| 1. |
- Petersson, Jessica, et al.
(författare)
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The human IFN-inducible p53 target gene TRIM22 colocalizes with the centrosome independently of cell cycle phase.
- 2010
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 316, s. 568-579
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Tidskriftsartikel (refereegranskat)abstract
- TRIM22 (Staf50), a member of the TRIM protein family, is an interferon (IFN)-inducible protein as well as a p53 target gene. The function of TRIM22 is largely unknown, but TRIM22 is suggested to play a role in viral defense by restriction of viral replication. In addition, TRIM22 may function as a ubiquitin E3 ligase. In contrast to previous reports showing solely cytoplasmic localization of exogenous TRIM22, we report here that endogenous TRIM22 is localized to both nucleus and cytosol in primary human mononuclear cells, as well as in the human osteosarcoma cell line U2OS. Moreover, we demonstrate a colocalization of TRIM22 with the centrosomes in primary cells as well as in U2OS cells, and show that this colocalization is independent of cell cycle phase. Additionally, our data suggest the colocalization with centrosomes to be independent on the microtubule network. Given that some viral protein assembly takes place in the close vicinity of the centrosome, our data suggest that important functions of TRIM22 such as regulation of viral replication and protein degradation may take place in the centrosome. However, further studies are warranted to certify this notion.
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| 2. |
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| 3. |
- Chylicki, Kristina, et al.
(författare)
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Characterization of the molecular mechanisms for p53-mediated differentiation
- 2000
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Ingår i: Cell Growth and Differentiation. - 1044-9523. ; 11:11, s. 561-571
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Tidskriftsartikel (refereegranskat)abstract
- The p53 tumor suppressor protein can induce both apoptosis and cell cycle arrest. Moreover, we and others have shown previously that p53 is a potent mediator of differentiation. For example, expression of ptsp53, a temperature-inducible form of p53, induces differentiation of leukemic monoblastic U-937 cells. The functions of p53 have for long been believed to be dependent on the transactivating capacity of p53. However, recent data show that both p53-induced cell cycle arrest and apoptosis can be induced independently of p53-mediated transcriptional activation, indicating alternative pathways for p53-induced apoptosis and cell cycle arrest. The bcl-2 proto-oncogene contributes to the development of certain malignancies, probably by inhibition of apoptosis. Interestingly, Bcl-2 has been shown to inhibit p53-mediated apoptosis as well as p53-mediated transcriptional activation. Asking whether Bcl-2 would interfere with the p53-mediated differentiation of U-937 cells, we stably transfected bcl-2 to U-937 cells inducibly expressing p53. Although the established Bcl-2-expressing clones were resistant to p53-mediated apoptosis, we did not observe any interference of Bcl-2 with the p53-mediated differentiation, suggesting separable pathways for p53 in mediating apoptosis and differentiation of U-937 cells. Neither did expression of Bcl-2 interfere with p53-induced expression of endogenous p21, suggesting that p53-induced differentiation might be dependent on the transcriptional activity of p53. To further investigate whether the p53-mediated differentiation of U-937 cells depends on the transcriptional activity of p53, we overexpressed transactivation-deficient p53, a transcriptionally inactive p53 mutant in these cells. However, in contrast to the effects of wild-type p53, expression of trans-activation-deficient p53 did neither induce signs of apoptosis nor of differentiation in U-937 cells. Our results indicate that the transcriptional activity of p53 is essential both for p53-mediated apoptosis and differentiation of U-937 cells.
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| 4. |
- Ehinger, Mats, et al.
(författare)
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Involvement of the tumor suppressor gene p53 in tumor necrosis factor-induced differentiation of the leukemic cell line K562
- 1995
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Ingår i: Cell Growth and Differentiation. - 1044-9523. ; 6:1, s. 9-17
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Tidskriftsartikel (refereegranskat)abstract
- The cDNA of the human wild-type p53 tumor suppressor gene was constitutively overexpressed in the leukemic cell line K562 (which lacks detectable amounts of p53 protein) in order to investigate the consequences for growth and differentiation. Several stable clones were established by transfection of the expression vector pc53SN3. Expression of p53 protein was characterized by biosynthetic labeling and immunoprecipitation with the monoclonal antibodies pAb 1801 (reacting with wild-type and mutant human p53), pAb 240 (reacting with mutant human p53) and pAb 1620 (reacting with wild-type human p53). All clones which were 1801+, 240-, 1620- or 1801+, 240-, 1620+ were defined as "wild-type-like p53-expressing" clones. Our results show that expression of p53 protein is compatible with continuous proliferation of K562 cells. The growth characteristics of wild-type-like p53-expressing clones did not differ from that of control clones. However, the former were more sensitive than p53-negative control clones to growth inhibition by tumor necrosis factor (TNF), a cytokine with a potential role in growth and differentiation of myeloid leukemic cells. In addition, a 2- to 4-fold increase of the amount of hemoglobin, a marker of erythroid differentiation, was observed when wild-type-like p53 protein-expressing clones were incubated with TNF. This suggests that differentiation is the mechanism responsible for the increased TNF sensitivity of these clones. Our results support a role for p53 in mediating growth inhibitory and differentiation inducing signals by TNF.
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| 5. |
- Kalliara, Eirini, et al.
(författare)
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Spatially Guided and Single Cell Tools to Map the Microenvironment in Cutaneous T-Cell Lymphoma
- 2023
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Ingår i: Cancers. - 2072-6694. ; 15:8, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Mycosis fungoides (MF) and Sézary syndrome (SS) are two closely related clinical variants of cutaneous T-cell lymphomas (CTCL). Previously demonstrated large patient-to-patient and intra-patient disease heterogeneity underpins the importance of personalized medicine in CTCL. Advanced stages of CTCL are characterized by dismal prognosis, and the early identification of patients who will progress remains a clinical unmet need. While the exact molecular events underlying disease progression are poorly resolved, the tumor microenvironment (TME) has emerged as an important driver. In particular, the Th1-to-Th2 shift in the immune response is now commonly identified across advanced-stage CTCL patients. Herein, we summarize the role of the TME in CTCL evolution and the latest studies in deciphering inter- and intra-patient heterogeneity. We introduce spatially resolved omics as a promising technology to advance immune-oncology efforts in CTCL. We propose the combined implementation of spatially guided and single-cell omics technologies in paired skin and blood samples. Such an approach will mediate in-depth profiling of phenotypic and molecular changes in reactive immune subpopulations and malignant T cells preceding the Th1-to-Th2 shift and reveal mechanisms underlying disease progression from skin-limited to systemic disease that collectively will lead to the discovery of novel biomarkers to improve patient prognostication and the design of personalized treatment strategies.
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| 6. |
- Kofoed Damm, Jesper, et al.
(författare)
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Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo.
- 2015
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Ingår i: Experimental hematology & oncology. - : Springer Science and Business Media LLC. - 2162-3619. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma.
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| 7. |
- Kumar, Parveen, et al.
(författare)
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The transcriptional co-repressor myeloid translocation gene 16 inhibits glycolysis and stimulates mitochondrial respiration.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- The myeloid translocation gene 16 product MTG16 is found in multiple transcription factor-containing complexes as a regulator of gene expression implicated in development and tumorigenesis. A stable Tet-On system for doxycycline-dependent expression of MTG16 was established in B-lymphoblastoid Raji cells to unravel its molecular functions in transformed cells. A noticeable finding was that expression of certain genes involved in tumor cell metabolism including 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4 (PFKFB3 and PFKFB4), and pyruvate dehydrogenase kinase isoenzyme 1 (PDK1) was rapidly diminished when MTG16 was expressed. Furthermore, hypoxia-stimulated production of PFKFB3, PFKFB4 and PDK1 was inhibited by MTG16 expression. The genes in question encode key regulators of glycolysis and its coupling to mitochondrial metabolism and are commonly found to be overexpressed in transformed cells. The MTG16 Nervy Homology Region 2 (NHR2) oligomerization domain and the NHR3 protein-protein interaction domain were required intact for inhibition of PFKFB3, PFKFB4 and PDK1 expression to occur. Expression of MTG16 reduced glycolytic metabolism while mitochondrial respiration and formation of reactive oxygen species increased. The metabolic changes were paralleled by increased phosphorylation of mitogen-activated protein kinases, reduced levels of amino acids and inhibition of proliferation with a decreased fraction of cells in S-phase. Overall, our findings show that MTG16 can serve as a brake on glycolysis, a stimulator of mitochondrial respiration and an inhibitor of cell proliferation. Hence, elevation of MTG16 might have anti-tumor effect.
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| 8. |
- Svensson, Emelie, et al.
(författare)
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The Wilms' tumor gene 1 (WT1) induces expression of the N-myc downstream regulated gene 2 (NDRG2)
- 2007
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Ingår i: DNA and Cell Biology. - : Mary Ann Liebert Inc. - 1044-5498 .- 1557-7430. ; 26:8, s. 589-597
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Tidskriftsartikel (refereegranskat)abstract
- The Wilms' tumor gene 1 (WT1) protein is a transcriptional regulator that is highly expressed in immature hematopoietic progenitor cells and in the majority of patients with acute and chronic myeloid leukemia. However, it is still unclear how WT1 exerts its function(s) in hematopoietic cells. The aim of this work was to investigate the function of WT1 as a transcription factor in human hematopoietic progenitor cells. To this end, an oligonucleotide array approach was used to study the gene expression in CD34(+) cells from human cord blood retrovirally transduced with WT1 or a control vector. We found that the expression of the putative tumor suppressor gene N-myc downstream regulated gene 2 (NDRG2) mRNA was induced by WT1 in CD34(+) cells and also in leukemic U937 cells. Furthermore, a novel transcription start site in the NDRG2 gene was identified in WT1-transduced cells, in addition to two previously reported transcription start sites. These results show that the expression of the NDRG2 gene is directly or indirectly induced by WT1, and provide the first insights into transcriptional regulation of the NDRG2 gene, including demonstration of a novel splice variant.
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| 9. |
- 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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| 10. |
- Ageberg, Malin, et al.
(författare)
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Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis.
- 2008
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 47, s. 276-287
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Tidskriftsartikel (refereegranskat)abstract
- The t(6;9)(p22;q34) chromosomal translocation is found in a subset of patients with acute myeloid leukemia (AML). The translocation results in a fusion between the nuclear phosphoprotein DEK and the nucleoporin NUP214 (previously CAN). The mechanism by which the fusion protein DEK-NUP214 contributes to leukemia development has not been identified, and disruptions of normal cellular functions by DEK-NUP214 have previously not been described. In the present study, a novel effect of the DEK-NUP214 fusion protein is demonstrated. Our findings reveal a substantial increase in global protein synthesis in DEK-NUP214 expressing cells. Furthermore, we conclude that this effect is not the result of dysregulated transcription but merely due to increased translation. Consistent with the association with AML, the increased protein synthesis mediated by DEK-NUP214 is restricted to cells of the myeloid lineage. Analysis of potential mechanisms for regulating protein synthesis shows that expression of DEK-NUP214 correlates to the phosphorylation of the translation initiation protein, EIF4E. The present data provide evidence that increase of translational activity constitutes a mechanism by which the leukemogenic effect of DEK-NUP124 may be mediated. (c) 2008 Wiley-Liss, Inc.
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