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An alternative splice variant of human thioredoxin
Wang Ying,Wang Yugang,Zhang Yingmei,Yuan Yong,Ma Dalong
Chinese Science Bulletin , 1998, DOI: 10.1007/BF02884539
Abstract: An alternative splice variant of human thioredoxin (hTRX) has been identified by using reverse transcription-polymerase chain reaction, cloning and expressing of hTRX-encoding gene, and DNA sequencing. This variant contains hTRX exons 1, 2, 4 and 5. The entire protcin encoding region of this variant, named hTRX63, is identical to hTRX except for the omission of exon 3. Human TRX and TRXδ3 cDNA has been expressed inE. coli. The catalytic activity of rhTRXδ3 on DTT-dependent insulin reduction is lower than that of rhTRX, although hTRXδ3 still contains the active site.
An intron 9 containing splice variant of PAX2
Antonia Busse, Anika Rietz, Stefan Schwartz, Eckhard Thiel, Ulrich Keilholz
Journal of Translational Medicine , 2009, DOI: 10.1186/1479-5876-7-36
Abstract: The expression of an intron 9 containing PAX2 splice variant was analyzed in neoplastic B cell and solid tumor cell lines as well as in primary tumor samples by quantitative RT-PCR. PAX2 proteins were detected by Western Blot in a subset of cell lines.All 14 lymphoma cell lines expressed an undescribed PAX2 splice variant containing the entire intron 9 sequence and the exon 10 sequence. This splice variant could also be detected in 35 solid tumor cell lines, in leukemia and lymphoma as well as in colon carcinoma and melanoma patient samples and in blood samples of healthy donors. Expression of this new splice variant on protein level was verified by Western Blot analysis.We discovered a previously undescribed intron 9 and exon 10 containing splice variant of PAX2 in B-cell neoplasia and in solid tumors on mRNA and protein level.The PAX gene family was first described in Drosophila and later found to be conserved across species [1]. PAX gene products function as transcription factors. They all share the evolutionarily conserved 128 amino acid paired domain at their N-terminal, which mediates attachment to DNA sequences [2]. Nine PAX genes (PAX1–PAX9) have so far been described in vertebrates; these proteins are subdivided into four classes based on the presence of conserved sequence motifs, the octapeptide (repression domaine) and the homeodomaine (DNA binding domaine) [3]. The PAX2 gene is located on the short arm of chromosome 10, locus 24–25 [4] and encodes a transcription factor that has a critical role in the development of the urogenital tract, the eyes and ears, and the CNS [5]. It belongs to the subgroup 2, characterized by the octapeptide sequence and a truncated homeodomaine [6] and is composed of 12 exons spanning approximately 86 kb [5].Although PAX2 is primarily expressed during embryonic development and expression is normally repressed upon terminal differentiation, PAX gene expression was frequently identified in tumor cell lines, including lymphoma, b
Discovery of a Mammalian Splice Variant of Myostatin That Stimulates Myogenesis  [PDF]
Ferenc Jeanplong, Shelley J. Falconer, Jenny M. Oldham, Mark Thomas, Tarra S. Gray, Alex Hennebry, Kenneth G. Matthews, Frederick C. Kemp, Ketan Patel, Carole Berry, Gina Nicholas, Christopher D. McMahon
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081713
Abstract: Myostatin plays a fundamental role in regulating the size of skeletal muscles. To date, only a single myostatin gene and no splice variants have been identified in mammals. Here we describe the splicing of a cryptic intron that removes the coding sequence for the receptor binding moiety of sheep myostatin. The deduced polypeptide sequence of the myostatin splice variant (MSV) contains a 256 amino acid N-terminal domain, which is common to myostatin, and a unique C-terminus of 65 amino acids. Western immunoblotting demonstrated that MSV mRNA is translated into protein, which is present in skeletal muscles. To determine the biological role of MSV, we developed an MSV over-expressing C2C12 myoblast line and showed that it proliferated faster than that of the control line in association with an increased abundance of the CDK2/Cyclin E complex in the nucleus. Recombinant protein made for the novel C-terminus of MSV also stimulated myoblast proliferation and bound to myostatin with high affinity as determined by surface plasmon resonance assay. Therefore, we postulated that MSV functions as a binding protein and antagonist of myostatin. Consistent with our postulate, myostatin protein was co-immunoprecipitated from skeletal muscle extracts with an MSV-specific antibody. MSV over-expression in C2C12 myoblasts blocked myostatin-induced Smad2/3-dependent signaling, thereby confirming that MSV antagonizes the canonical myostatin pathway. Furthermore, MSV over-expression increased the abundance of MyoD, Myogenin and MRF4 proteins (P<0.05), which indicates that MSV stimulates myogenesis through the induction of myogenic regulatory factors. To help elucidate a possible role in vivo, we observed that MSV protein was more abundant during early post-natal muscle development, while myostatin remained unchanged, which suggests that MSV may promote the growth of skeletal muscles. We conclude that MSV represents a unique example of intra-genic regulation in which a splice variant directly antagonizes the biological activity of the canonical gene product.
Survivin 2α: a novel Survivin splice variant expressed in human malignancies
Hugo Caldas, Laura E Honsey, Rachel A Altura
Molecular Cancer , 2005, DOI: 10.1186/1476-4598-4-11
Abstract: In the present study, we identify and characterize a novel survivin isoform that we designate survivin 2α. Structurally, the transcript consists of 2 exons: exon 1 and exon 2, as well as a 3' 197 bp region of intron 2. Acquisition of a new in-frame stop codon within intron 2 results in an open reading frame of 225 nucleotides, predicting a truncated 74 amino acid protein. Survivin 2α is expressed at high levels in several malignant cell lines and primary tumors. Functional assays show that survivin 2α attenuates the anti-apoptotic activity of survivin. Subcellular localization and immunoprecipitation of survivin 2α suggests a physical interaction with survivin.We characterized a novel survivin splice variant that we designated survivin 2α. We hypothesize that survivin 2α can alter the anti-apoptotic functions of survivin in malignant cells. Thus survivin 2α may be useful as a therapeutic tool in sensitizing chemoresistant tumor cells to chemotherapy.Alternative splicing is estimated to occur in 40–60% of all human genes, accounting for some of the discrepancies between the large number of known proteins and the three-fold lower number of human genes in the genome. Alternative splicing generates a multitude of isoforms that have overlapping but distinct functions during embryonic development and that also contribute to maintaining homeostasis in adult differentiated tissues (reviewed in [1]). Alternative splice forms of key proteins in cancer, TP53, MDM2 [2] and c-MYC [3], have been shown to play a role in oncogenesis.Survivin was originally identified by structural homology to IAPs in human B-cell lymphoma [4]. It is composed of a single BIR domain and an extended carboxy-terminal coiled coil domain [5]. Transcription from the Survivin locus gives rise to alternatively spliced transcripts identified in both human and mice [6-8]. To date, three alternatively spliced isoforms have been described in humans [6-8]. Survivin-2B is generated by the insertion of an alternat
Ikaros isoforms: The saga continues  [cached]
Zhanjun Li,Laura A Perez-Casellas,Aleksandar Savic,Chunhua Song
World Journal of Biological Chemistry , 2011, DOI: 10.4331/wjbc.v2.i6.140
Abstract: Through alternate splicing, the Ikaros gene produces multiple proteins. Ikaros is essential for normal hematopoiesis and possesses tumor suppressor activity. Ikaros isoforms interact to form dimers and potentially multimeric complexes. Diverse Ikaros complexes produced by the presence of different Ikaros isoforms are hypothesized to confer distinct functions. Small dominant-negative Ikaros isoforms have been shown to inhibit the tumor suppressor activity of full-length Ikaros. Here, we describe how Ikaros activity is regulated by the coordinated expression of the largest Ikaros isoforms IK-1 and IK-H. Although IK-1 is described as full-length Ikaros, IK-H is the longest Ikaros isoform. IK-H, which includes residues coded by exon 3B (60 bp that lie between exons 3 and 4), is abundant in human but not murine hematopoietic cells. Specific residues that lie within the 20 amino acids encoded by exon 3B give IK-H DNA-binding characteristics that are distinct from those of IK-1. Moreover, IK-H can potentiate or inhibit the ability of IK-1 to bind DNA. IK-H binds to the regulatory regions of genes that are upregulated by Ikaros, but not genes that are repressed by Ikaros. Although IK-1 localizes to pericentromeric heterochromatin, IK-H can be found in both pericentromeric and non-pericentromeric locations. Anti-silencing activity of gamma satellite DNA has been shown to depend on the binding of IK-H, but not other Ikaros isoforms. The unique features of IK-H, its influence on Ikaros activity, and the lack of IK-H expression in mice suggest that Ikaros function in humans may be more complex and possibly distinct from that in mice.
SpliceMiner: a high-throughput database implementation of the NCBI Evidence Viewer for microarray splice variant analysis
Ari B Kahn, Michael C Ryan, Hongfang Liu, Barry R Zeeberg, D Curtis Jamison, John N Weinstein
BMC Bioinformatics , 2007, DOI: 10.1186/1471-2105-8-75
Abstract: SpliceMiner is a web interface for querying Evidence Viewer Database (EVDB). EVDB is a comprehensive, non-redundant compendium of splice variant data for human genes. We constructed EVDB as a queryable implementation of the NCBI Evidence Viewer (EV). EVDB is based on data obtained from NCBI Entrez Gene and EV. The automated EVDB build process uses only complete coding sequences, which may or may not include partial or complete 5' and 3' UTRs, and filters redundant splice variants. Unlike EV, which supports only one-at-a-time queries, SpliceMiner supports high-throughput batch queries and provides results in an easily parsable format. SpliceMiner maps probes to splice variants, effectively delineating the variants identified by a probe.EVDB can be queried by gene symbol, genomic coordinates, or probe sequence via a user-friendly web-based tool we call SpliceMiner (http://discover.nci.nih.gov/spliceminer webcite). The EVDB/SpliceMiner combination provides an interface with human splice variant information and, going beyond the very valuable NCBI Evidence Viewer, supports fluent, high-throughput analysis. Integration of EVDB information into microarray analysis and design pipelines has the potential to improve the analysis and bioinformatic interpretation of gene expression data, for both batch and interactive processing. For example, whenever a gene expression value is recognized as important or appears anomalous in a microarray experiment, the interactive mode of SpliceMiner can be used quickly and easily to check for possible splice variant issues.There is a substantial difference between the number of genes in the human genome and the number of expressed transcripts and proteins. Alternative splicing largely accounts for that discrepancy. Based on experimental evidence and computational approaches (e.g. realignments of transcripts or hidden Markov models), the percentage of genes that exhibit alternative splicing has been estimated as anywhere from 30% to 99% [1,2]
Levels of estrogen receptor B splice variant (ERBΔ5) mRNA correlates with progesterone receptor in breast carcinomas
Mandu?i? Vesna,Popov-?eleketi? Du?an,Ne?kovi?-Konstantinovi? Zora,Kanjer Ksenija
Archives of Biological Sciences , 2010, DOI: 10.2298/abs1002257m
Abstract: It is well known that breast tumors which are estrogen positive ER(+) are more likely to respond to hormone therapy. However, a certain percentage of ER(+)/PR(+) tumors do not respond to this therapy. Identification of the second estrogen receptor, named estrogen receptor beta (ERβ), as well as the existence of numerous isoforms/splice variants of both ERα and ERβ, suggests that a complex regulation of estrogen action exists. In this study, we analyzed the expression ratio of ERβ1 isoform and ERβΔ5 splice variant mRNAs, and its correlation with ER/PR status by quantitative RT-PCR and clinical and histopathological parameters. We found that the relative proportion of ERβΔ5 in the total ERβ1 transcript 'pool' inversely correlates with the PR level (p = -0,359, p< 0,003, Spearman). It may be that the ERβΔ5 variant modulates the ERα activity of downstream targets. In addition, we suggest that the determination of the expression profiles of ERα and ERβ isoforms and splice variants in the defined groups of patients are necessary for elucidating their involvement in endocrine resistance.
Elevated Oestrogen Receptor Splice Variant ERαΔ5 Expression in Tumour-adjacent Hormone-responsive Tissue  [PDF]
Sian E. Taylor,Imran I. Patel,Paras B. Singh,Caroline M. Nicholson,Helen F. Stringfellow,R. K. Gopala Krishna,Shyam S. Matanhelia,Pierre L. Martin-Hirsch,Francis L. Martin
International Journal of Environmental Research and Public Health , 2010, DOI: 10.3390/ijerph7113871
Abstract: Susceptibility to prostate or endometrial cancer is linked with obesity, a state of oestrogen excess. Oestrogen receptor (ER) splice variants may be responsible for the tissue-level of ER activity. Such micro-environmental regulation may modulate cancer initiation and/or progression mechanisms. Real-time reverse transcriptase (RT) polymerase chain reaction (PCR) was used to quantitatively assess the levels of four ER splice variants ( ER α Δ 3, ER α Δ 5, ER β2 and ER β 5), plus the full-length parent isoforms ER α and ER β 1, in high-risk [tumour-adjacent prostate ( n = 10) or endometrial cancer ( n = 9)] vs. low-risk [benign prostate ( n = 12) or endometrium ( n = 9)], as well as a comparison of UK ( n = 12) vs. Indian ( n = 15) benign prostate. All three tissue groups expressed the ER splice variants at similar levels, apart from ER α Δ 5. This splice variant was markedly raised in all of the tumour-adjacent prostate samples compared to benign tissues. Immunofluorescence analysis for ER β2 in prostate tissue demonstrated that such splice variants are present in comparable, if not greater, amounts as the parent full-length isoform. This small pilot study demonstrates the ubiquitous nature of ER splice variants in these tissue sites and suggests that ER α Δ5 may be involved in progression of prostate adenocarcinoma.
Expression of an IKKγ Splice Variant Determines IRF3 and Canonical NF-κB Pathway Utilization in ssRNA Virus Infection  [PDF]
Ping Liu,Muping Lu,Bing Tian,Kui Li,Roberto P. Garofalo,Deborah Prusak,Thomas G. Wood,Allan R. Brasier
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008079
Abstract: Single stranded RNA (ssRNA) virus infection activates the retinoic acid inducible gene I (RIG-I)- mitochondrial antiviral signaling (MAVS) complex, a complex that coordinates the host innate immune response via the NF-κB and IRF3 pathways. Recent work has shown that the IκB kinase (IKK)γ scaffolding protein is the final common adapter protein required by RIG-I·MAVS to activate divergent rate-limiting kinases downstream controlling the NF-κB and IRF3 pathways. Previously we discovered a ubiquitous IKKγ splice-variant, IKKγΔ, that exhibits distinct signaling properties.
Identification of a New Splice Variant of the Human ABCC6 Transporter
Maria Francesca Armentano,Angela Ostuni,Vittoria Infantino,Vito Iacobazzi,Maria Antonietta Castiglione Morelli,Faustino Bisaccia
Biochemistry Research International , 2008, DOI: 10.1155/2008/912478
Abstract: ABCC6 is a member of the adenosine triphosphate-binding cassette (ABC) gene subfamily C that encodes a protein (MRP6) involved in active transport of intracellular compounds to the extracellular environment. Mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), an autosomal recessive disorder of the connective tissue characterized by progressive calcification of elastic structures in the skin, the eyes, and the cardiovascular system. MRP6 is codified by 31 exons and contains 1503 amino acids. In addition to a full-length transcript of ABCC6, we have identified an alternatively spliced variant of ABCC6 from a cDNA of human liver that lacks exons 19 and 24. The novel isoform was named ABCC6 Δ19Δ24. PCR analysis from cDNA of cell cultures of primary human hepatocites and embryonic kidney confirms the presence of the ABCC6Δ19Δ24 isoform. Western blot analysis of the embryonic kidney cells shows a band corresponding to the molecular weight of the truncated protein.
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