| 1. |
- Wu, Siqin, et al.
(författare)
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TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity
- 2009
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 315:18, s. 3099-3111
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta1 enforced G(1) cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but could not alone induce G(1) arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression.
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| 2. |
- Andersson, Leif
(författare)
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Genome-wide association analysis in domestic animals : a powerful approach for genetic dissection of trait loci
- 2009
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Ingår i: Genetica. - : Springer. - 0016-6707 .- 1573-6857. ; 136:2, s. 341-349
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Tidskriftsartikel (refereegranskat)abstract
- Domestic animals have a sufficiently old history (thousands of generations) to allow evolution of phenotypes, but also a sufficiently young history (approximately 10,000 years) to allow powerful genetic dissection of phenotypic diversity. Domestic animals are therefore a unique resource for exploring genotype-phenotype relationships. Quantitative Trait Locus (QTL) mapping has been very successful in domestic animals but the identification of Quantitative Trait Mutations (QTMs) has been hard although a few prominent success histories have been reported. Genome-wide association analysis is now emerging as a powerful method for high-resolution mapping of loci controlling phenotypic traits in domestic animals. In two recent proof-of-principle studies we have used this approach to identify the mutations underlying two monogenic trait loci in dogs, white spotting and the hair ridge in Ridgeback dogs. In each case, we used only about 10 cases and 10 controls and mapped the locus to a region of about one mega base pair. In both cases the underlying mutations were non-coding underscoring the significance of regulatory mutations as a source for phenotypic diversity. Furthermore, we were able to shed light on the evolution of the allelic series at the white spotting (S) locus in dogs which encodes the microphthalmia-associated transcription factor (MITF). Our data showed that the three variant alleles described at this locus (Irish spotting, piebald and extreme white) do not represent three independent mutations but rather different combinations of a set of regulatory mutations affecting MITF expression. This is an excellent illustration of how the characterization of alleles selected during animal domestication contributes to an improved understanding of genotype-phenotype relationships.
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| 3. |
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| 4. |
- Artois, M., et al.
(författare)
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Outbreaks of highly pathogenic avian influenza in Europe : the risks associated with wild birds
- 2009
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Ingår i: Revue scientifique et technique (International Office of Epizootics). - : O.I.E (World Organisation for Animal Health). - 0253-1933 .- 1608-0637. ; 28:1, s. 69-92
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Forskningsöversikt (refereegranskat)abstract
- The infection of wild birds by highly pathogenic strains of avian influenza (Al) virus was virtually unknown--apart from one instance of the disease appearing in common terns in South Africa in 1961--before the Asian strain of highly pathogenic AI virus (AIV), H5N1, began to expand across the world. Outbreaks of clinical disease in Eurasia have resulted in visible mortality among populations of free-ranging wild birds in a multitude of species. The circulation pattern of influenza viruses in natural ecosystems results from a selection pressure towards strains which are indirectly transmitted by droppings from water birds and contaminated fomites, and which exhibit low pathogenicity. Some of these viruses, of the subtypes H5 or H7, can mutate into highly pathogenic strains after being introduced into domestic poultry farms. The maintenance of highly pathogenic AIV (HPAIV) H5N1 in several parts of the world exposes wild birds to infected poultry, resulting in long-distance virus transmission. There is great concern that these wild birds may, in turn, propagate these HPAIV or introduce them into domestic birds. Rigorous disease control and biosecurity measures to protect poultry farms are the only solution presently available to mitigate such a risk.
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| 5. |
- Baranowska, Izabella, et al.
(författare)
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Sensory ataxic neuropathy in golden retriever dogs is caused by a deletion in the mitochondrial tRNATyr gene
- 2009
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 5:5, s. e1000499-
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Tidskriftsartikel (refereegranskat)abstract
- Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNA(Tyr) gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0-11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNA(Tyr) had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNA(Tyr) gene is the causative mutation for SAN.
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| 6. |
- Barrio, Alvaro Martínez, et al.
(författare)
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Annotation and visualization of endogenous retroviral sequences using the Distributed Annotation System (DAS) and eBioX
- 2009
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Ingår i: BMC Bioinformatics. - : BioMed Central. - 1471-2105. ; 10 Suppl. 6, s. S18-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Distributed Annotation System (DAS) is a widely used network protocol for sharing biological information. The distributed aspects of the protocol enable the use of various reference and annotation servers for connecting biological sequence data to pertinent annotations in order to depict an integrated view of the data for the final user. RESULTS: An annotation server has been devised to provide information about the endogenous retroviruses detected and annotated by a specialized in silico tool called RetroTector. We describe the procedure to implement the DAS 1.5 protocol commands necessary for constructing the DAS annotation server. We use our server to exemplify those steps. Data distribution is kept separated from visualization which is carried out by eBioX, an easy to use open source program incorporating multiple bioinformatics utilities. Some well characterized endogenous retroviruses are shown in two different DAS clients. A rapid analysis of areas free from retroviral insertions could be facilitated by our annotations. CONCLUSION: The DAS protocol has shown to be advantageous in the distribution of endogenous retrovirus data. The distributed nature of the protocol is also found to aid in combining annotation and visualization along a genome in order to enhance the understanding of ERV contribution to its evolution. Reference and annotation servers are conjointly used by eBioX to provide visualization of ERV annotations as well as other data sources. Our DAS data source can be found in the central public DAS service repository, http://www.dasregistry.org, or at http://loka.bmc.uu.se/das/sources.
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| 7. |
- Barrio, Alvaro Martinez, et al.
(författare)
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Targeted Resequencing and Analysis of the Diamond-Blackfan Anemia Disease Locus RPS19
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:7, s. e6172-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1). CONCLUSIONS: Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.
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| 8. |
- Besnier, Francois, et al.
(författare)
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A genetic algorithm based method for stringent haplotyping of family data
- 2009
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The linkage phase, or haplotype, is an extra level of information that in addition to genotype and pedigree can be useful for reconstructing the inheritance pattern of the alleles in a pedigree, and computing for example Identity By Descent probabilities. If a haplotype is provided, the precision of estimated IBD probabilities increases, as long as the haplotype is estimated without errors. It is therefore important to only use haplotypes that are strongly supported by the available data for IBD estimation, to avoid introducing new errors due to erroneous linkage phases.Results: We propose a genetic algorithm based method for haplotype estimation in family data that includes a stringency parameter. This allows the user to decide the error tolerance level when inferring parental origin of the alleles. This is a novel feature compared to existing methods for haplotype estimation. We show that using a high stringency produces haplotype data with few errors, whereas a low stringency provides haplotype estimates in most situations, but with an increased number of errors.Conclusion: By including a stringency criterion in our haplotyping method, the user is able to maintain the error rate at a suitable level for the particular study; one can select anything from haplotyped data with very small proportion of errors and a higher proportion of non-inferred haplotypes, to data with phase estimates for every marker, when haplotype errors are tolerable. Giving this choice makes the method more flexible and useful in a wide range of applications as it is able to fulfil different requirements regarding the tolerance for haplotype errors, or uncertain marker-phases.
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| 9. |
- Braga, Tiago, et al.
(författare)
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Reduction with dithiothreitol causes serglycin-specific defects in secretory granule integrity of bone marrow derived mast cells
- 2009
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 46:3, s. 422-428
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Tidskriftsartikel (refereegranskat)abstract
- Mast cell granule maturation and storage of granule components has previously been shown to be critically dependent on serglycin (SG), a proteoglycan abundantly stored in mast cell secretory granules. The N-terminal portion of serglycin contains a conserved disulfide motif that is similar to motifs found in secretory granule compounds of neuroendocrine cells. Interference with such motifs of neuroendocrine cells with dithiothreitol (DTT) has previously been shown to cause cellular missorting. To investigate the implication for serglycin, serglycin(+/+) and serglycin(-/-) bone marrow derived mast cells (BMMCs) were treated with DTT followed by assessment of proteoglycan synthesis and secretory granule integrity. Treatment of serglycin(+/+) BMMCs with DTT almost completely abolished biosynthetic incorporation of (35)S-sulfate into proteoglycans, caused a dramatic reduction of granular staining with May Grünwald/Giemsa as well as disruption of granule dense core formation as shown by transmission electron microscopy. In addition, the storage of carboxypeptidase A, a major secretory granule compound, was markedly reduced following DTT treatment. In contrast, none of these effects were seen after treatment of SG(-/-) BMMCs with DTT, indicating that they were serglycin-specific. Notably, DTT treated serglycin(+/+) BMMCs showed similar morphology as did the serglycin(-/-) BMMCs. DTT treatment affected neither the viability of the BMMCs nor the mRNA levels for serglycin or carboxypeptidase A. Together, these data indicate that DTT causes dramatic, serglycin-specific effects on mast cell granule. These findings are thus in accordance with a role for the N-terminal disulfide motif in serglycin for regulation of mast cell secretory granule integrity.
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| 10. |
- Branth, Stefan, et al.
(författare)
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Metabolic stress-like condition can be induced by prolonged strenuous exercise in athletes
- 2009
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Ingår i: Upsala Journal of Medical Sciences. - : Taylor & Francis. - 0300-9734 .- 2000-1967. ; 114:1, s. 12-25
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Tidskriftsartikel (refereegranskat)abstract
- Few studies have examined energy metabolism during prolonged, strenuous exercise. We wanted therefore to investigate energy metabolic consequences of a prolonged period of continuous strenuous work with very high energy expenditure. Twelve endurance-trained athletes (6 males and 6 females) were recruited. They performed a 7-h bike race on high work-load intensity. Physiological, biochemical, endocrinological, and anthropometric muscular compartment variables were monitored before, during, and after the race. The energy expenditure was high, being 5557 kcal. Work-load intensity (% of VO2 peak) was higher in females (77.7%) than in men (69.9%). Muscular glycogen utilization was pronounced, especially in type I fibres (>90%). Additionally, muscular triglyceride lipolysis was considerably accelerated. Plasma glucose levels were increased concomitantly with an unchanged serum insulin concentration which might reflect an insulin resistance state in addition to proteolytic glyconeogenesis. Increased reactive oxygen species (malondialdehyde (MDA)) were additional signs of metabolic stress. MDA levels correlated with glycogen utilization rate. A relative deficiency of energy substrate on a cellular level was indicated by increased intracellular water of the leg muscle concomitantly with increased extracellular levels of the osmoregulatory amino acid taurine. A kindred nature of a presumed insulin-resistant state with less intracellular availability of glucose for erythrocytes was also indicated by the findings of decreased MCV together with increased MCHC (haemoconcentration) after the race. This strenuous energy-demanding work created a metabolic stress-like condition including signs of insulin resistance and deteriorated intracellular glucose availability leading to compromised fuelling of ion pumps, culminating in a disturbed cellular osmoregulation indicated by taurine efflux and cellular swelling. © 2009 Informa UK Ltd All rights reserved.
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