| 1. |
- Nilsson, Helena Jernmark, et al.
(författare)
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The transcriptional coregulator NAB2 is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:50, s. 87136-87150
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Tidskriftsartikel (refereegranskat)abstract
- The Wilms' tumor gene 1 (WT1) is recurrently mutated in acute myeloid leukemia. Mutations and high expression of WT1 associate with a poor prognosis. In mice, WT1 cooperates with the RUNX1/RUNX1T1 (AML1/ETO) fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development. Molecular mechanisms for WT1 are, however, incompletely understood. Here, we identify the transcriptional coregulator NAB2 as a target gene of WT1. Analysis of gene expression profiles of leukemic samples revealed a positive correlation between the expression of WT1 and NAB2, as well as a non-zero partial correlation. Overexpression of WT1 in hematopoietic cells resulted in increased NAB2 levels, while suppression of WT1 decreased NAB2 expression. WT1 bound and transactivated the proximal NAB2 promoter, as shown by ChIP and reporter experiments, respectively. ChIP experiments also revealed that WT1 can recruit NAB2 to the IRF8 promoter, thus modulating the transcriptional activity of WT1, as shown by reporter experiments. Our results implicate NAB2 as a previously unreported target gene of WT1 and that NAB2 acts as a transcriptional cofactor of WT1.
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| 2. |
- Ullmark, Tove, et al.
(författare)
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Anti-apoptotic quinolinate phosphoribosyltransferase (QPRT) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells
- 2017
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 482:4, s. 802-807
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Tidskriftsartikel (refereegranskat)abstract
- Wilms' tumor gene 1 (WT1) is a zinc finger transcription factor that has been implicated as an oncogene in leukemia and several other malignancies. When investigating possible gene expression network partners of . WT1 in a large acute myeloid leukemia (AML) patient cohort, one of the genes with the highest correlation to . WT1 was quinolinate phosphoribosyltransferase (QPRT), a key enzyme in the . de novo nicotinamide adenine dinucleotide (NAD+) synthesis pathway. To investigate the possible relationship between . WT1 and . QPRT, we overexpressed . WT1 in hematopoietic progenitor cells and cell lines, resulting in an increase of . QPRT expression. WT1 knock-down gave a corresponding decrease in . QPRT gene and protein expression. Chromatin-immunoprecipitation revealed WT1 binding to a conserved site in the first intron of the . QPRT gene. Upon overexpression in leukemic K562 cells, QPRT conferred partial resistance to the anti-leukemic drug imatinib, indicating possible anti-apoptotic functions, consistent with previous reports on glioma cells. Interestingly, the rescue effect of QPRT overexpression was not correlated to increased NAD + levels, suggesting NAD + independent mechanisms. We conclude that . QPRT, encoding a protein with anti-apoptotic properties, is a novel and direct target gene of WT1 in leukemic cells.
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| 3. |
- Ullmark, Tove, et al.
(författare)
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Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells
- 2017
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 102:2, s. 336-345
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Tidskriftsartikel (refereegranskat)abstract
- The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is rather enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with involvement of WT1 in acute myeloid leukemia.
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| 4. |
- Abrahamsson, S., et al.
(författare)
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Multifocus structured illumination microscopy for fast volumetric super-resolution imaging
- 2017
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Ingår i: Biomedical Optics Express. - : OSA - The Optical Society. - 2156-7085. ; 8:9, s. 4135-4140
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Tidskriftsartikel (refereegranskat)abstract
- We here report for the first time the synergistic implementation of structured illumination microscopy (SIM) and multifocus microscopy (MFM). This imaging modality is designed to alleviate the problem of insufficient volumetric acquisition speed in superresolution biological imaging. SIM is a wide-field super-resolution technique that allows imaging with visible light beyond the classical diffraction limit. Employing multifocus diffractive optics we obtain simultaneous wide-field 3D imaging capability in the SIM acquisition sequence, improving volumetric acquisition speed by an order of magnitude. Imaging performance is demonstrated on biological specimens.
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| 5. |
- Adman, Per, et al.
(författare)
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171 forskare: ”Vi vuxna bör också klimatprotestera”
- 2019
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Ingår i: Dagens nyheter (DN debatt). - Stockholm. - 1101-2447.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- DN DEBATT 26/9. Vuxna bör följa uppmaningen från ungdomarna i Fridays for future-rörelsen och protestera eftersom det politiska ledarskapet är otillräckligt. Omfattande och långvariga påtryckningar från hela samhället behövs för att få de politiskt ansvariga att utöva det ledarskap som klimatkrisen kräver, skriver 171 forskare i samhällsvetenskap och humaniora.
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| 6. |
- Bendre, Megha, et al.
(författare)
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Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
- 2019
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Ingår i: Alcohol. - : Elsevier BV. - 0741-8329 .- 1873-6823. ; 79, s. 7-16
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Tidskriftsartikel (refereegranskat)abstract
- Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions.
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| 7. |
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| 8. |
- Bondesson, Tina, et al.
(författare)
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A study to examine the influence of health professionals' advice and support on work capacity and sick leave after breast cancer surgery
- 2016
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Ingår i: Supportive Care in Cancer. - : Springer Science and Business Media LLC. - 0941-4355 .- 1433-7339. ; 24:10, s. 4141-4148
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to investigate how women, shortly after breast cancer surgery, experienced encounters with, and information from, healthcare professionals regarding work and sick leave and if these experiences were associated with self-reported work capacity and sick leave.METHODS: This is a cross-sectional study based on questionnaire data from 605 women who had had breast cancer surgery, aged 20-63 years. Exclusion criteria were known distant metastases, pre surgical therapy, and/or previous breast cancer. Data on age, type of surgery, global health, and work environment were included as covariates in multivariable logistic regression analysis.RESULTS: Five percent of the women had not received any advice concerning work or sick leave. Women reporting receiving useful advice or support related to paid work had lower risk of reporting reduced physical or psychological/social work capacity due to the cancer or treatment (OR 0.46 (95 % CI 0.26-0.81) respective OR 0.45 (95 % CI 0.26-0.77)). There were no associations between having received useful advice or support concerning work and being on sick leave. Women encouraged to take sick leave had an OR of 2.17 (95 % CI 1.39-3.37) of being sickness absent. They also to a higher extent had reduced physical and psychological/social work capacity. Women who reported to have been encouraged to work were sickness absent to a lower extent (OR 0.64; 95 % CI 0.41-0.98) and reported higher physical work capacity.CONCLUSIONS: Work and sick leave is being discussed during consultations with women with breast cancer and the advice given seems to be in line with the women's subjective work capacity.
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| 9. |
- Bondesson, Tina, et al.
(författare)
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A study to examine the influence of health professionals' advice and support on work capacity and sick leave after breast cancer surgery
- 2016
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Ingår i: Supportive Care in Cancer. - : Springer. - 0941-4355 .- 1433-7339. ; 24:10, s. 4141-4148
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to investigate how women, shortly after breast cancer surgery, experienced encounters with, and information from, healthcare professionals regarding work and sick leave and if these experiences were associated with self-reported work capacity and sick leave.METHODS: This is a cross-sectional study based on questionnaire data from 605 women who had had breast cancer surgery, aged 20-63 years. Exclusion criteria were known distant metastases, pre surgical therapy, and/or previous breast cancer. Data on age, type of surgery, global health, and work environment were included as covariates in multivariable logistic regression analysis.RESULTS: Five percent of the women had not received any advice concerning work or sick leave. Women reporting receiving useful advice or support related to paid work had lower risk of reporting reduced physical or psychological/social work capacity due to the cancer or treatment (OR 0.46 (95 % CI 0.26-0.81) respective OR 0.45 (95 % CI 0.26-0.77)). There were no associations between having received useful advice or support concerning work and being on sick leave. Women encouraged to take sick leave had an OR of 2.17 (95 % CI 1.39-3.37) of being sickness absent. They also to a higher extent had reduced physical and psychological/social work capacity. Women who reported to have been encouraged to work were sickness absent to a lower extent (OR 0.64; 95 % CI 0.41-0.98) and reported higher physical work capacity.CONCLUSIONS: Work and sick leave is being discussed during consultations with women with breast cancer and the advice given seems to be in line with the women's subjective work capacity.
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| 10. |
- Burlaka, Ievgeniia, et al.
(författare)
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Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease
- 2016
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Ingår i: Kidney International. - : Nature Publishing Group. - 0085-2538 .- 1523-1755. ; 90:1, s. 135-148
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Tidskriftsartikel (refereegranskat)abstract
- There is a great need for treatment that arrests progression of chronic kidney disease. Increased albumin in urine leads to apoptosis and fibrosis of podocytes and tubular cells and is a major cause of functional deterioration. There have been many attempts to target fibrosis, but because of the lack of appropriate agents, few have targeted apoptosis. Our group has described an ouabain-activated Na,K-ATPase/IP3R signalosome, which protects from apoptosis. Here we show that albumin uptake in primary rat renal epithelial cells is accompanied by a time-and dose-dependent mitochondrial accumulation of the apoptotic factor Bax, down-regulation of the antiapoptotic factor Bcl-xL and mitochondrial membrane depolarization. Ouabain opposes these effects and protects from apoptosis in albumin-exposed proximal tubule cells and podocytes. The efficacy of ouabain as an antiapoptotic and kidney-protective therapeutic tool was then tested in rats with passive Heymann nephritis, a model of proteinuric chronic kidney disease. Chronic ouabain treatment preserved renal function, protected from renal cortical apoptosis, up-regulated Bax, down-regulated Bcl-xL, and rescued from glomerular tubular disconnection and podocyte loss. Thus we have identified a novel clinically feasible therapeutic tool, which has the potential to protect from apoptosis and rescue from loss of functional tissue in chronic proteinuric kidney disease.
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