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| 2. |
- Kuchenbauer, Florian, et al.
(författare)
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Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:12, s. 3350-8
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Tidskriftsartikel (refereegranskat)abstract
- Processing of pre-miRNA through Dicer1 generates an miRNA duplex that consists of an miRNA and miRNA* strand. Despite the general view that miRNA*s have no functional role, we further investigated miRNA* species in 10 deep-sequencing libraries from mouse and human tissue. Comparisons of miRNA/miRNA* ratios across the miRNA sequence libraries revealed that 50% of the investigated miRNA duplexes exhibited a highly dominant strand. Conversely, 10% of miRNA duplexes showed a comparable expression of both strands, whereas the remaining 40% exhibited variable ratios across the examined libraries, as exemplified by miR-223/miR-223* in murine and human cell lines. Functional analyses revealed a regulatory role for miR-223* in myeloid progenitor cells, which implies an active role for both arms of the miR-223 duplex. This was further underscored by the demonstration that miR-223 and miR-223* targeted the insulin-like growth factor 1 receptor/phosphatidylinositol 3-kinase axis and that high miR-223* levels were associated with increased overall survival in patients with acute myeloid leukemia. Thus, we found a supporting role for miR-223* in differentiating myeloid cells in normal and leukemic cell states. The fact that the miR-223 duplex acts through both arms extends the complexity of miRNA-directed gene regulation of this myeloid key miRNA.
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| 3. |
- Pudelko, L., et al.
(författare)
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Erratum : Glioblastoma and glioblastoma stem cells are dependent on functional MTH1 (Oncotarget (2017) 8 (84671-84684) DOI: 10.18632/oncotarget.19404)
- 2020
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Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- This article has been corrected: The Funding information has been updated. The complete Funding list is shown below: FUNDING This work was supported by the Karolinska Institutes KID funding (LP), the Seve Ballesteros Foundation to MS, the Marie Curie foundation (CIG-618751 MS), the Knut and Alice Wallenberg Foundation (KAW2014.273 TH), the Swedish Foundation for Strategic Research (RB13-0224 TH), the Swedish Cancer Society (TH), the Swedish Research Council (2015-00162 TH), the Göran Gustafsson Foundation (TH), the Swedish Children’s Cancer Foundation (to TH), the Swedish Pain Relief Foundation (PR20140048 TH), the Torsten and Ragnar Söderberg Foundation (TH), and the European Research Council (TAROX-695376).
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| 4. |
- Arabanian, Laleh S., et al.
(författare)
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The endothelin receptor type A is a downstream target of Hoxa9 and Meis1 in acute myeloid leukemia
- 2018
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126. ; 75, s. 61-68
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Tidskriftsartikel (refereegranskat)abstract
- Endothelin receptor type A (EDNRA) is known as a mediator of cell proliferation and survival. Aberrant regulation of EDNRA has been shown to play a role in tumor growth and metastasis. Using a global gene expression screen, we found that expression of Ednra was upregulated in murine leukemia inducing cells co-expressing Hoxa9 and Meis1 compared to cells only expressing Hoxa9. The aim of this study was to explore the role of Ednra in leukemogenesis further. In a murine bone marrow transplantation model, mice transplanted with cells overexpressing Ednra and Hoxa9 succumbed to leukemia significantly earlier than mice transplanted with cells overexpressing Hoxa9 only. Furthermore, overexpression of Ednra led to increased proliferation and resistance to apoptosis of bone marrow cells in vitro. We could also show that Meis1 binds to the Ednra promoter region, suggesting a regulatory role for Meis1 in Ednra expression. Taken together, our results suggest a role for Ednra in Hoxa9/Meis1-driven leukemogenesis.
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| 6. |
- Mahajan, Rashmi, et al.
(författare)
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Highly Efficient Synthesis and Assay of Protein-Imprinted Nanogels by Using Magnetic Templates
- 2019
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Ingår i: Angewandte Chemie International Edition. - : Wiley-VCH Verlagsgesellschaft. - 1433-7851 .- 1521-3773. ; 58:3, s. 727-730
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Tidskriftsartikel (refereegranskat)abstract
- We report an approach integrating the synthesis of protein-imprinted nanogels ("plastic antibodies") with a highly sensitive assay employing templates attached to magnetic carriers. The enzymes trypsin and pepsin were immobilized on amino-functionalized solgel-coated magnetic nanoparticles (magNPs). Lightly crosslinked fluorescently doped polyacrylamide nanogels were subsequently produced by high-dilution polymerization of monomers in the presence of the magNPs. The nanogels were characterised by a novel competitive fluorescence assay employing identical protein-conjugated nanoparticles as ligands to reversibly immobilize the corresponding nanogels. Both nanogels exhibited K-d<10 pM for their respective target protein and low cross-reactivity with five reference proteins. This agrees with affinities reported for solid-phase-synthesized nanogels prepared using low-surface-area glass-bead supports. This approach simplifies the development and production of plastic antibodies and offers direct access to a practical bioassay.
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| 7. |
- Mohr, Sebastian, et al.
(författare)
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Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia.
- 2017
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Ingår i: Cancer cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 31:4
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression butis currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
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| 8. |
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| 9. |
- Samie, M., et al.
(författare)
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Near wall coherence in wall-bounded flows and implications for flow control
- 2020
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Ingår i: International Journal of Heat and Fluid Flow. - : Elsevier B.V.. - 0142-727X .- 1879-2278. ; 86
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Tidskriftsartikel (refereegranskat)abstract
- Opposition-control of the energetic cycle of near wall streaks in wall-bounded turbulence, using numerical approaches, has shown promise for drag reduction. For practical implementation, real-time opposition control is only realizable if there is a degree of coherence between the turbulent velocities passing a sensor and the target point within the flow; for practicality, a sensor (and actuator) should be wall-based to avoid parasitic drag. As such, we here inspect the feasibility of real-time control of the near wall cycle, by considering the coherence between a measurable wall-quantity, being the wall-shear stress fluctuations, and the streamwise and wall-normal velocity fluctuations in a turbulent boundary layer. Synchronized spatial and temporal velocity data from two direct numerical simulations and a fine large eddy simulation at Reτ≈590 and 2000 are employed. This study shows that the spectral energy of the streamwise velocity fluctuations that is stochastically incoherent with wall signals is independent of Reynolds number in the near wall region (up to the viscous-scaled wall-normal height z+≈20). Consequently, the streamwise energy-fraction that is stochastically wall-coherent grows with Reynolds number due to the increasing range of energetic large scales. This thus implies that a wall-based control system has the ability to manipulate a larger portion of the total turbulence energy at off-wall locations, at higher Reynolds numbers, while the efficacy of predicting/targeting the small scales of the near wall cycle remains indifferent with varying Reynolds number. Coherence values of 0.55 and 0.4 were found between the streamwise and wall-normal velocity fluctuations at the near wall peak in the energy spectrogram, respectively, and the streamwise fluctuating friction velocity. These coherence values, which are considerably lower than 1 (maximum possible coherence) suggest that a closed-loop drag reduction scheme targeting near wall cycle streaks alone (based on sensed friction velocity fluctuations) will be of limited success in practice.
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| 10. |
- Singleton, D. C., et al.
(författare)
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Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis
- 2015
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Ingår i: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 34:36, s. 4713-4722
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1 alpha (HIF1 alpha) in tumours causes transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1 alpha-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis.
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