis of trait values and the module eigengenes, i.e. the first principal component of a given module...
2015: PloS One
M Ma, S Luo, X Chen, F Yuan, J Cai, L Lu, F Yin
This study was to identify differentially expressed genes (DEGs) in post-menopausal females with osteopenia and further screened the potentially involved transcription factors (TFs) and microRNAs (miRNAs). Data set GSE13850 of circulating B lymphocytes from post-menopausal females with low or high bone mineral density (BMD) was downloaded from Gene Expression Omnibus. Limma package in R was used to identify DEGs following raw data processing. Enrichment analysis was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery) and visualized using plug-in EnrichmentMap of Cytoscape software...
March 2015: Scandinavian Journal of Immunology
Francesca Cargnin, Tamilla Nechiporuk, Karin Müllendorff, Deborah J Stumpo, Perry J Blackshear, Nurit Ballas, Gail Mandel
The RE1 Silencing Transcription Factor (REST) acts as a governor of the mature neuronal phenotype by repressing a large consortium of neuronal genes in non-neuronal cells. In the developing nervous system, REST is present in progenitors and downregulated at terminal differentiation to promote acquisition of mature neuronal phenotypes. Paradoxically, REST is still detected in some regions of the adult nervous system, but how REST levels are regulated, and whether REST can still repress neuronal genes, is not known...
December 10, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Marc De Braekeleer, Nadia Guéganic, Corine Tous, Marie-Josée Le Bris, Audrey Basinko, Frédéric Morel, Nathalie Douet-Guilbert
Several chromosomal rearrangements involving band 3q26 are known to induce EVI1 overexpression. They include inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22) and t(3;12)(q26;p13). Translocations involving the short arm of chromosome 2 and 3q26 have been reported in more than 50 patients with myeloid disorders. However, although the breakpoints on 2p are scattered over a long segment, their distribution had only been analyzed in 9 patients. We performed fluorescent in situ hybridization with a library of BAC (Bacterial Artificial Chromosome) clones in 4 patients with t(2;3)(p15-23;q26)...
February 2015: Blood Cells, Molecules & Diseases
Shungo Adachi, Masae Homoto, Rikou Tanaka, Yusaku Hioki, Hiroshi Murakami, Hiroaki Suga, Masaki Matsumoto, Keiichi I Nakayama, Tomohisa Hatta, Shun-ichiro Iemura, Tohru Natsume
Low-density lipoprotein receptor (LDLR) mRNA is unstable, but is stabilized upon extracellular signal-regulated kinase (ERK) activation, possibly through the binding of certain proteins to the LDLR mRNA 3'-untranslated region (UTR), although the detailed mechanism underlying this stability control is unclear. Here, using a proteomic approach, we show that proteins ZFP36L1 and ZFP36L2 specifically bind to the 3'-UTR of LDLR mRNA and recruit the CCR4-NOT-deadenylase complex, resulting in mRNA destabilization...
September 2014: Nucleic Acids Research
Joseph R McCorkle, Mary K Leonard, Susan D Kraner, Eric M Blalock, Deqin Ma, Stephen G Zimmer, David M Kaetzel
NME1 is a well-documented metastasis suppressor gene, with suppressor activity demonstrated across a wide spectrum of human cancers including melanoma and carcinomas of the breast, stomach and thyroid. A primary aim of the current study was to identify profiles of genes whose expression is regulated by NME1 in cell lines of melanoma and thyroid carcinoma origin. Impact of NME1 was determined by forcing its expression transiently in cell lines using a novel Ad5-based adenoviral vector (Ad5-NME1), followed 48 h later by analysis of RNA expression profiles using the U133A microarray chip...
July 2014: Cancer Genomics & Proteomics
Anna Zekavati, Asghar Nasir, Amor Alcaraz, Maceler Aldrovandi, Phil Marsh, John D Norton, John J Murphy
The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3' untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the 'maximum information coefficient' (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin...
2014: PloS One
Christopher B Ball, Karina F Rodriguez, Deborah J Stumpo, Fernando Ribeiro-Neto, Kenneth S Korach, Perry J Blackshear, Lutz Birnbaumer, Silvia B V Ramos
ZFP36L2 protein destabilizes AU-rich element-containing transcripts and has been implicated in female fertility. In the C57BL/6NTac mouse, a mutation in Zfp36l2 that results in the decreased expression of a form of ZFP36L2 in which the 29 N-terminal amino acid residues have been deleted, ΔN-ZFP36L2, leads to fertilized eggs that arrest at the two-cell stage. Interestingly, homozygous ΔN-Zfp36l2 females in the C57BL/6NTac strain release 40% fewer eggs than the WT littermates (Ramos et al., 2004), suggesting an additional defect in ovulation and/or oocyte maturation...
2014: PloS One
Perry J Blackshear, Lalith Perera
In humans, the tristetraprolin or TTP family of CCCH tandem zinc finger (TZF) proteins comprises 3 members, encoded by the genes ZFP36, ZFP36L1, and ZFP36L2. These proteins have direct orthologues in essentially all vertebrates studied, with the exception of birds, which appear to lack a version of ZFP36. Additional family members are found in rodents, amphibians, and fish. In general, the encoded proteins contain 2 critical macromolecular interaction domains: the CCCH TZF domain, which is necessary for high-affinity binding to AU-rich elements in mRNA; and an extreme C-terminal domain that, in the case of TTP, interacts with NOT1, the scaffold of a large multi-protein complex that contains deadenylases...
April 2014: Journal of Interferon & Cytokine Research
Wi S Lai, Deborah J Stumpo, Elizabeth A Kennington, Adam B Burkholder, James M Ward, David L Fargo, Perry J Blackshear
Both innate and adaptive immunity in birds are different from their mammalian counterparts. Understanding bird immunity is important because of the enormous potential impact of avian infectious diseases, both in their role as food animals and as potential carriers of zoonotic diseases in man. The anti-inflammatory protein tristetraprolin (TTP) is an important component of the mammalian innate immune response, in that it binds to and destabilizes key cytokine mRNAs. TTP knockout mice exhibit a severe systemic inflammatory syndrome, and they are abnormally sensitive to innate immune stimuli such as LPS...
October 1, 2013: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
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