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Pedro Serrano, John A Hammond, Michael Geralt, Kurt Wüthrich
Splicing factor RBM10 and its close homologues RBM5 and RBM6 govern the splicing of oncogenes such as Fas, NUMB, and Bcl-X. The molecular architecture of these proteins includes zinc fingers (ZnFs) and RNA recognition motifs (RRMs). Three of these domains in RBM10 that constitute the RNA binding part of this splicing factor were found to individually bind RNAs with micromolar affinities. It was thus of interest to further investigate the structural basis of the well-documented high-affinity RNA recognition by RMB10...
March 13, 2018: Biochemistry
Tayaza Fadason, Cameron Ekblad, John R Ingram, William S Schierding, Justin M O'Sullivan
The mechanisms that underlie the association between obesity and type 2 diabetes are not fully understood. Here, we investigated the role of the 3D genome organization in the pathogeneses of obesity and type-2 diabetes. We interpreted the combined and differential impacts of 196 diabetes and 390 obesity associated single nucleotide polymorphisms (SNPs) by integrating data on the genes with which they physically interact (as captured by Hi-C) and the functional [i.e., expression quantitative trait loci (eQTL)] outcomes associated with these interactions...
2017: Frontiers in Genetics
Aaron F McDaid, Peter K Joshi, Eleonora Porcu, Andrea Komljenovic, Hao Li, Vincenzo Sorrentino, Maria Litovchenko, Roel P J Bevers, Sina Rüeger, Alexandre Reymond, Murielle Bochud, Bart Deplancke, Robert W Williams, Marc Robinson-Rechavi, Fred Paccaud, Valentin Rousson, Johan Auwerx, James F Wilson, Zoltán Kutalik
The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR)...
July 27, 2017: Nature Communications
Miko Valori, Lilja Jansson, Anna Kiviharju, Pekka Ellonen, Hanna Rajala, Shady Adnan Awad, Satu Mustjoki, Pentti J Tienari
Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated...
February 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Felix R Day, Hannes Helgason, Daniel I Chasman, Lynda M Rose, Po-Ru Loh, Robert A Scott, Agnar Helgason, Augustine Kong, Gisli Masson, Olafur Th Magnusson, Daniel Gudbjartsson, Unnur Thorsteinsdottir, Julie E Buring, Paul M Ridker, Patrick Sulem, Kari Stefansson, Ken K Ong, John R B Perry
The ages of puberty, first sexual intercourse and first birth signify the onset of reproductive ability, behavior and success, respectively. In a genome-wide association study of 125,667 UK Biobank participants, we identify 38 loci associated (P < 5 × 10(-8)) with age at first sexual intercourse. These findings were taken forward in 241,910 men and women from Iceland and 20,187 women from the Women's Genome Health Study. Several of the identified loci also exhibit associations (P < 5 × 10(-8)) with other reproductive and behavioral traits, including age at first birth (variants in or near ESR1 and RBM6-SEMA3F), number of children (CADM2 and ESR1), irritable temperament (MSRA) and risk-taking propensity (CADM2)...
June 2016: Nature Genetics
Elias G Bechara, Endre Sebestyén, Isabella Bernardis, Eduardo Eyras, Juan Valcárcel
RBM5, a regulator of alternative splicing of apoptotic genes, and its highly homologous RBM6 and RBM10 are RNA-binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation, and its modulation recapitulates or antagonizes the effects of RBM5, 6, and 10 in cell colony formation...
December 12, 2013: Molecular Cell
Eli Rosenbaum, Shahnaz Begum, Mariana Brait, Marianna Zahurak, Leonel Maldonado, Leslie A Mangold, Mario A Eisenberger, Jonathan I Epstein, Alan W Partin, David Sidransky, Mohammad O Hoque
PURPOSE: To evaluate the prognostic significance of six epigenetic biomarkers (AIM1, CDH1, KIF1A, MT1G, PAK3, and RBM6 promoter hypermethlation) in a homogeneous group of prostate cancer patients, following radical prostatectomy (RP). PATIENTS AND METHODS: Biomarker analyses were performed retrospectively on tumors from 95 prostate cancer patients all with a Gleason score of 3 + 4 = 7 and a minimum follow-up period of 8 years. Using Quantitative Methylation Specific PCR (QMSP), we analyzed the promoter region of six genes in primary prostate tumor tissues...
July 1, 2012: Prostate
Emma Heath, Fred Sablitzky, Garry T Morgan
RNA-binding motif (RBM) proteins comprise a large family of RNA-binding proteins whose functions are poorly understood. Since some RBM proteins are candidate alternative splicing factors we examined whether one such member of the family, RBM6, exhibited a pattern of nuclear distribution and targeting consistent with this role. Using antibodies raised against mouse RBM6 to immunostain mammalian cell lines we found that the endogenous protein was both distributed diffusely in the nucleus and concentrated in a small number of nuclear foci that corresponded to splicing speckles/interchromatin granule clusters (IGCs)...
December 2010: Chromosome Research
Leslie C Sutherland, Ke Wang, Andrew G Robinson
RBM5 is one member of a group of structurally related genes that includes RBM6 and RBM10. RBM10 maps to Xp11.23, and one allele is inactivated as a result of X chromosome inactivation. Both RBM5 and RBM6 map to 3p21.3, a tumor suppressor region that experiences loss of heterozygosity in the majority of lung cancers. Overexpression of RBM5, which encodes an RNA-binding protein involved in the regulation of alternative splicing and retards ascites associated tumor growth in immunocompromised mice, a phenomenon that may be related to an associated ability to modulate apoptosis...
March 2010: Journal of Thoracic Oncology
Ke Wang, Gino Ubriaco, Leslie C Sutherland
UNLABELLED: Transcription-induced chimerism, a mechanism involving the transcription and intergenic splicing of two consecutive genes, has recently been estimated to account for approximately 5% of the human transcriptome. Despite this prevalence, the regulation and function of these fused transcripts remains largely uncharacterised. RESULTS: We identified three novel transcription-induced chimeras resulting from the intergenic splicing of a single RNA transcript incorporating the two neighbouring 3p21...
2007: BMC Genomics
Ting-lei Gu, Thomas Mercher, Jeffrey W Tyner, Valerie L Goss, Denise K Walters, Melanie G Cornejo, Cynthia Reeves, Lana Popova, Kimberly Lee, Michael C Heinrich, John Rush, Masanori Daibata, Isao Miyoshi, D Gary Gilliland, Brian J Druker, Roberto D Polakiewicz
Activated tyrosine kinases have been frequently implicated in the pathogenesis of cancer, including acute myeloid leukemia (AML), and are validated targets for therapeutic intervention with small-molecule kinase inhibitors. To identify novel activated tyrosine kinases in AML, we used a discovery platform consisting of immunoaffinity profiling coupled to mass spectrometry that identifies large numbers of tyrosine-phosphorylated proteins, including active kinases. This method revealed the presence of an activated colony-stimulating factor 1 receptor (CSF1R) kinase in the acute megakaryoblastic leukemia (AMKL) cell line MKPL-1...
July 1, 2007: Blood
Nina D Rintala-Maki, Carolyn A Goard, Colleen E Langdon, Vanessa E Wall, Kathryn E A Traulsen, Cory D Morin, Michel Bonin, Leslie C Sutherland
The aim of this study was to examine the expression of the RBM5 tumor suppressor, in relation to RBM6 and RBM10, to obtain a better understanding of the potential role played by these RBM5-related factors in the regulation of RBM5 tumor-suppressor activity. Paired non-tumor and tumor samples were obtained from 73 breast cancer patients. RNA and protein expression were examined by semi-quantitative reverse transcription-polymerase chain reaction and immunoblot, respectively. Data were analyzed using various statistical methods to test for correlations amongst the RBM5-related factors, and between the factors and various pathological parameters...
April 15, 2007: Journal of Cellular Biochemistry
Leslie C Sutherland, Nina D Rintala-Maki, Ryan D White, Cory D Morin
RBM5 is a known modulator of apoptosis, an RNA binding protein, and a putative tumor suppressor. Originally identified as LUCA-15, and subsequently as H37, it was designated "RBM" (for RNA Binding Motif) due to the presence of two RRM (RNA Recognition Motif) domains within the protein coding sequence. Recently, a number of proteins have been attributed with this same RBM designation, based on the presence of one or more RRM consensus sequences. One such protein, RBM3, was also recently found to have apoptotic modulatory capabilities...
January 1, 2005: Journal of Cellular Biochemistry
Y M Heng, M Fox, F Sablitzky
No abstract text is available yet for this article.
2000: Cytogenetics and Cell Genetics
T Timmer, P Terpstra, A van den Berg, P M Veldhuis, A Ter Elst, A Y van der Veen, K Kok, S L Naylor, C H Buys
In searching for a tumor suppressor gene in the 3p21.3 region, we isolated two genes, RBM5 and RBM6. Sequence analysis indicated that these genes share similarity. RBM5 and-to a lesser extent-RBM6 also have similarity to DXS8237E at Xp11.3-11.23, which maps less than 20 kb upstream of UBE1. A homologue of UBE1, UBE1L, is located at 3p21. 3. FISH analysis showed that the distance between UBE1L and RBM5 in 3p21.3 is about 265 kb. DXS8237E and UBE1 on the X chromosome have the same orientation, whereas on chromosome 3 the orientation of RBM5 and that of RBM6 are opposite to the orientation of UBE1L...
September 1, 1999: Genomics
T Timmer, P Terpstra, A van den Berg, P M Veldhuis, A Ter Elst, G Voutsinas, M M Hulsbeek, T G Draaijers, M W Looman, K Kok, S L Naylor, C H Buys
In the search for a tumour suppressor gene in the 3p21.3 region we isolated two genes, RBM5 and RBM6. Gene RBM5 maps to the region which is homozygously deleted in the small cell lung cancer cell line GLC20; RBM6 crosses the telomeric breakpoint of this deletion. Sequence comparison revealed that at the amino acid level both genes show 30% identity. They contain two zinc finger motifs, a bipartite nuclear signal and two RNA binding motifs, suggesting that the proteins for which RBM5 and RBM6 are coding have a DNA/RNA binding function and are located in the nucleus...
May 1999: European Journal of Human Genetics: EJHG
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