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Article ; Online: The eukaryotic translation initiation factor eIF4E reprograms alternative splicing.

Ghram, Mehdi / Morris, Gavin / Culjkovic-Kraljacic, Biljana / Mars, Jean-Clement / Gendron, Patrick / Skrabanek, Lucy / Revuelta, Maria Victoria / Cerchietti, Leandro / Guzman, Monica L / Borden, Katherine L B

The EMBO journal

2023 Volume 42, Issue 7, Page(s) e110496

Abstract: Aberrant splicing is typically attributed to splice-factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation-independent means to extensively reprogram alternative splicing (AS). We ... ...

Abstract	Aberrant splicing is typically attributed to splice-factor (SF) mutation and contributes to malignancies including acute myeloid leukemia (AML). Here, we discovered a mutation-independent means to extensively reprogram alternative splicing (AS). We showed that the dysregulated expression of eukaryotic translation initiation factor eIF4E elevated selective splice-factor production, thereby impacting multiple spliceosome complexes, including factors mutated in AML such as SF3B1 and U2AF1. These changes generated a splicing landscape that predominantly supported altered splice-site selection for ~800 transcripts in cell lines and ~4,600 transcripts in specimens from high-eIF4E AML patients otherwise harboring no known SF mutations. Nuclear RNA immunoprecipitations, export assays, polysome analyses, and mutational studies together revealed that eIF4E primarily increased SF production via its nuclear RNA export activity. By contrast, eIF4E dysregulation did not induce known SF mutations or alter spliceosome number. eIF4E interacted with the spliceosome and some pre-mRNAs, suggesting its direct involvement in specific splicing events. eIF4E induced simultaneous effects on numerous SF proteins, resulting in a much larger range of splicing alterations than in the case of mutation or dysregulation of individual SFs and providing a novel paradigm for splicing control and dysregulation.
MeSH term(s)	Humans ; Alternative Splicing ; RNA Splicing Factors/metabolism ; Eukaryotic Initiation Factor-4E/metabolism ; RNA Splicing ; Eukaryotic Initiation Factors/genetics ; Leukemia, Myeloid, Acute/genetics ; Mutation
Chemical Substances	RNA Splicing Factors ; Eukaryotic Initiation Factor-4E ; Eukaryotic Initiation Factors
Language	English
Publishing date	2023-02-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2021110496
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Article ; Online: The eukaryotic translation initiation factor eIF4E elevates steady-state m

Culjkovic-Kraljacic, Biljana / Skrabanek, Lucy / Revuelta, Maria V / Gasiorek, Jadwiga / Cowling, Victoria H / Cerchietti, Leandro / Borden, Katherine L B

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 43, Page(s) 26773–26783

Abstract: Methyl-7-guanosine ( ... ...

Abstract	Methyl-7-guanosine (m
MeSH term(s)	Cell Line, Tumor ; Eukaryotic Initiation Factor-4E/chemistry ; Eukaryotic Initiation Factor-4E/genetics ; Eukaryotic Initiation Factor-4E/metabolism ; Guanosine/analogs & derivatives ; Guanosine/chemistry ; Guanosine/genetics ; Guanosine/metabolism ; Humans ; Polyribosomes/metabolism ; RNA Caps/chemistry ; RNA Caps/genetics ; RNA Caps/metabolism ; RNA, Messenger/chemistry ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Transcriptome/genetics
Chemical Substances	8-methylguanosine ; Eukaryotic Initiation Factor-4E ; RNA Caps ; RNA, Messenger ; Guanosine (12133JR80S)
Language	English
Publishing date	2020-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2002360117
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Article ; Online: Scan2S: increasing the precision of PROSITE pattern motifs using secondary structure constraints.

Skrabanek, Lucy / Niv, Masha Y

Proteins

2008 Volume 72, Issue 4, Page(s) 1138–1147

Abstract: Sequence signature databases such as PROSITE, which include protein pattern motifs indicative of a protein's function, are widely used for function prediction studies, cellular localization annotation, and sequence classification. Correct annotation ... ...

Abstract	Sequence signature databases such as PROSITE, which include protein pattern motifs indicative of a protein's function, are widely used for function prediction studies, cellular localization annotation, and sequence classification. Correct annotation relies on high precision of the motifs. We present a new and general approach for increasing the precision of established protein pattern motifs by including secondary structure constraints (SSCs). We use Scan2S, the first sequence motif-scanning program to optionally include SSCs, to augment PROSITE pattern motifs. The constraints were derived from either the DSSP secondary structure assignment or the PSIPRED predictions for PROSITE-documented true positive hits. The secondary structure-augmented motifs were scanned against all SwissProt sequences, for which secondary structure predictions were precalculated. Against this dataset, motifs with PSIPRED-derived SSCs exhibited improved performance over motifs with DSSP-derived constraints. The precision of 763 of the 782 PSIPRED-augmented motifs remained unchanged or increased compared to the original motifs; 26 motifs showed an absolute precision increase of 10-30%. We provide the complete set of augmented motifs and the Scan2S program at http://physiology.med.cornell.edu/go/scan2s. Our results suggest a general protocol for increasing the precision of protein pattern detection via the inclusion of SSCs.
MeSH term(s)	Amino Acid Motifs ; Animals ; Databases, Protein ; Humans ; Lipocalins/chemistry ; Protein Structure, Secondary ; Sequence Analysis, Protein/methods ; Software
Chemical Substances	Lipocalins
Language	English
Publishing date	2008-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.22008
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Article ; Online: Unique Immune Cell Coactivators Specify Locus Control Region Function and Cell Stage.

Chu, Chi-Shuen / Hellmuth, Johannes C / Singh, Rajat / Ying, Hsia-Yuan / Skrabanek, Lucy / Teater, Matthew R / Doane, Ashley S / Elemento, Olivier / Melnick, Ari M / Roeder, Robert G

Molecular cell

2020 Volume 80, Issue 5, Page(s) 845–861.e10

Abstract: Locus control region (LCR) functions define cellular identity and have critical roles in diseases such as cancer, although the hierarchy of structural components and associated factors that drive functionality are incompletely understood. Here we show ... ...

Abstract	Locus control region (LCR) functions define cellular identity and have critical roles in diseases such as cancer, although the hierarchy of structural components and associated factors that drive functionality are incompletely understood. Here we show that OCA-B, a B cell-specific coactivator essential for germinal center (GC) formation, forms a ternary complex with the lymphoid-enriched OCT2 and GC-specific MEF2B transcription factors and that this complex occupies and activates an LCR that regulates the BCL6 proto-oncogene and is uniquely required by normal and malignant GC B cells. Mechanistically, through OCA-B-MED1 interactions, this complex is required for Mediator association with the BCL6 promoter. Densely tiled CRISPRi screening indicates that only LCR segments heavily bound by this ternary complex are essential for its function. Our results demonstrate how an intimately linked complex of lineage- and stage-specific factors converges on specific and highly essential enhancer elements to drive the function of a cell-type-defining LCR.
MeSH term(s)	Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; Cell Line, Tumor ; Germinal Center/cytology ; Germinal Center/immunology ; HEK293 Cells ; Humans ; Locus Control Region/immunology ; MEF2 Transcription Factors/genetics ; MEF2 Transcription Factors/immunology ; Mice ; Mice, Knockout ; Organic Cation Transporter 2/genetics ; Organic Cation Transporter 2/immunology ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-bcl-6/genetics ; Proto-Oncogene Proteins c-bcl-6/immunology ; Trans-Activators/genetics ; Trans-Activators/immunology
Chemical Substances	BCL6 protein, human ; Bcl6 protein, mouse ; MAS1 protein, human ; MEF2 Transcription Factors ; MEF2B protein, human ; Mef2b protein, mouse ; Organic Cation Transporter 2 ; POU2AF1 protein, human ; Pou2af1 protein, mouse ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-bcl-6 ; SLC22A2 protein, human ; Slc22a2 protein, mouse ; Trans-Activators
Language	English
Publishing date	2020-11-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.10.036
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Article ; Online: Mining expressed sequence tags identifies cancer markers of clinical interest.

Campagne, Fabien / Skrabanek, Lucy

BMC bioinformatics

2006 Volume 7, Page(s) 481

Abstract: Background: Gene expression data are a rich source of information about the transcriptional dis-regulation of genes in cancer. Genes that display differential regulation in cancer are a subtype of cancer biomarkers.: Results: We present an approach ... ...

Abstract	Background: Gene expression data are a rich source of information about the transcriptional dis-regulation of genes in cancer. Genes that display differential regulation in cancer are a subtype of cancer biomarkers. Results: We present an approach to mine expressed sequence tags to discover cancer biomarkers. A false discovery rate analysis suggests that the approach generates less than 22% false discoveries when applied to combined human and mouse whole genome screens. With this approach, we identify the 200 genes most consistently differentially expressed in cancer (called HM200) and proceed to characterize these genes. When used for prediction in a variety of cancer classification tasks (in 24 independent cancer microarray datasets, 59 classifications total), we show that HM200 and the shorter gene list HM100 are very competitive cancer biomarker sets. Indeed, when compared to 13 published cancer marker gene lists, HM200 achieves the best or second best classification performance in 79% of the classifications considered. Conclusion: These results indicate the existence of at least one general cancer marker set whose predictive value spans several tumor types and classification types. Our comparison with other marker gene lists shows that HM200 markers are mostly novel cancer markers. We also identify the previously published Pomeroy-400 list as another general cancer marker set. Strikingly, Pomeroy-400 has 27 genes in common with HM200. Our data suggest that a core set of genes are responsive to the deregulation of pathways involved in tumorigenesis in a variety of tumor types and that these genes could serve as transcriptional cancer markers in applications of clinical interest. Finally, our study suggests new strategies to select and evaluate cancer biomarkers in microarray studies.
MeSH term(s)	Animals ; Biomarkers, Tumor/genetics ; Expressed Sequence Tags ; Gene Expression Regulation, Neoplastic ; Genomics/methods ; Humans ; Mice ; Neoplasms/genetics ; Neoplasms/metabolism ; RNA, Messenger/metabolism ; RNA-Binding Proteins/genetics ; Signal Transduction ; Transcription, Genetic
Chemical Substances	Biomarkers, Tumor ; RNA, Messenger ; RNA-Binding Proteins
Language	English
Publishing date	2006-11-01
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	2041484-5
ISSN	1471-2105 ; 1471-2105
ISSN (online)	1471-2105
ISSN	1471-2105
DOI	10.1186/1471-2105-7-481
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Article ; Online: Mining expressed sequence tags identifies cancer markers of clinical interest

Skrabanek Lucy / Campagne Fabien

BMC Bioinformatics, Vol 7, Iss 1, p

2006 Volume 481

Abstract: Abstract Background Gene expression data are a rich source of information about the transcriptional dis-regulation of genes in cancer. Genes that display differential regulation in cancer are a subtype of cancer biomarkers. Results We present an approach ...

Abstract	Abstract Background Gene expression data are a rich source of information about the transcriptional dis-regulation of genes in cancer. Genes that display differential regulation in cancer are a subtype of cancer biomarkers. Results We present an approach to mine expressed sequence tags to discover cancer biomarkers. A false discovery rate analysis suggests that the approach generates less than 22% false discoveries when applied to combined human and mouse whole genome screens. With this approach, we identify the 200 genes most consistently differentially expressed in cancer (called HM200) and proceed to characterize these genes. When used for prediction in a variety of cancer classification tasks (in 24 independent cancer microarray datasets, 59 classifications total), we show that HM200 and the shorter gene list HM100 are very competitive cancer biomarker sets. Indeed, when compared to 13 published cancer marker gene lists, HM200 achieves the best or second best classification performance in 79% of the classifications considered. Conclusion These results indicate the existence of at least one general cancer marker set whose predictive value spans several tumor types and classification types. Our comparison with other marker gene lists shows that HM200 markers are mostly novel cancer markers. We also identify the previously published Pomeroy-400 list as another general cancer marker set. Strikingly, Pomeroy-400 has 27 genes in common with HM200. Our data suggest that a core set of genes are responsive to the deregulation of pathways involved in tumorigenesis in a variety of tumor types and that these genes could serve as transcriptional cancer markers in applications of clinical interest. Finally, our study suggests new strategies to select and evaluate cancer biomarkers in microarray studies.
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
Subject code	004 ; 610
Language	English
Publishing date	2006-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Unique Immune Cell Coactivators Specify Locus Control Region Function and Cell Stage

Chu, Chi-Shuen / Hellmuth, Johannes C / Singh, Rajat / Ying, Hsia-Yuan / Skrabanek, Lucy / Teater, Matthew R / Doane, Ashley S / Elemento, Olivier / Melnick, Ari M / Roeder, Robert G

Molecular cell. 2020 Dec. 03, v. 80, no. 5

2020

Abstract	Locus control region (LCR) functions define cellular identity and have critical roles in diseases such as cancer, although the hierarchy of structural components and associated factors that drive functionality are incompletely understood. Here we show that OCA-B, a B cell-specific coactivator essential for germinal center (GC) formation, forms a ternary complex with the lymphoid-enriched OCT2 and GC-specific MEF2B transcription factors and that this complex occupies and activates an LCR that regulates the BCL6 proto-oncogene and is uniquely required by normal and malignant GC B cells. Mechanistically, through OCA-B-MED1 interactions, this complex is required for Mediator association with the BCL6 promoter. Densely tiled CRISPRi screening indicates that only LCR segments heavily bound by this ternary complex are essential for its function. Our results demonstrate how an intimately linked complex of lineage- and stage-specific factors converges on specific and highly essential enhancer elements to drive the function of a cell-type-defining LCR.
Keywords	loci ; lymph nodes ; proto-oncogenes
Language	English
Dates of publication	2020-1203
Size	p. 845-861.e10.
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.10.036
Database	NAL-Catalogue (AGRICOLA)

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Article: Computational prediction of protein-protein interactions.

Skrabanek, Lucy / Saini, Harpreet K / Bader, Gary D / Enright, Anton J

Molecular biotechnology

2007 Volume 38, Issue 1, Page(s) 1–17

Abstract: Recently a number of computational approaches have been developed for the prediction of protein-protein interactions. Complete genome sequencing projects have provided the vast amount of information needed for these analyses. These methods utilize the ... ...

Abstract	Recently a number of computational approaches have been developed for the prediction of protein-protein interactions. Complete genome sequencing projects have provided the vast amount of information needed for these analyses. These methods utilize the structural, genomic, and biological context of proteins and genes in complete genomes to predict protein interaction networks and functional linkages between proteins. Given that experimental techniques remain expensive, time-consuming, and labor-intensive, these methods represent an important advance in proteomics. Some of these approaches utilize sequence data alone to predict interactions, while others combine multiple computational and experimental datasets to accurately build protein interaction maps for complete genomes. These methods represent a complementary approach to current high-throughput projects whose aim is to delineate protein interaction maps in complete genomes. We will describe a number of computational protocols for protein interaction prediction based on the structural, genomic, and biological context of proteins in complete genomes, and detail methods for protein interaction network visualization and analysis.
MeSH term(s)	Biotechnology ; Computer Simulation ; Databases, Genetic ; Gene Fusion ; Genomics ; Models, Molecular ; Multiprotein Complexes ; Phylogeny ; Protein Array Analysis ; Protein Interaction Mapping/statistics & numerical data ; Proteomics ; Software ; Two-Hybrid System Techniques
Chemical Substances	Multiprotein Complexes
Language	English
Publishing date	2007-08-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1193057-3
ISSN	1559-0305 ; 1073-6085
ISSN (online)	1559-0305
ISSN	1073-6085
DOI	10.1007/s12033-007-0069-2
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Zs.A 4031: Show issues

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Article ; Online: Features of Circulating Parainfluenza Virus Required for Growth in Human Airway.

Palermo, Laura M / Uppal, Manik / Skrabanek, Lucy / Zumbo, Paul / Germer, Soren / Toussaint, Nora C / Rima, Bert K / Huey, Devra / Niewiesk, Stefan / Porotto, Matteo / Moscona, Anne

mBio

2016 Volume 7, Issue 2, Page(s) e00235

Abstract: Unlabelled: Respiratory paramyxoviruses, including the highly prevalent human parainfluenza viruses, cause the majority of childhood croup, bronchiolitis, and pneumonia, yet there are currently no vaccines or effective treatments. Paramyxovirus research ...

Abstract	Unlabelled: Respiratory paramyxoviruses, including the highly prevalent human parainfluenza viruses, cause the majority of childhood croup, bronchiolitis, and pneumonia, yet there are currently no vaccines or effective treatments. Paramyxovirus research has relied on the study of laboratory-adapted strains of virus in immortalized cultured cell lines. We show that findings made in such systems about the receptor interaction and viral fusion requirements for entry and fitness-mediated by the receptor binding protein and the fusion protein-can be drastically different from the requirements for infection in vivo. Here we carried out whole-genome sequencing and genomic analysis of circulating human parainfluenza virus field strains to define functional and structural properties of proteins of circulating strains and to identify the genetic basis for properties that confer fitness in the field. The analysis of clinical strains suggests that the receptor binding-fusion molecule pairs of circulating viruses maintain a balance of properties that result in an inverse correlation between fusion in cultured cells and growth in vivo. Future analysis of entry mechanisms and inhibitory strategies for paramyxoviruses will benefit from considering the properties of viruses that are fit to infect humans, since a focus on viruses that have adapted to laboratory work provides a distinctly different picture of the requirements for the entry step of infection. Importance: Mechanistic information about viral infection-information that impacts antiviral and vaccine development-is generally derived from viral strains grown under laboratory conditions in immortalized cells. This study uses whole-genome sequencing of clinical strains of human parainfluenza virus 3-a globally important respiratory paramyxovirus-in cell systems that mimic the natural human host and in animal models. By examining the differences between clinical isolates and laboratory-adapted strains, the sequence differences are correlated to mechanistic differences in viral entry. For this ubiquitous and pathogenic respiratory virus to infect the human lung, modulation of the processes of receptor engagement and fusion activation occur in a manner quite different from that carried out by the entry glycoprotein-expressing pair of laboratory strains. These marked contrasts in the viral properties necessary for infection in cultured immortalized cells and in natural host tissues and animals will influence future basic and clinical studies.
MeSH term(s)	Animals ; Genome, Viral ; Humans ; Respiratory System/virology ; Respirovirus/isolation & purification ; Respirovirus/pathogenicity ; Respirovirus/physiology ; Respirovirus/ultrastructure ; Respirovirus Infections/virology ; Sequence Analysis, DNA ; Sigmodontinae ; Virulence ; Virus Internalization
Language	English
Publishing date	2016-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.00235-16
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Article ; Online: Building protein diagrams on the web with the residue-based diagram editor RbDe.

Skrabanek, Lucy / Campagne, Fabien / Weinstein, Harel

Nucleic acids research

2003 Volume 31, Issue 13, Page(s) 3856–3858

Abstract: The residue-based diagram editor (RbDe) is web-based software that greatly simplifies the construction of schematic diagrams of proteins. Residue-based diagrams display the sequence of a given protein in the context of its secondary and tertiary ... ...

Abstract	The residue-based diagram editor (RbDe) is web-based software that greatly simplifies the construction of schematic diagrams of proteins. Residue-based diagrams display the sequence of a given protein in the context of its secondary and tertiary structure. Such diagrams are frequently used to summarize mutations or sequence features, in the context of the overall topology of a protein. The initial version of RbDe was designed for transmembrane proteins and has enabled many users to create diagrams of large systems such as G protein-coupled receptors or transporters. We present an extended diagram editor that supports other families of proteins. Users can now import custom-diagram layouts, use them to render members of any protein family and generate high-quality output for publication purposes. RbDe is available free over the web, at http://icb.mssm.edu/crt/RbDe
MeSH term(s)	Amino Acid Sequence ; Calmodulin/chemistry ; Computer Graphics ; Humans ; Internet ; Membrane Proteins/chemistry ; Membrane Transport Proteins/chemistry ; Models, Molecular ; Protein Conformation ; Proteins/chemistry ; Software ; User-Computer Interface
Chemical Substances	Calmodulin ; Membrane Proteins ; Membrane Transport Proteins ; Proteins
Language	English
Publishing date	2003-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkg552
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