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At least 19 recordsLinked to original sources
PubMed2001

The splice of life: alternative splicing and neurological disease.

Splicing of pre-messenger RNA is regulated differently in the brain compared with other tissues. Recognition of aberrations in splicing events that are associated with neurological disease has contributed to our understanding of disease pathogenesis in some cases. Neuron-specific proteins involved in RNA splicing and metabolism are also affected in several neurological disorders. These findings have begun to bridge what we know about the mechanisms regulating neuron-specific splicing and our understanding of neural function and disease.

Alternative Splicing↗
PubMed1999

SR protein kinases: the splice of life.

The eukaryotic genome codes for most of its proteins though discontinuous coding sequences called exons, which are separated by noncoding sequences known as introns. Following transcription of a gene, these exons must be spliced precisely, removing the intervening introns, to form meaningful mature messenger RNAs (mRNA) that are transported to the cytoplasm and translated by the ribosomal machinery. To add yet another level of complexity, a process known as alternative splicing exists, whereby a single pre-mRNA can give rise to two or more mature mRNAs depending on the combination of exons spliced together. Alternative splicing of pre-mRNAs is emerging as an important mechanism for gene regulation in many organisms. The classic example of splicing as a regulator of genetic information during a developmental process is sex determination in Drosophila. The now well-characterized cascade of sex-specific alternative splicing events demonstrates nicely how the control of splice site selection during pre-mRNA processing can have a profound effect on the development of an organism. The factors involved in pre-mRNA splicing and alternative splice site selection have been the subject of active study in recent years. Emerging from these studies is a picture of regulation based on protein-protein, protein-RNA, and RNA-RNA interactions. How the interaction of the various splicing constituents is controlled, however, is still poorly understood. One of the mechanisms of regulation that has received attention recently is that of posttranslational phosphorylation. In the following article, we cite the evidence for a role of phosphorylation in constitutive and alternative splicing and discuss some of the recent information on the biochemistry and biology of the enzymes involved.

Alternative Splicing↗
PubMed1989

Sex in flies: the splice of life.

The discovery that the primary transcripts of many genes are processed to produce more than one kind of messenger RNA focuses attention on the control of RNA processing as a developmental regulatory mechanism. In the fruit-fly Drosophila melanogaster, differential splicing of a hierarchy of regulatory genes determines sex, and thus the molecular biology of sex determination in the fruit-fly may lead to insights into the mechanisms by which alternative splicing is regulated.

Animals↗
PubMed1989

Splice of life: toward understanding genetic determinants of oral diseases.

The introduction of recombinant DNA technology has led to a rapid advancement of our knowledge of genes and genomic structure. Such technology, applied to the human genome, has provided valuable information concerning the nature and possible treatment of inherited disorders throughout the human life span. A number of oral diseases can be attacked by use of molecular biological techniques in conjunction with genetic linkage analysis. It will be possible to identify carriers of inherited diseases, to utilize prenatal and antenatal diagnosis when appropriate, and to pursue studies on the mode of inheritance of specific oral diseases. Present and projected advances in this dimension of dental research provide the knowledge and strategies for approaching and solving a number of major problems as we continue to pave the way for improvements in the diagnosis, treatment, and prevention of many oral and craniofacial diseases. This position paper examines a few of the promising areas and suggests future goals toward establishing a knowledge of the genetic determinants for oral diseases.

Humans↗
PubMed1990

Human gene therapy and congress.

Congress was the scene of conspicuous debate about human gene therapy during the 1980s. Congressional interest was sparked primarily by concerns about germ-line gene therapy expressed by clerics and public interest groups. The initial debate was provoked by Martin Cline's misadventures in 1980 and rekindled in 1983 by congressional resolution against germ-line intervention sponsored by Senator Mark Hatfield. The first hearing on gene therapy was held upon the release of the President's Commission report Splicing Life, in November, 1982, before a House subcommittee chaired by Congressman Albert Gore, Jr. Representative Gore later requested a report on gene therapy, which was released by the Office of Technology Assessment in December, 1984. He also sponsored the legislation that established the Biomedical Ethics Board and Biomedical Ethics Advisory Committee, Congress's abortive attempt to reestablish a federal bioethics commission. Implications of advances in human genetics, including gene therapy, were to be among the first topics addressed. Congress passed no substantive legislation affecting gene therapy research or clinical trials, but served principally as a national theater for debate. If and when germ-line gene therapy is contemplated, Congress will be faced with difficult choices, but will likely take no action to block trials that appear safe and are intended to produce clinical benefit for particular individuals.

Advisory Committees↗
PubMed1990

Human gene therapy, the public, and public policy.

The public's involvement in the debate over human gene therapy is used to illustrate two points. First, complex bioethical issues often come to the public's attention because of a scandal, in this case the Cline episode; enlightened discussion and public understanding are difficult to achieve under these conditions. Second, even with unfavorable circumstances at the outset, the debate can become channeled into politically responsible institutions which then can develop effective public policy. For gene therapy, four significant forums emerged: the President's Commission's Report Splicing Life, the 1982 Congressional Hearings, the OTA Report, and the RAC's Points to Consider document.

Advisory Committees↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2006

Spliced mRNAs detected during the life cycle of Chicken anemia virus.

The existence of spliced mRNA in Chicken anemia virus (CAV) was investigated, as three proteins appeared to be derived from a single 2.0 kb mRNA species. Human Torque teno virus (TTV), which displays a number of genomic similarities to CAV, is known to transcribe three mRNA species, suggesting that CAV may also have multiple mRNAs. Northern analysis of infected chicken MDCC-MSB1 cells revealed a 2.0 kb mRNA 3 h post-infection (p.i.) and additional 1.6, 1.3 and 1.2 kb bands visible at 48 and 72 h p.i. MDCC-MSB1 or COS1 cells transfected with a CAV clone showed similar results. The poly(A)+ RNA of infected cells was subjected to RT-PCR using a suite of CAV-specific primers. The major 2.0 kb RNA reacted with every primer, but the 1.3 and 1.2 kb RNAs only annealed to certain primers. The 2.0 kb mRNA had no deletions or mutations and was capable of encoding all three known CAV proteins. The 1.3 kb RNA had a splice site joining nt 1222 to nt 1814 and encoded head/tail viral protein 1 (VP1) without a frameshift. In addition, the 1.2 kb RNA possessed a splice site joining nt 994 to nt 1095 and encoded several putative, novel proteins with frameshift mutations. These splice sites conformed to the previously described GT-AG splicing rule. One further 0.8 kb RNA species appeared to be derived from a homologous recombination event. Discovery of the presence of spliced mRNA in CAV strengthens the similarity between CAV and TTV.

Animals↗
PubMed1999

A short region in the genome of hepatitis B virus is critical for maintenance of high transcript levels.

The majority of hepatitis B virus (HBV) transcripts are not normally spliced during the viral life cycle, but several splice donor and acceptor sites are conserved on HBV transcripts. In particular, the genome region between nt 450 and 500 of the HBV genome appears to be rich in such sequences. In this study we deleted a short 30-nt sequence between a conserved splice donor site at HBV genome position 462 and a splice acceptor site at position 491, thus deleting the surface/polymerase open reading frames by 10 amino acid residues. At the transcriptional level, this deletion led to >99% reduction of the 2.1-kb class of subgenomic transcripts in transfected cells. Nuclear run-on experiments revealed that the transcription rate of the deleted 2.1-kb transcript is unchanged when compared with the wildtype, suggesting a posttranscriptional mechanism for the downregulation of the deleted transcript. In addition, experiments with a replication-competent HBV mutant containing the 30-nt deletion showed that the corresponding 10-amino-acid sequence within the reverse transcriptase domain of the polymerase protein appeared to be nonessential.

Amino Acid Sequence↗
PubMed2005

Autoantibodies to heterogeneous nuclear ribonucleoproteins.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are among the most abundant proteins in the eukaryotic cell nucleus and play a direct role in several aspects of the RNA life including splicing, export of the mature RNAs and translation. To date, approximately 30 proteins have been identified. A growing body of evidence points to hnRNPs as an important target of the autoimmune response in rheumatic diseases. Autoantibodies to A and B proteins of the hnRNP complex have been detected in late 1980s in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Beyond their role as diagnostic test in clinical practice, these autoantibodies are starting to be regarded as important tools to obtain deeper insight into the pathogenesis of autoimmune rheumatic diseases. Furthermore, new anti-hnRNP antibodies have been recognized in the last ten years extending the spectrum of anti-hnRNP reactivity in different autoimmune disorders.

Animals↗
PubMed1997

Characterization of an internal ribosomal entry segment within the 5' leader of avian reticuloendotheliosis virus type A RNA and development of novel MLV-REV-based retroviral vectors.

The murine leukemia virus (MLV)-related type C viruses constitute a major class of retroviruses that includes numerous endogenous and exogenous mammalian viruses and the related avian spleen necrosis virus (SNV). The MLV-related viruses possess a long and multifunctional 5' untranslated leader involved in key steps of the viral life cycle--splicing, translation, RNA dimerization, encapsidation, and reverse transcription. Recent studies have shown that the 5' leader of Friend murine leukemia virus and Moloney murine leukemia virus can direct cap independent translation of gag precursor proteins (Berlioz et al., 1995; Vagner et al., 1995b). These data, together with structural homology studies (Koning et al., 1992), prompted us to undertake a search for new internal ribosome entry segment (IRES) of retroviral origin. Here we describe an IRES element within the 5' leader of avian reticuloendotheliosis virus type A (REV-A) genomic RNA. Data show that the REV-A 5' IRES element maps downstream of the packaging/dimerization (E/DLS) sequence (Watanabe and Temin, 1982; Darlix et al., 1992) and the minimal IRES sequence appears to be within a 129 nt fragment (nucleotides 452-580) of the 5' leader, immediately upstream of the gag AUG codon. The REV-A IRES has been successfully utilized in the construction of novel high titer MLV-based retroviral vectors, containing one or more IRES elements of retroviral origin. These retroviral constructs, which represent a starting point for the design of novel vectors suitable for gene therapy, are also of interest as a model system of internal translation initiation and its possible regulation during development, cancer, or virus infection.

3T3 Cells↗